Prostate cancer has received a great deal of publicity from some very prominent public figures with the courage to talk to the public about their disease. It has become the most common form of cancer in men and is the second leading cause of death. About 200,000 new cases are diagnosed every year. In general, it is a disease of older men occurring in about 69 per 100,000 men in the United States. About 3% of American men will die from the disease or about 41,800 deaths. The incidence increases with age and surprisingly one important autopsy study from a medical examiners office found that there is a 34% incidence of clinically inapparent prostate cancer in men younger than 50 years old, who die of trauma (J Urol 1993;150:379-385).
The difference in incidence and races also suggests environmental factors. Androgens are clearly involved as they are in benign prostatic hyperplasia. The cancer cells possess androgen receptors as in normal prostate. In about 10% of cases, a linkage to prostate cancer susceptibility genes can be identified. One third of these cases have been mapped to chromosome 1q24-25. Other cancer-suppressor genes which may be lost in these cases may be found on chromosome 8p, 10q, 12p, and 16q.
The diagnosis usually begins with a digital rectal examination. This has been augmented by transrectal ultrasonography (TRUS) and serum PSA measurements. A biopsy is usually obtained through the transrectal approach. Unfortunately, some cases of prostate cancer are first diagnosed by a biopsy of a metastatic lesion. In these cases, immunohistochemical stains for PSA may be helpful in identifying the prostate as the source.
Pathologists have been instrumental in identifying precursor lesions. Prostatic intraepithelial neoplasia or PIN can be found in up to 70-80% of prostate glands which have been removed for carcinoma. These glands have enlarged and hyperchromatic nuclei sharing many cytologic characteristics of carcinoma but still confined to the gland by a well-defined basal epithelial layer and intact basement membrane. In addition, molecular changes present in carcinoma are also present in PIN. About 1/3 of cases will progress to invasive carcinoam within 10 years. Currently, pathologists divide PIN into low grade and high grade lesions. Most pathologists will only mention a high grade PIN in the final diagnosis. If a diagnosis of high grade PIN is made on a needle biopsy of the prostate, a repeat biopsy will reveal an infiltrating carcinoma in 50% of cases (Urology 1997;158:12-22).
The lymph nodes, bones, lung, and liver are the most common sites of metastasis. There are two well established routes of spread. The first occurs through the inferior vena cava with spread to the lungs. The second route occurs through a backward flow through the spinal veins to the vertebral column. Metastasis to the bone have a peculiar osteoblastic appearance on radiographs, implying new bone formation.
The pathologist's most important task is assigning a histologic grade to the tumor. Though several grading schemes have been proposed, the Gleason's grading system has stood the test of time and reproducibility. This system utilizes the architectural pattern of growth. A primary major pattern and a secondary minor pattern of growth are identified. Thus, a final score can be given as 3+4/10. A 10 is the highest score that can be given while a 2 is the lowest.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/Immunohistochemistry Differential Diagnosis Prognosis and Treatment
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EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION INCIDENCE Most common visceral malignancy in American men, with approximately 9.5% of the male population expected to receive a diagnosis of prostate cancer within their lifetime AGE Increasing age EJACULATION FREQUENCY
Ejaculation frequency and subsequent risk of prostate cancer.
Leitzmann MF, Platz EA, Stampfer MJ, Willett WC, Giovannucci E.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md 20892, USA.
JAMA. 2004 Apr 7;291(13):1578-86. Abstract quote
CONTEXT: Sexual activity has been hypothesized to play a role in the development of prostate cancer, but epidemiological data are virtually limited to case-control studies, which may be prone to bias because recall among individuals with prostate cancer could be distorted as a consequence of prostate malignancy or ongoing therapy.
OBJECTIVE: To examine the association between ejaculation frequency, which includes sexual intercourse, nocturnal emission, and masturbation and risk of prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: Prospective study using follow-up data from the Health Professionals Follow-up Study (February 1, 1992, through January 31, 2000) of 29 342 US men aged 46 to 81 years, who provided information on history of ejaculation frequency on a self-administered questionnaire in 1992 and responded to follow-up questionnaires every 2 years to 2000. Ejaculation frequency was assessed by asking participants to report the average number of ejaculations they had per month during the ages of 20 to 29 years, 40 to 49 years, and during the past year (1991).
MAIN OUTCOME MEASURE: Incidence of total prostate cancer.
- RESULTS: During 222 426 person-years of follow-up, there were 1449 new cases of total prostate cancer, 953 organ-confined cases, and 147 advanced cases of prostate cancer. Most categories of ejaculation frequency were unrelated to risk of prostate cancer. However, high ejaculation frequency was related to decreased risk of total prostate cancer. The multivariate relative risks for men reporting 21 or more ejaculations per month compared with men reporting 4 to 7 ejaculations per month at ages 20 to 29 years were 0.89 (95% confidence interval [CI], 0.73-1.10); ages 40 to 49 years, 0.68 (95% CI, 0.53-0.86); previous year, 0.49 (95% CI, 0.27-0.88); and averaged across a lifetime, 0.67 (95% CI, 0.51-0.89). Similar associations were observed for organ-confined prostate cancer. Ejaculation frequency was not statistically significantly associated with risk of advanced prostate cancer.
CONCLUSIONS: Our results suggest that ejaculation frequency is not related to increased risk of prostate cancer.
RACE Lower for Asians, higher among whites and blacks
Blacks present with higher stage but have equivalent survival figures
Migration from low to high incidence countries leads to an increase in clinical prostate cancer
- Prostate cancer in native Japanese and Japanese-American men: effects of dietary differences on prostatic tissue.
Marks LS, Kojima M, Demarzo A, Heber D, Bostwick DG, Qian J, Dorey FJ, Veltri RW, Mohler JL, Partin AW.
Department of Urology, University of California, Los Angeles, Geffen School of Medicine, Los Angeles, California, USA.
Urology. 2004 Oct;64(4):765-71 Abstract quote.
OBJECTIVES: To investigate the relationship between diet and prostate cancer (CaP) among native Japanese (NJ) and second-generation or third-generation Japanese-American (J-A) men--focusing on the effects of animal fat and soy on prostatic tissues.
METHODS: The subjects were 50 Japanese men undergoing radical prostatectomy, 25 NJ living in Nagoya, Japan and 25 U.S.-born J-A men, living in Los Angeles, California. A priori, the NJ men were believed to be a low-fat, high-soy group and the J-A men, a high-fat, low-soy group. The studies included postoperative measurements of diet (Block questionnaire), body fat (bioimpedance), blood, urine, and prostatic biomarkers in malignant and adjacent normal tissue, using a tissue microarray made from the original paraffin blocks.
RESULTS: The NJ and J-A men were similar in age (65 to 70 years old; P <0.05), prostate-specific antigen level (7.1 to 8.6 ng/mL), prostate volume (35 to 38 cm3), and Gleason score (5.6 to 6.6), but their body composition differed. J-A men had more body fat (24% versus 19%), higher serum triglyceride levels (245 versus 106 mg/dL), lower estradiol levels (27 versus 31 ng/mL), and much lower urinary soy-metabolite levels (1:3) than NJ men (P <0.02). In both NJ and J-A groups, expression of numerous tissue biomarkers separated normal from CaP tissue, including markers for apoptosis (Bcl-2, caspase-3), growth factor receptors (epidermal growth factor receptor), racemase, 5-lipoxygenase, kinase inhibition (p27), and cell proliferation (Ki-67; all P <0.02). Furthermore, within both normal and CaP tissues, caspase-3 and 5-lipoxygenase were expressed more in NJ than in J-A men (P <0.01). Nuclear morphometry showed that the chromatin in each of the four groups (normal versus CaP, NJ versus J-A) was different (area under the curve 85% to 94%, P <0.01), despite fundamental genetic homogeneity.
CONCLUSIONS: NJ and J-A men, products of similar genetics but differing environments, were shown to have differences in body composition that could influence CaP evolution. The CaP specimens from the NJ and J-A men were histologically similar, but tissue biomarker expression, especially of lipoxygenase and the caspase family, suggested differing mechanisms of carcinogenesis. Differences in nuclear morphometry suggested the additional possibility of gene-nutrient interactions.
Vasectomy and risk of prostate cancer.
Cox B, Sneyd MJ, Paul C, Delahunt B, Skegg DC.
Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, University of Otago Medical School, PO Box 913, Dunedin, New Zealand.
JAMA 2002 Jun 19;287(23):3110-5 Abstract quote
CONTEXT: Vasectomy is a common method of contraception, but concern exists about a reported association with risk of prostate cancer.
OBJECTIVE: To examine whether vasectomy increases risk of prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: National population-based case-control study of 923 new cases of prostate cancer among men aged 40 to 74 years from the New Zealand Cancer Registry who were on the general electoral roll. Controls (n = 1224) were randomly selected from the general electoral roll, with frequency matching to cases in 5-year age groups. Cases (3-15 months after diagnosis) and controls were interviewed by telephone between January 1997 and November 1999.
MAIN OUTCOME MEASURES: Relative risk (RR) of prostate cancer for men who had had a vasectomy vs those who had not.
RESULTS: There was no association between prostate cancer and vasectomy (RR, 0.92; 95% confidence interval [CI], 0.75-1.14) nor with time since vasectomy (RR, 0.92; 95% CI, 0.68-1.23 for > or = 25 years since vasectomy). Adjustment for social class, geographic region, religious affiliation, and a family history of prostate cancer did not affect these RRs.
CONCLUSIONS: Vasectomy does not increase the risk of prostate cancer, even after 25 years or more.
DISEASE ASSOCIATIONS CHARACTERIZATION LYMPHOMA
- Incidental and concurrent malignant lymphomas discovered at the time of prostatectomy and prostate biopsy: a study of 29 cases.
Chu PG, Huang Q, Weiss LM.
From the Department of Pathology, City of Hope National Medical Center, Duarte, CA.
Am J Surg Pathol. 2005 May;29(5):693-9. Abstract quote
The incidence and histologic features of malignant lymphomas discovered at the time of prostate biopsy, transurethral resection, and prostatectomy are not well documented.
We searched our surgical pathology files for malignant lymphomas identified from prostate surgical specimens from 1989 to 2004. Of 4,831 cases of prostate specimens (3,405 biopsies, 266 transurethral resections, 1,160 prostatectomies) examined at the City of Hope during this period, 29 cases of malignant lymphomas involving the prostate and pelvic lymph nodes were identified (0.6%).
These malignant lymphomas can be divided into two groups: 1) 18 incidental cases (0.37%) without prior history of malignant lymphoma; and 2) 11 cases (0.23%) with concurrent known malignant lymphoma. For the first group, the patients with pelvic node involvement ranged in age from 59 to 78 years (mean, 69.2 years; median, 70 years), and the patients with prostate involvement ranged in age from 45 to 78 years (mean, 64.6 years; median, 67.5 years). For the second group, the patients ranged in age from 53 to 80 years (mean, 66.8 years; median, 69 years).
Diagnoses of all cases were confirmed by immunohistochemistry or molecular analysis. Ten of 18 cases in the first group involved pelvic nodes only, and the other 8 cases were primary prostatic lymphoma. Of 18 cases in the first group, 13 were small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), 3 were marginal zone B-cell lymphoma, and 1 was mantle cell lymphoma. These lymphomas were not readily apparent in most cases by histologic examination, and may be confused with chronic prostatitis when the prostate was involved or with reactive lymphoid hyperplasia when pelvic nodes were involved.
Immunohistochemistry and molecular studies may be necessary to confirm the diagnosis. For the second group, prostate and pelvic lymph nodes were involved as part of systemic dissemination of concurrent malignant lymphoma. The diagnosis was usually easily established in these cases. Of 11 cases, 4 were SLL/CLL, 4 were follicular lymphoma, 2 were mantle cell lymphoma, and 1 was diffuse large B-cell lymphoma.
PATHOGENESIS CHARACTERIZATION APOPTOSIS
Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27, and Smad4 in benign, premalignant, and malignant human prostate.
Zeng L, Rowland RG, Lele SM, Kyprianou N.
Hum Pathol 2004;35:290-297 Abstract quote
Deregulation of apoptosis is involved in prostate cancer development and progression. This study involved an immunohistochemical "profiling" of prostate tissue specimens from patients who underwent prostatectomy for localized prostate cancer, to identify apoptosis-specific alterations associated with premalignant precursor lesions. Prostate tissue was pathologically evaluated, and areas of benign acini, high-grade prostate intraepithelial neoplasia (HGPIN), and prostate cancer were identified.
Immunohistochemical analysis was performed to determine the expression of p27(Kip1), a key cell cycle regulator, transforming growth factor (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta; Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key apoptosis regulator; and prostate-specific antigen (PSA), a clinical marker of prostate cancer. The apoptotic index of the same cell populations was determined using the transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end labeling assay. Our findings indicate a significant reduction in p27(Kip1) immunoreactivity in HGPIN (P <0.0001) and prostate cancer (P <0.0001) compared with the benign tissue. A significant down-regulation was detected in TbetaRII expression in HGPIN and prostate cancer compared with benign prostatic hyperplasia (BPH)(P <0.001). A significant decrease was also observed in Smad4 levels in HGPIN and prostate cancer compared with BPH (P <0.001). Evaluation of the incidence of apoptosis revealed a significant decrease in the apoptotic index among the epithelial cell populations in HGPIN and a further decrease in prostate carcinoma (P <0.01). This reduced apoptotic index correlated with a significant increase in p53 immunoreactivity in the prostatic carcinoma foci. Prostate cancer cells exhibited strong nuclear staining for p53 compared with adjacent HGPIN (P <0.05) and the benign lesions of the same prostate specimens (P <0.05). A significant reduction in PSA immunostaining was detected in HGPIN and prostate carcinoma foci compared with the benign glandular epithelia (P <0.001).
These results further define deregulation of TGF-beta signaling effectors as a molecular basis for loss of apoptotic control contributing to the development of prostate tumors. Identification of apoptotic regulators in precursor premalignant lesions may have prognostic significance in disease progression as well as therapeutic value for targeting prostate cancer.
- Erythropoietin and erythropoietin receptor expression in human prostate cancer.
Arcasoy MO, Amin K, Vollmer RT, Jiang X, Demark-Wahnefried W, Haroon ZA.
 1Department of Medicine, Duke University Medical Center, Durham, NC, USA  4Veterans Administration Medical Center, Durham, NC, USA.
Mod Pathol. 2005 Mar;18(3):421-30. Abstract quote
Erythropoietin is a hematopoietic cytokine that regulates the production of red blood cells. Erythropoietin is normally produced in the adult kidney in a hypoxia-inducible manner. The recombinant form of human erythropoietin is in clinical use for the prevention and treatment of anemia that is associated with cancer and its treatment with chemoradiation therapy. A series of recent studies from our laboratory and others have reported the expression of receptors for erythropoietin in several different types of human cancer cells.
In the present study, we investigated the expression of erythropoietin receptor and its ligand erythropoietin in human prostate cancer. In clinical specimens of prostate cancer, we found abundant expression of erythropoietin receptor protein in all primary tumors examined using immunohistochemistry. Furthermore, we observed erythropoietin coexpression in prostate cancer cells by immunohistochemical analysis. To determine whether monolayer cultures of continuous cell lines derived from prostate cancer also express erythropoietin receptor and erythropoietin, we studied well-characterized hormone-responsive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines.
We performed reverse-transcription and polymerase chain reaction assays to detect erythropoietin receptor and erythropoietin mRNA transcripts, and also immunoprecipitation and immunoblotting to detect erythropoietin receptor protein expression in prostate cancer cells. These experiments revealed the expression of both erythropoietin receptor and erythropoietin in LNCaP and PC-3 cells suggesting that these prostate cancer cell lines may serve as useful experimental models for further studies of erythropoietin and erythropoietin receptor function in prostate cancer.
The coexpression of erythropoietin receptor and its ligand erythropoietin in human prostate cancer cells suggests the potential for growth regulation by erythropoietin-erythropoietin receptor in an autocrine or paracrine manner.
ROLE OF PROSTATIC INTRAEPITHELIAL NEOPLASIA
Prostatic intraepithelial neoplasia and invasive carcinoma in total prostatectomy specimens: distribution, volumes and DNA ploidy.
de la Torre M, Haggman M, Brandstedt S, Busch C.
Department of Pathology, University Hospital of Uppsala, Sweden.
Br J Urol 1993 Aug;72(2):207-13 Abstract quote
Prostatic intraepithelial neoplasia (PIN) has been postulated to be the main precursor of invasive carcinoma of the prostate (IC). The occurrence, distribution and volumes of PIN and IC in addition to grade were studied in 54 patients who underwent total prostatectomy because of localised IC (T0d-T2 NO MO).
PIN always occurred multifocally, localised generally in the peripheral zone (PZ) and was found in all cases. PIN 1 was the most common grade, PIN 3 the least. PIN 3 occurred exclusively in the PZ, in the vicinity of or intermingled with high grade IC. PIN and IC grades were usually concordant. The relative volumes of IC and PIN showed an inverse relationship, i.e. at small IC + PIN volumes PIN dominated, whereas at large IC + PIN volumes both relative and absolute PIN volumes were lower. Furthermore, with increasing PIN grade a tendency towards an increase in tumour volume, Gleason score and frequency of disruption of the basal cell layer was observed. These findings indicate progression from PIN to IC. DNA ploidy of PIN areas was determined by means of flow cytometry. Areas containing PIN 1, 2 or 3 were sampled (1 plug/ml of PIN). All foci displayed only diploid DNA profiles regardless of PIN volume and grade, even with coexistent IC displaying heterogeneous DNA patterns.
Our results support the claim that low and medium grade prostatic carcinoma arises from near-diploid PIN stemlines and may progress into heterogeneous tumours containing non-diploid stemlines.
Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: predictive accuracy in needle biopsies.
Davidson D, Bostwick DG, Qian J, Wollan PC, Oesterling JE, Rudders RA, Siroky M, Stilmant M.
Nichols Laboratories, Lincoln, Nebraska, USA.
J Urol 1995 Oct;154(4):1295-9 Abstract quote
PURPOSE: High grade prostatic intraepithelial neoplasia is considered the most likely precursor of prostatic adenocarcinoma. However, the natural history and predictive value of prostatic intraepithelial neoplasia for cancer are unknown.
MATERIALS AND METHODS: To examine the predictive value of high grade prostatic intraepithelial neoplasia, we conducted a retrospective clinic based comparative study of 100 patients with high grade prostatic intraepithelial neoplasia and 112 without prostatic intraepithelial neoplasia on needle biopsies matched for digital rectal examination findings, patient age and serum prostate specific antigen level. Only patients who had 1 or more followup biopsies were included.
RESULTS: Adenocarcinoma was identified in 35% of subsequent biopsies from patients with prostatic intraepithelial neoplasia, compared with 13% of control biopsies. The likelihood of finding cancer increased as the interval from initial biopsy increased. High grade prostatic intraepithelial neoplasia, patient age and serum prostate specific antigen concentration were jointly highly significant predictors of cancer, with prostatic intraepithelial neoplasia providing the highest risk ratio of 14.93 (95% confidence intervals 5.6 to 39.8). No other candidate predictor was significant, including digital rectal examination findings, transrectal ultrasound results, amount of prostatic intraepithelial neoplasia on biopsy and architectural pattern of prostatic intraepithelial neoplasia.
CONCLUSIONS: These results indicate that the presence of high grade prostatic intraepithelial neoplasia on needle biopsy is strongly predictive of carcinoma. Prostatic intraepithelial neoplasia should be reported in needle biopsies and biopsy repeated. These finding support the hypothesis that prostatic intraepithelial neoplasia is a precursor of prostate cancer.
The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma.
Qian J, Wollan P, Bostwick DG.
Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Hum Pathol 1997 Feb;28(2):143-8 Abstract quote
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.
Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens.
Pacelli A, Bostwick DG.
Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Urology 1997 Sep;50(3):355-9 Abstract quote
OBJECTIVES: High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of invasive prostatic adenocarcinoma. The incidence and clinical significance of this lesion have not been previously defined in specimens from transurethral resections of the prostate (TURP).
METHODS: To determine the frequency of PIN in TURP specimens and its relationship with adenocarcinoma, we reviewed 698 resections performed at Mayo Clinic between 1989 and 1990. A mean of 6 slides was analyzed for each case (range 1 to 36). The presence, extent, and architectural pattern of PIN were recorded. The results were correlated with many clinical and pathologic features, including patient age, Gleason score, stage, serum prostate-specific antigen (PSA) concentration, and patient follow-up. In a 1:2 nested matching case-control study, we compared the outcome of cases with PIN alone with that of the control group. Each patient with PIN alone (16 patients) was matched randomly with 2 patients with benign prostatic hyperplasia (BPH) alone (32 patients) according to age (+/- 5 years) and serum PSA concentration (+/- 1 ng/mL).
RESULTS: Of 698 TURP specimens, 570 (81.7%) contained BPH and 128 (18.3%) contained adenocarcinoma and BPH. High-grade PIN was identified in 29 cases (4.2%), including 16 (2.8%) of those with BPH and 13 (10.2%) of those with cancer and BPH. Follow-up revealed adenocarcinoma in 3 of 14 patients (21.4%) with PIN and BPH only after 3, 5, and 7 years, respectively; mean follow-up for the 14 patients was 6 years (range 4 to 7 years), and none of the patients died of prostate cancer. Conversely, none of the patients (0%) without PIN in TURP specimens in the case-control study had subsequent adenocarcinoma.
CONCLUSIONS: The overall incidence of PIN in TURP specimens was 4.2%, including 2.8% without cancer and 10.2% with coexistent cancer. Prostatic adenocarcinoma was diagnosed within 7 years in 21.4% of patients with PIN in TURP specimen. Conversely, none of those without PIN matched for age and serum PSA had adenocarcinoma at follow-up. These results indicate that high-grade PIN is uncommon in TURP specimens and, when found, indicates a significant risk of cancer. The presence of PIN in TURP specimens should be reported by the pathologist; in addition, the entire specimen should be submitted for histologic examination to exclude carcinoma.
Is prostatic intraepithelial neoplasia in the transition/central zone a true precursor of cancer? A long-term retrospective study in Norway.
Harvei S, Skjorten FJ, Robsahm TE, Berner A, Tretli S.
Cancer Registry of Norway, Institute for Epidemiological Cancer Research, Oslo.
Br J Cancer 1998 Jul;78(1):46-9 Abstract quote
Prostatic intraepithelial neoplasia (PIN) has been considered as a precursor of prostatic cancer. Few reports have dealt with the long-term follow-up of PIN lesions, and there is still a lack of proof that PIN is a true premalignant lesion.
The objective of this study was to evaluate PIN in the transition/central zone as a marker for subsequent development of prostatic cancer.
The PIN status of tissue specimens from 789 men without prostate cancer was determined in 508 transurethral resections and 281 transvesical prostatic enucleations. All slides were reviewed blind and independently by two pathologists. The patients were followed for an average of 11 years, and the incidence of subsequent cancer and cause-specific survival were analysed. Thirty-six cases of clinical prostatic cancer occurred among the cohort of 789 men through follow-up.
No association between the presence of PIN in the transition/central zone and subsequent cancer development was found. There was also no difference in survival related to PIN status among the subsequent cancer patients.
Prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia. Relationship to pathologic parameters, volume and spatial distribution of carcinoma of the prostate.
Sakr WA, Grignon DJ.
Department of Pathology, Harper Hospital, Wayne State University, Detroit, Michigan 48201, USA.
Anal Quant Cytol Histol 1998 Oct;20(5):417-23 Abstract quote
OBJECTIVE: To summarize studies that have investigated the morphologic, spatial and volumetric relationship between prostate cancer and its putative precursors, high grade prostatic intraepithelial neoplasia (HGPIN) and atypical adenomatous hyperplasia (AAH).
METHODS: Studies addressing the relationship between morphologic parameters of prostate cancer (i.e., stage, grade, volume and anatomic distribution) and both HGPIN and AAH are reviewed. Similar data based on our institutional experience with surgical and autopsy series of step-sectioned, totally embedded prostate glands are also presented.
RESULTS: Most investigators have demonstrated significant associations between HGPIN and carcinoma in terms of coexistence, "zonal" origin and physical proximity. The two lesions have a high tendency to be present simultaneously; both originate predominantly in the peripheral zone and are often found within the same microscopic field. Reports on the relationship between HGPIN and the stage of prostate cancer are less consistent, and the associations of this lesion with cancer grade and volume are exceedingly complex. HGPIN appears to be associated with moderately to poorly differentiated, smaller, often-multifocal tumors and is less frequent in large, high grade cancers. There are data suggesting a trend-of a reciprocal relationship between more extensive and diffuse HGPIN and large-volume prostate cancers. Conversely, there is a wide spectrum of volume distribution of the two lesions in glands harboring smaller tumors. Similar data concerning AAH are limited.
CONCLUSION: There are strong and consistent data supporting various aspects of the morphologic associations between HGPIN and prostate cancer. The indications that glands harboring larger tumors tend to contain less extensive HGPIN could raise the hypothesis that as carcinoma becomes larger, it may replace areas of the gland previously occupied by HGPIN. Alternatively, prostate cancer can evolve from ducts with HGPIN and gradually overgrow their precursor. There is a relative dearth of similar information concerning AAH.
Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy.
Kronz JD, Allan CH, Shaikh AA, Epstein JI.
Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland 21231, USA.
Am J Surg Pathol 2001 Aug;25(8):1079-85 Abstract quote
Most studies on the risk of cancer after high-grade prostatic intraepithelial neoplasia (PIN) on biopsy have been small (fewer than 100 men), have not analyzed in detail if histologic features can predict cancer, and have not assessed the risk of cancer with multiple repeat biopsies.
We analyzed 245 men in whom the only abnormal finding on the initial biopsy was high-grade PIN and who had at least one follow-up biopsy.
Repeat biopsy identified cancer in 32.2% of men. If only one follow-up biopsy had been performed on the 245 men, only 24.5% of men would have been found to have cancer. The only independent histologic predictor of a cancer diagnosis was the number of cores with high-grade PIN; risk of cancer: 30.2% with 1 or 2 cores, 40% with 3 cores, and 75% with >3 cores. The following did not predict cancer: number of high-grade PIN glands, maximum percentage of gland involved by high-grade PIN, nucleolar prominence, percentage of cells with prominent nucleoli, pattern of high-grade PIN (flat, tufting, micropapillary, cribriform), marked pleomorphism, digital rectal examination, transrectal ultrasound findings, family history of prostate cancer, serum prostate specific antigen (PSA) at time of high-grade PIN diagnosis, and rate of change of serum PSA. Eighty-one (33%) men had more than one follow-up biopsy; in these cases the following findings on the original high-grade PIN biopsy predicted cancer: the presence of mitoses, the number of positive cores, predominant micropapillary and cribriform high-grade PIN, and very large prominent nucleoli. Of 81 men with more than one follow-up biopsy, if the first repeat biopsy were benign, high-grade PIN, or atypical, the eventual cancer rate was 10%, 25.9%, and 57.1%, respectively (p = 0.002). Of 15 men with more than two repeat biopsies, only two (13.3%) had cancer.
In summary, approximately one third of men with high-grade PIN on biopsy have cancer on follow-up. If cancer is not found on the first two follow-up biopsies, it will unlikely be found. Although clinical findings at the time of diagnosis of high-grade PIN are not useful to predict who might have cancer, histologic findings may help identify who needs additional biopsies.
p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens
Jaudah Al-Maghrabi, M.D., FRCPC, Lada Vorobyova, M.D., William Chapman, M.D., FRCPC, Michael Jewett, M.D., FRCS, Maria Zielenska, Ph.D. and Jeremy A. Squire, Ph.D.
Ontario Cancer Institute (JA-M, LV, WC, MJ, JAS), Princess Margaret Hospital (JA-M, LV, WC, MJ, JAS), Toronto General Hospital (JA-M, WC, MJ, JAS), University Health Network (JA-M, LV, WC, MJ, JAS), and Departments of Laboratory Medicine and Pathobiology (JA-M, LV, SC, JAS), Medical Biophysics (JAS), Surgical Oncology (MJ), and Pediatric Laboratory Medicine, Hospital for Sick Children (MZ), Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Mod Pathol 2001;14:1252-1262 Abstract quote
p53 mutation has been shown to be associated with chromosomal instability (CI) in many human dysplastic and neoplastic lesions. However, the precise role of p53 in the pathogenesis of prostate carcinoma (Pca) is unknown.
Topographic analysis of p53 alteration using immunohistochemistry (IHC) was performed on 35 archived prostatectomy specimens containing Pca foci; high-grade prostrate intraepithelial neoplasia (HPIN) foci intermingled with cancer (HPINI) and situated away (HPINA). Specimens from 2 patients were topographically genotyped using laser capture microdissection, PCR amplification, and direct sequencing of p53 exons 5–9.
CI was evaluated in the same tissue foci by interphase in situ hybridization (IFISH) using centromere probes for chromosomes 7, 8, and Y. p53 immunoreactivity was found in 20%, 17%, 0, and 0 in Pca, HPINI, HPINA, and benign epithelium, respectively. p53 molecular analysis in the specimens examined confirmed the IHC findings. IFISH revealed numerical chromosomal alterations in keeping with CI in 71% and 25% of p53+ and p53- Pca, respectively (P = .1), 67% and 0 of p53+ and p53- HPIN, respectively (P < .02), and in 27% and 0 of HPINI and HPINA, respectively.
We concluded that p53 mutation is an early change in at least a subset of Pca. HPINI foci tend to have higher overall p53 immunoreactivity and CI than HPINA. The presence of p53 mutation in HPIN was associated with the presence of CI as determined by IFISH.
Our study also provided additional evidence in support of the concept that HPIN might be the earliest precursor of cancer. Furthermore, our studies identify genomic similarities in HPINI and Pca, implying that carcinoma may arise from progression of certain HPIN foci that most likely harbor p53 mutation and/or more CI.
Identification of Numerical Chromosomal Changes Detected by Interphase Fluorescence In Situ Hybridization in High-Grade Prostate Intraepithelial Neoplasia as a Predictor of Carcinoma
Jaudah Al-Maghrabi, MD, FRCPC, Lada Vorobyova, MD, A. Toi, MD, FRCPC, William Chapman, MD, FRCPC, Maria Zielenska, PhD, and Jeremy A. Squire, PhD
From the Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada (Drs Al-Maghrabi, Vorobyova, Chapman, and Squire); Toronto General Hospital, Toronto, Ontario, Canada (Dr Squire); University Health Network, Toronto, Ontario, Canada (Drs Al-Maghrabi, Vorobyova, Chapman, and Squire); and the Departments of Laboratory Medicine and Pathobiology (Drs Al-Maghrabi, Vorobyova, Chapman, and Squire), Medical Biophysics (Dr Squire), Radiology (Drs Al-Maghrabi and Toi), and Pathology (Dr Zielenska), Hospital for Sick Children, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Arch Pathol Lab Med 2002;Vol. 126, No. 2, pp. 165169. Abstract quote
Context.High-grade prostate intraepithelial neoplasia (HPIN) is the most likely precursor of prostate cancer. The condition of many patients with a diagnosis of HPIN in prostate needle core biopsy could, if left untreated, progress to invasive cancer. Currently there is no available clinical, immunohistochemical, or morphologic criteria that are predictive of this progression.
Objective.To determine whether chromosomal instability in these precursor lesions could increase their predictive value for cancer detection.
Design.Dual-color interphase fluorescence in situ hybridization analysis was performed on archived prostate needle core biopsies from 54 patients with initial diagnosis of isolated HPIN and follow-up of 3 years or more. We used commercially available centromere probes for chromosomes 4, 7, 8, and 10. We had interpretable results in 44 patients as follows: (1) group A: 24 HPIN patients with persistent HPIN and/or benign lesions in the follow-up biopsies, and (2) group B: 20 HPIN patients with progression to prostate carcinoma.
Results.Twenty-five percent of the patients in group B displayed numeric chromosomal aberrations. Only 8.3% of the patients from group A had chromosomal abnormalities (P = .1). The observed overall chromosomal changes in HPIN were higher than those in normal or hyperplastic epithelium, with a statistically significant difference (P < .05). All aberrations were detected in the form of chromosomal gain. Overall, the commonest aberration was gain of chromosome 8, followed by gains of chromosomes 7 and 10.
Conclusion.These results indicated that although no single numeric chromosomal abnormality could be assigned as a predictor of HPIN progression to carcinoma, the overall level of numeric chromosomal abnormalities shows a trend of elevation in HPIN patients whose condition subsequently progressed to carcinoma.
- Molecular genetics of human prostate cancer.
Rubin MA, De Marzo AM.
1Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Mod Pathol 2004;17:380-388 Abstract quote
Multiple factors contribute to the high incidence and prevalence of prostate cancer including race, ethnicity, diet, environment, widespread awareness through prostate-specific antigen screening and genetics.
Linkage analysis has identified several candidate sites for hereditary prostate cancer gene loci. Molecular studies have also identified genes that are frequently altered in sporadic prostate cancer. It appears that due to the heterogeneity of prostate cancer, multiple genes may be involved in the neoplastic process.
Identification of a novel gene on chromosome 13 between BRCA-2 and RB-1.
Schmidt U, Fiedler U, Pilarsky CP, Ehlers W, Fussel S, Haase M, Faller G, Sauter G, Wirth MP.
Department of Urology, Technical University of Dresden, Dresden, Germany.
Prostate 2001 May 1;47(2):91-101 Abstract quote
METHODS AND RESULTS: By differential display we isolated a new cDNA-fragment, named C13, that is downregulated in malignant prostate tissues. Northern hybridization revealed the fragment to be part of 3.0 and 4.4 kb mRNAs. Fluorescence in situ hybridization, Southern blotting and radiation hybrid mapping demonstrated a chromosomal localization of C13 on 13q12-14 closest to the SHGC-34125 marker. In the 5% chromosomal environment of C13 we detected changes of the allelic status in 13 of 21 prostate cancers. A downregulation was detected at the mRNA level in patients with advanced carcinoma. The 3.0 kb full length cDNA clone encodes a protein with an open reading frame of 2,202 bp or 733 amino acids. The corresponding protein contains a putative nuclear localization signal, several glutamine clusters and an alpha-helix-rich domain. By in situ RNA hybridization we could demonstrate the mainly epithelial expression of the C13 mRNA in prostatic tissue.
CONCLUSIONS: The localization of C13 between the tumor suppressor genes BRCA-2 and RB-1, the detected allelic imbalances, the downregulation of its mRNA in some prostatic cancer tissues, the epithelial expression and the described protein structure suggest that this gene encodes a protein that may have tumor or metastasis suppressing function in prostate tissue
A candidate prostate cancer susceptibility gene at chromosome 17p.
Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon-Albright LA.
Myriad Genetics, Inc., Salt Lake City, Utah, USA.
Nat Genet 2001 Feb;27(2):172-80 Abstract quote
It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p.
We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees.
In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria.
The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).
OTHER MECHANISMS ATM (ATAXIA-TELANGIECTASIA MUTATED GENE PRODUCT) ATM Protein Overexpression in Prostate Tumors Possible Role in Telomere Maintenance
Sandra Angèle, PhD, Alison Falconer, MRCP, FRCR, Christopher S. Foster, DSc, Phillipe Taniere, PhD, MD, Ros A. Eeles, PhD, FRCR, FRCP, and Janet Hall, PhD
Am J Clin Pathol 2004;121:231-236 Abstract quote
It has been postulated that telomere dysfunction and telomerase activation have important roles in prostate tumorigenesis. Since the ataxia-telangiectasia mutated gene product (ATM protein) is involved in maintaining telomere length and integrity, we hypothesized that its expression might be altered in prostate tumors and, thus, examined its profile in 49 tumor samples.
The majority (32/49) had ATM protein levels higher than those observed in normal tissues, with only 5 of 49 tissue samples showing reduced or absent ATM levels. Three of these were from the group of 6 young-onset or sibling-pair tumors. There was a trend toward higher ATM expression in tumors with a higher Gleason score (23/32 [72%] for grade 8-10 vs 9/17 [53%] for grades 5-7), although this difference was not statistically significant.
These findings support our hypothesis that the presence of the ATM protein at the same or a higher level than that in normal prostate cells might have an important role in the maintenance of the shortened telomeres commonly found in prostate cancer cells.
BRCA1 and prostate cancer.
Rosen EM, Fan S, Goldberg ID.
Department of Radiation Oncology, Long Island Jewish Medical Center, Long Island Campus, Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, NY 11040, USA.
Cancer Invest 2001;19(4):396-412 Abstract quote
The breast cancer susceptibility gene BRCA1 on chromosome 17q21 encodes an 1863 amino acid protein that is important for normal embryonic development. Germline mutations of this gene are linked to a significantly increased lifetime risk for breast and/or ovarian cancer, and recent studies suggest that the same may be true for prostate cancer.
Several activities that may contribute to the tumor suppressor function of BRCA1 have been identified via in vitro and experimental animal studies. These include (i) regulation of cell proliferation; (ii) participation in DNA repair/recombination processes related to the maintenance of genomic integrity; (iii) induction of apoptosis in damaged cells; and (iv) regulation of transcription. A second breast cancer susceptibility gene (BRCA2) operates in some of the same molecular pathways as BRCA1, and mutations of this gene predispose to breast and ovarian cancer and probably to other tumor types, including prostate cancer.
Finally, recent studies from our laboratory suggest that BRCA1 modulates proliferation, chemosensitivity, repair of DNA strand breaks, apoptosis induction, and expression of certain key cellular regulatory proteins (including BRCA2 and p300) in human prostate cancer cells. These activities are consistent with a putative prostate tumor suppressor function of BRCA1.
Down-regulation of drs mRNA in human prostate carcinomas.
Kim CJ, Shimakage M, Kushima R, Mukaisho K, Shinka T, Okada Y, Inoue H.
Hum Pathol. 2003 Jul;34(7):654-7. Abstract quote
We have previously reported that the drs gene has the ability to suppress transformation by v-src and v-K-ras in the rat cell line F2808. We have also shown that the expression of drs mRNA is markedly reduced in a variety of human cancer cell lines, suggesting that down-regulation of drs mRNA is correlated with the development of human cancers.
To clarify the role of the drs gene in prostate carcinogenesis, we examined the expression of the drs gene in 3 normal prostate, 13 prostate carcinoma, 5 benign prostate hyperplasia (BPH), and 2 prostatic intraepithelial neoplasia (PIN) tissue specimens by in situ hybridization and in 3 prostate carcinoma cell lines (PC3, LNCaP, and DU145) and 2 BPH tissues by Northern blot analysis. Furthermore, the deletion, and rearrangement of the drs gene were analyzed by Southern blot analysis. The drs mRNA was significantly expressed in normal prostate and BPH tissues, whereas it was markedly down-regulated in prostate carcinoma tissues and prostate carcinoma cell lines. In 2 tissues from PIN, drs mRNA was weakly expressed. There were no differences between prostate carcinoma cell lines and BPH tissues in terms of their banding patterns of Southern blot analysis.
These results indicate that down-regulation of drs mRNA is closely correlated with development of prostate carcinoma, suggesting a tumor-suppressor function of the drs gene in this cancer.
Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma
Sarki A. Abdulkadir, MD, PhD Joseph M. Carbone, MD
Cathy K. Naughton, MD
Peter A. Humphrey, MD, PhD
William J. Catalona, MD
Jeffrey Milbrandt, MD, PhD
Hum Pathol 2001;32:935-939 Abstract quote
The transcription factor EGR1 is frequently overexpressed in human prostate cancer and regulates the expression of several genes important for tumor progression. In addition, mice lacking the Egr1 gene show a defect in prostate tumorigenesis. NAB2 is a novel corepressor molecule that modulates EGR1 activity and is induced by the same stimuli that induce EGR1. The human NAB2 gene has been localized to 12q13.3-14.1, within a chromosomal region that is thought to harbor a prostate tumor suppressor.
We have examined the expression of NAB2 in human prostate carcinoma specimens.
We show here that NAB2 protein expression is lost in a majority of primary prostate carcinoma specimens, including many samples that have high EGR1 levels. This loss occurs early in the tumorigenic process and is sustained, as it is seen in precursor prostatic intraepithelial neoplasia lesions as well as in metastases. Furthermore, loss of NAB2 did not correlate with the tumor grade or stage. Our findings suggest that high levels of EGR1 coupled with low levels of NAB2 can result in high, unrestrained EGR1 transcriptional activity in human prostate cancers.
The polycomb group protein EZH2 is involved in progression of prostate cancer.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Nature 2002 Oct 10;419(6907):624-9 Abstract quote
Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable.
Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis.
Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
FATTY ACID SYNTHASE GENE
Hum Pathol. 2006 Apr;37(4):401-9. Epub 2006 Feb 7. Abstract quote
Cancer cells frequently exhibit a significant increase in overexpression and activity of fatty acid synthase (FASN). Elevated FASN pathway activity also occurs in prostate cancer, the second leading cause of cancer-related death in men in the United States. Studies show that genes associated with an increase in protein expression, such as HER2/neu in breast cancer, are associated with an increase in gene copy number as well as an increase in transcription. In the present study, we evaluated whether FASN follows a similar paradigm in prostate cancer. To date, elevated FASN expression in prostate cancer has not been correlated with gene copy number alterations.
Using immunohistochemistry and fluorescence in situ hybridization analysis in paraffin-embedded tissue microarrays, we observed gene copy gain in 24% of all prostate adenocarcinoma specimens examined with concurrent increased FASN protein expression. Immunohistochemistry alone showed 59% of prostate cancer specimens in the same tissue microarray with high FASN expression. Increased FASN gene was observed in 53% of all prostate tissues expressing elevated FASN protein levels and in 2 of 5 prostate tumor cell lines tested.
These findings suggest that FASN gene copy number increases may be involved in the resultant increase in FASN protein expression observed in prostatic disease.
HER2 Protein Expression and Gene Amplification in Androgen-Independent Prostate Cancer
David M. Reese, MD, Eric J. Small, MD, Gregg Magrane, PhD, Frederic M. Waldman, MD, PhD, Karen Chew, and Daniel Sudilovsky, MD
Am J Clin Pathol 2001;116:234-239 Abstract quote
The role of the HER2 receptor remains uncertain in the pathogenesis and progression of human prostate cancer. Previous studies have reported widely divergent rates for HER2 expression in primary prostate tumors, probably owing to significant methodologic differences in the studies. Few data exist about the frequency of HER2 protein overexpression and gene amplification in androgen-independent prostate cancer (AIPC), although recent xenograft models suggest HER2 expression may be up-regulated in the transition from androgen-dependent to androgen-independent disease.
We studied the role of HER2 protein in AIPC by immunohistochemical and fluorescence in situ hybridization (FISH) analyses on AIPC specimens using well-characterized and validated reagents. Fourteen (36%) of 39 specimens expressed HER2; however, only 2 (5%) ha
d moderate (2+) expression, and 2 (5%) had high-level (3+) expression. Two (6%) of 36 specimens had gene amplification by FISH. These data suggest that HER2 protein overexpression and gene amplification are relatively uncommon in AIPC.
Glutathione S-transferase Pi Gene methylation
Adv Anat Pathol 2000;7:382-389
Methylation of this promoter of the glutathione S-transferase pi (GSTP) gene has been detected in 90% of samples of prostatic adenocarcinoma and in <10% of benign prostate tissue
To date, it has not been described in other nonprostatic tissues
MITOGEN ACTIVATED PROTEIN KINASES
Regulation of proliferation/apoptosis equilibrium by mitogen-activated protein kinases in normal, hyperplastic, and carcinomatous human prostate.
Royuela M, Arenas MI, Bethencourt FR, Sanchez-Chapado M, Fraile B, Paniagua R.
Department of Cell Biology and Genetics, University of Alcala, and the Department of Urology, Hospital Principe de Asturias, Alcala de Henares, Madrid, Spain.
Hum Pathol 2002 Mar;33(3):299-306 Abstract quote
This study investigate the expression of the mitogen-activated protein kinases (MAPKs) in normal prostate, benign prostatic hyperplasia (BPH), and prostatic cancer (PC), and also the possible relationship between the activity of these MAPKs and the apoptosis/proliferation index.
Immunochemical techniques were carried out using 2 mouse monoclonal antibodies against human extracellular signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK), and 1 goat polyclonal antibody against mouse p38. To compare the results obtained in the 3 specimens, the average percentages of both epithelial and stromal immunostained cells were calculated on immunostained sections. For each of the 3 kinases studied, the percentage of immunostained stromal cells did not change with prostatic alterations. For both ERK and p38, the percentage of immunostained epithelial cells increased significantly in BPH and even more so in PC. For JNK, the percentage of immunostained epithelial cells increased significantly only in PC.
These results suggest that ERK could be involved in the elevated proliferation indexes reported in BPH and PC, whereas p38 might contribute to the increased apoptotic index reported in PC. The most probable action of JNK in PC would be cell proliferation stimulation. Overexpression of MAPKs, involved in the development of prostatic hyperplasia and neoplasia, might be secondary to the overexpression of several growth factors.
Abnormal Expression of MDM2 in Prostate Carcinoma
Katia R. M. Leite, etal.
Mod Pathol 2001;14:428-436 Abstract quote
Mutation of p53 is rare in localized prostate carcinoma. The oncoprotein MDM2, whose gene has a response element for p53, promotes the degradation of p53 protein and inhibits its transcriptional activation of genes related to cell cycle arrest and apoptosis, constituting a negative feedback control.
We studied p53 and MDM2 expression by immunohistochemistry and looked for mutations in p53 exons 5 to 8 by polymerase chain reaction-single strand conformational polymorphism in 118 patients submitted to radical prostatectomy for localized prostate cancer. In 28 cases, we studied cell proliferation by immunohistochemistry, using antibody for Ki-67, and apoptosis by the deoxynucleotidyl transferase mediated dUTP biotin nick end labeling technique.
Although no p53 mutations were found, p53 protein was detected in 31.4% of the cases, and these cases had higher Gleason scores (P = .03) and more advanced tumor stages (P = .02). MDM2 was overexpressed in 40.7% of the cases, and these cases had greater tumor volumes (P = .001). Tumors that were positive for both p53 and MDM2 were larger (P = .003) and of more advanced stage (P = .03). Within the 28-case subset, the proliferative index was higher among MDM2-positive tumors (P = .046), and the apoptotic index was lower among p53-positive tumors (P = .01).
We conclude that, although p53 mutation is a rare event in prostate carcinogenesis, the detection of p53 protein by immunohistochemistry is common and is associated with decreased apoptosis and increased histologic grade and tumor stage. We also conclude that the overexpression of MDM2 has a role in prostate carcinogenesis, being frequently detected and associated with increased cell proliferation and tumor volume. Finally, we propose that the MDM2-positive/p53-positive phenotype identifies prostate cancers with aggressive behavior.
NEURAL CELL ADHESION MOLECULE
Neural cell adhesion molecule is upregulated in nerves with prostate cancer invasion.
Li R, Wheeler T, Dai H, Ayala G.
Hum Pathol. 2003 May;34(5):457-61. Abstract quote
Currently postulated mechanisms of perineural invasion (PNI) include interaction between tumor cells and nerves. Neural cell adhesion molecule (N-CAM), one of the well-known members of the immunoglobulin super-family of adhesion molecules, was implicated in PNI and metastasis in various types of cancer.
Tissue microarray technology was used to build 2 sets of tissue array (with versus without PNI) from 50 prostate cancers (PCa). The slides were stained immunohistochemically, and the results were evaluated semiquantitatively using a 0 to 3+ scoring system. N-CAM staining was observed in all nerves with variable intensity. N-CAM expression was upregulated in 73% (31 of 42) of the nerves with PNI compared with nerves without PNI (P >.001). The results suggested that N-CAM is probably involved in PNI in PCa.
It is conceivable that cancer cells, through a yet-to-be-established paracrine loop, signal the nerve to increase N-CAM production and increase adhesion. N-CAM upregulation in nerves may also facilitate cancer cells to migrate toward nerves and promote the process of perineural spread through increased survival using the nuclear factor kappa B pathway.
Expression of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Flk-1 in Benign, Premalignant, and Malignant Prostate Tissue
Jens Köllermann, MD, and Burkhard Helpap, MD
Am J Clin Pathol 2001;116:115-121 Abstract quote
Vascular endothelial growth factor (VEGF) is one of the most potent mitogenic, highly specific tumor angiogenic factors, which acts via binding to 2 specific tyrosine kinase receptors. There are few studies analyzing VEGF receptor expression in prostate cancer cells, and results are contradictory.
In an immunohistochemical study, we analyzed VEGF and VEGF receptor fetal liver kinase (Flk)-1 expression in benign glands, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostatic carcinomas of different Gleason scores, obtained from 21 radical prostatectomy specimens. In all benign glands, VEGF and Flk-1 expression was confined almost exclusively to the basal cell layer (proliferative cell compartment). In HGPIN, labeling was no longer confined to the basal cell layer, but also was seen in all neoplastic secretory cells. All carcinomas stained positive for both markers. There was a trend for increasing labeling intensity with increasing cellular dedifferentiation.
We concluded that tumor growth stimulated by the VEGF-Flk-1 system is promoted not only by neoangiogenesis, but also by tumor cell autostimulation. The VEGF-Flk-1 system may have an important role in the process of malignant transformation and tumor progression.
Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.
Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Gronberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J.
Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
Nat Genet 2002 Feb;30(2):181-4 Abstract quote
Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition.
Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene.
We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele.
Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
CHARACTERIZATION Radiographs CT scan and MRI
Imaging and prostate cancer chemoprevention: Current diagnosis and future directions.
Karmanos Cancer Institute, Detroit, Michigan, USA.
Urology 2001 Apr;57(4 Suppl 1):121-3 Abstract quote
Identifying appropriate patients as targets for prostate cancer chemoprevention is a daunting task due to the multiple known and unknown factors contributing to patients' risk profiles. Confirmation of the extent and location of early prostate cancers, as well as prostatic intraepithelial neoplasia (PIN), also requires improved image guidance of biopsy to contain costs.
Prostate-specific antigen (PSA) in conjunction with transrectal ultrasound (TRUS) and digital rectal examination (DRE) have been the front-line tests for early prostate cancer. Although advances in MRI continue to improve its accuracy, limited availability and higher costs preclude its widespread use for chemoprevention trials. Improved biopsy risk assessment has been achieved by categorizing TRUS grayscale and vascular findings for each biopsy region. In addition, concomitant suspicious TRUS findings also improved cancer yield per biopsy, as well as the amount and grade of tumor per core. However, TRUS remains operator dependent despite advancements in grayscale and vascular imaging. Additional risk parameters are needed to better localize small disease foci and improve the overall diagnostic performance while containing costs.
Future work may improve the specificity of tissue characterization to produce reliable noninvasive biomarkers for monitoring chemoprevention responses of early prostate cancer or PIN.
Morphometric analysis of borderline atypia in prostatic aspiration biopsy specimens.
Layfield LJ, Goldstein NS.
Department of Pathology and Laboratory Medicine, University of California, Los Angeles School of Medicine 90024.
Anal Quant Cytol Histol 1991 Aug;13(4):288-92 Abstract quote
In a prior study of 411 fine needle aspirates of the prostate (FNAPs), we identified a subset of 50 (12%) aspirates in which the findings were designated cytologically atypical. These equivocal cases formed a heterogeneous group composed of both histologically benign and malignant proliferations in which cutting needle biopsy was necessary to further delineate the nature of the abnormality. In an attempt to define quantitative and morphologic criteria for the separation of these proliferations into benign and malignant categories and to reduce the need for diagnostic cutting needle biopsies, we performed a cytomorphometric analysis of smears from 12 FNAPs (6 histologically proven benign and 6 histologically proven malignant) with equivocal cytologic atypia.
We were unable to define any cytomorphometric criteria that accurately subdivided these cases into benign and malignant categories.
LABORATORY MARKERS EARLY PROSTATE CANCER ANTIGEN (EPCA) PROSTATE SPECIFIC ANTIGEN
Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence?
Sirovich BE, Schwartz LM, Woloshin S.
VA Outcomes Group, 111B, Department of Veterans Affairs Medical Center, White River Junction, VT 05009.
JAMA 2003 Mar 19;289(11):1414-20 Abstract quote
CONTEXT: The debate about the efficacy of prostate-specific antigen (PSA) screening for prostate cancer has received substantial attention in the medical literature and the media, but the extent to which men are actually screened is unknown. If practice were evidence-based, PSA screening would be less common among men than colorectal cancer screening, a preventive service of broad acceptance and proven efficacy.
OBJECTIVE: To compare the prevalences of PSA and colorectal cancer screening among US men.
DESIGN, SETTING, AND POPULATION: The 2001 Behavioral Risk Factor Surveillance System, an annual population-based telephone survey of US adults conducted by the Centers for Disease Control and Prevention, was used to gather data on a representative sample of men aged 40 years or older from all 50 states and the District of Columbia (n = 49 315).
MAIN OUTCOME MEASURES: Proportions of men ever screened and up to date on screening for prostate cancer (with PSA testing) and colorectal cancer (with fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy).
RESULTS: Overall, men are more likely to report having ever been screened for prostate cancer than for colorectal cancer; 75% of those aged 50 years or older have had a PSA test vs 63% for any colorectal cancer test (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.18-1.21). Up-to-date PSA screening is also more common than colorectal cancer screening for men of all ages. Among men aged 50 to 69 years (those for whom there is the greatest consensus in favor of screening), 54% reported an up-to-date PSA screen, while 45% reported up-to-date testing for colorectal cancer (RR, 1.19; 95% CI, 1.16-1.21). In state-level analyses of this age group, men were significantly more likely to be up to date on prostate cancer screening compared with colorectal cancer screening in 27 states, while up-to-date colorectal cancer screening was more common in only 1 state.
CONCLUSION: Among men in the United States, prostate cancer screening is more common than colorectal cancer screening. Physicians should ensure that men who choose to be screened for cancer are aware of the known mortality benefit of colorectal cancer screening and the uncertain benefits of screening for prostate cancer.
Factors That Influence the Measurement of Prostate Cancer DNA Ploidy and Proliferation in Paraffin Embedded Tissue Evaluated by Flow Cytometry
Mathew J. So, John C. Cheville, M.D., Jerry A. Katzmann, Ph.D., Darren L. Riehle, B.S., Christine M. Lohse, B.S., V. Shane Pankratz, Ph.D. and Thomas J. Sebo, M.D., Ph.D.
Swarthmore College,Swarthmore, Pennsylvania (MJS); and Department of Laboratory Medicine and Pathology (JCC, JAK, DLR, TJS), and Section of Biostatistics (CML, VSP), Mayo Clinic, Rochester, Minnesota
Mod Pathol 2001;14:906-912 Abstract qoute
DNA ploidy and proliferation have been shown in several studies to be prognostic markers for prostate cancer. Flow cytometry (FCM) is often used in the determination of ploidy and proliferation. However, FCM cannot readily distinguish among benign epithelium, stromal and inflammatory cells, high grade prostatic intraepithelial neoplasia (HGPIN), and cancer cells.
In this study, we evaluated H&E histologic features of 322 radical prostatectomy formalin-fixed, paraffin-embedded tissue blocks used for determining DNA ploidy, percent S-phase (%S), and %S + %G2M by FCM. The microscopic findings included Gleason score, extent of cancer and HGPIN in the tissue block, and presence of a needle track. The amount of cancer in the block was expressed as a percentage of the total tissue surface area in quartiles: 25%, 26–50%, 51–75%, and 76%. The extent of HGPIN was recorded in rough 5% intervals. Needle track effect was defined as a combination of fibrohistiocytic reaction, fibrin clot, granuloma formation, and chronic inflammation. The associations between these histologic features and DNA ploidy and proliferation (%S and %S + %G2M) were assessed.
In multivariate analyses, Gleason score, the amount of tumor in the tissue block, and the extent of HGPIN were significantly associated with ploidy. Gleason score was the only parameter significantly associated with the proliferation measure of %S. If we included %G2M as part of the proliferative fraction of the histogram, however, both Gleason score and the amount of tumor in the block were significantly associated with this measure of proliferation. The presence of a needle track was not significantly associated with DNA ploidy, %S, or %S + %G2M.
In summary, prostate cancer DNA ploidy and proliferation results assessed by FCM in paraffin-embedded tissue blocks were associated with the Gleason score, amount of cancer in the tissue block, and extent of HGPIN. However, the presence of a needle track was not associated with the FCM results.
Limitations of detection of bone-marrow micrometastasis in prostate carcinoma patients by CK18/PSA immunocytochemistry and PSA RT-PCR.
Albers P, Ko Y, Wardelmann E, Schmidt D, Adam M, Vetter H, Muller SC.
Department of Urology, Bonn University, Germany.
Anticancer Res 2000 May-Jun;20(3B):2107-11 Abstract quote
BACKGROUND: The aim of this study was to prove the reliability of cytokeratin 18/prostate specific antigen (CK18/PSA) immunocytochemistry to detect tumor cells in the bone marrow of patients with prostate cancer (CaP) compared with a control group without CaP.
PATIENTS AND METHODS: In bone marrow aspirates of 34 patients with CaP and 11 control patients without CaP, CK18/PSA immunocytochemistry was performed and compared with PSA RT-PCR in bone marrow and blood.
RESULTS: 12% of tumors showed a positive staining with PSA and and 17% with CK 18 immunocytochemistry. There was no correlation with the stage or grade of the CaP. False positive results occurred in 2 out of 6 males without CaP and in 2 out of 5 women. 35% of the samples were found to have PSA-mRNA signals in RT-PCR which were neither associated with the histological stage or grade nor the PSA staining in immunocytochemistry.
CONCLUSION: False positive staining results were obtained in control patients. Detection of PSA-mRNA was not associated with immunocytochemistry. Neither immunocytochemical nor PCR results were associated with the histological stage of the CaP. Thus, detection of micrometastasis using immunocytochemical methods has to be interpreted with caution and cannot be recommended as a clinical staging procedure.
Diagnosing minimal adenocarcinoma on prostate needle biopsy by real-time dynamic telepathology through the internet: Evaluation of an economic technology for remote consultation.
Pan CC, Liang WY, Huang CW, Chiang H.
Department of Pathology, National Yang-Ming University and Veterans General Hospital-Taipei, Taiwan; and the Department of Pathology, Tao-Yuan Veterans Hospital, Taiwan.
Hum Pathol 2002 Feb;33(2):242-6 Abstract quote
Computer-aided telepathology was introduced about 10 years ago, but has not yet met with worldwide acceptance. Recently, the internet has been used for image transmission in telepathology.
We set up an easily assembled system comprising a common microscope, a charge-coupled device (CCD) camera, a personal computer, and a commercial internet surveillance program with internet accessibility. The consultant then views the real-time images using a common web browser at the remote site. The purpose of the study was to assess the ability of the system to transmit images of sufficient quality to achieve high concordance between the diagnoses made at the home base and at the remote site.
We chose cases of minimal adenocarcinoma on prostate needle biopsy, because these lesions are liable to be overlooked and, even if discovered, are subject to differences in interpretation due to their limited size and subtle histologic changes. One hundred prostate needle biopsy specimens, including 45 minimal adenocarcinoma, 11 atypical small acinar proliferation, and 44 benign lesions, were tested. Two pathologists, unaware of the final diagnoses, were recruited to provide intra- and interinstitutional consultation. The overall concordance rates between telepathology diagnoses and final diagnoses were 97% and 94% for the two pathologists, respectively.
Our results demonstrate that this method is effective for teleconsultation. Similar systems using the internet can be easily set up by ordinary pathology laboratories to facilitate remote consultation.
TISSUE MICROARRAY SAMPLING
Evaluation of the interobserver reproducibility of gleason grading of prostatic adenocarcinoma using tissue microarrays.
De La Taille A, Viellefond A, Berger N, Boucher E, De Fromont M, Fondimare A, Molinie V V, Piron D, Sibony M, Staroz F, Triller M, Peltier E, Thiounn N, Rubin MA.
Hum Pathol. 2003 May;34(5):444-449. Abstract quote
The Gleason system is the internationally recognized standard for grading prostate cancer, due mainly to its strong prognostic capability. However, interobserver reproducibility is variable in the community setting.
Herein we present a novel approach to evaluating Gleason grading among pathologists using high-density tissue microarrays (TMAs). A CD-ROM containing 537 different TMA spot images of 0.6-mm diameter was sent to 10 genitourinary pathologists in France. The pathologists were expected to score each TMA spot based on their experience evaluating standard prostate biopsies, transurethral resections, and prostatectomy samples.
There was no consensus meeting beforehand to agree on how the group would apply the Gleason grading system for this project. Percentage of agreement and kappa value were used to assess the level of agreement. A short questionnaire was sent to assess pathologists' opinion on this new approach to evaluating Gleason grading.
An average of 311 images were analyzed (range, 104 to 537; median, 256.5). Four of the pathologists evaluated all 537 images and assigned Gleason grades to 149 images with an overall kappa for interobserver agreement for the exact score between 0.31 and 0.52 and between 0.45 to 0.69 if 3 Gleason categories (</=6, 7, and >7) were used. When 2 categories were considered (</=7 or >7), kappa ranged from 0.58 to 0.83. All pathologists analyzed 104 images. Similar results were obtained with an agreement between 0.28 and 0.54 for the 3 Gleason categories. After finishing this test, 90% of genitourinary pathologists considered this approach useful for resident training and 90% for pathology teaching.
We conclude that a Gleason score can be easily assigned to each TMA spot of a 0.6-mm-diameter prostate cancer sample. These data also indicated that using TMA spot images may be a good approach for teaching the Gleason grading system due to the small area of tissue.
Tissue Microarray Sampling Strategy for Prostate Cancer Biomarker Analysis
Mark A. Rubin, M.D.; Rodney Dunn, M.S.; Myla Strawderman, M.S.; Kenneth J. Pienta, M.D.
From the Departments of Pathology (M.A.R.), Urology (M.A.R., R.D., K.J.P.), Internal Medicine (K.J.P.), Division of Hematology/Oncology, Biostatistics (R.D., M.S.), and the University of Michigan Comprehensive Cancer Center (M.A.R., R.D., M.S., K.J.P.), Ann Arbor, Michigan, U.S.A.
Am J Surg Pathol 2002;26:312-319 Abstract quote
High-density tissue microarrays (TMA) are useful for profiling protein expression in a large number of samples but their use for clinical biomarker studies may be limited in heterogeneous tumors like prostate cancer.
In this study, the optimization and validation of a tumor sampling strategy for a prostate cancer outcomes TMA is performed. Prostate cancer proliferation determined by Ki-67 immunohistochemistry was tested. Ten replicate measurements of proliferation using digital image analysis (CAS200, Bacus Labs, Lombard, IL, USA) were made on 10 regions of prostate cancer from a standard glass slide. Five matching tissue microarray sample cores (0.6 mm diameter) were sampled from each of the 10 regions in the parallel study. A bootstrap resampling analysis was used to statistically simulate all possible permutations of TMA sample number per region or sample. Statistical analysis compared TMA samples with Ki-67 expression in standard pathology immunohistochemistry slides. The optimal sampling for TMA cores was reached at 3 as fewer TMA samples significantly increased Ki-67 variability and a larger number did not significantly improve accuracy. To validate these results, a prostate cancer outcomes tissue microarray containing 10 replicate tumor samples from 88 cases was constructed. Similar to the initial study, 1 to 10 randomly selected cores were used to evaluate the Ki-67 expression for each case, computing the 90th percentile of the expression from all samples used in each model.
Using this value, a Cox proportional hazards analysis was performed to determine predictors of time until prostate-specific antigen (PSA) recurrence after radical prostatectomy for clinically localized prostate cancer. Examination of multiple models demonstrated that 4 cores was optimal. Using a model with 4 cores, a Cox regression model demonstrated that Ki-67 expression, preoperative PSA, and surgical margin status predicted time to PSA recurrence with hazard ratios of 1.49 (95% confidence interval [CI] 1.012.20, p = 0.047), 2.36 (95% CI 1.154.85, p = 0.020), and 9.04 (95% CI 2.4233.81, p = 0.001), respectively. Models with 3 cores to determine Ki-67 expression were also found to predict outcome.
In summary, 3 cores were required to optimally represent Ki-67 expression with respect to the standard tumor slide. Three to 4 cores gave the optimal predictive value in a prostate cancer outcomes array. Sampling strategies with fewer than 3 cores may not accurately represent tumor protein expression. Conversely, more than 4 cores will not add significant information.
This prostate cancer outcomes array should be useful in evaluating other putative prostate cancer biomarkers.
CLINICAL VARIANTS/GROSS DISEASE CHARACTERIZATION
Adenocarcinoma of the prostate in men younger than 40 years of age: diagnosis and treatment with emphasis on radical prostatectomy findings.
Ruska KM, Partin AW, Epstein JI, Kahane H.
Department of Pathology, Johns Hopkins University School of Medicine and the James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.
Urology 1999 Jun;53(6):1179-83 Abstract quote
OBJECTIVES: Prostate cancer is rarely diagnosed in men younger than 40 years of age. It is thought, although not documented, that these tumors behave particularly aggressively.
METHODS: We studied 87 men younger than 40 years old who underwent prostate needle biopsy and were from three populations: (a) 71 cases (63 benign, 7 cancer) from Dianon Systems; (b) 9 needle biopsies with cancer sent to one of us (J.I.E.) in consultation; and (c) 7 men with cancer who came to Johns Hopkins for consultation.
RESULTS: The median age of men with a benign biopsy was 35 years (mean 33.9, range 22 to 39); the median age of men with cancer was 38 years (mean 35.9, range 22 to 39) (P = 0.004). The most common indications for biopsy were abnormal digital rectal examination (DRE) (n = 61); elevated prostate-specific antigen (PSA) (n = 14), and inflammatory symptoms (n = 12). Other reasons cited included hematuria, abnormal ultrasound, pain, ejaculatory problems, obstructive symptoms, and family history of prostate cancer. The median PSA was 2.6 ng/mL (mean 4.8, range 0.3 to 66) for all men, 1.2 ng/mL (mean 3.4, range 0.3 to 19.9) for benign cases, and 4.4 ng/mL (mean 8.7, range 2.1 to 66) for cancer (P = 0.0004). Abnormal DRE was not predictive of cancer. Of the 55 patients whose family history was known, 40 men had no family history of prostate cancer, and of those, only 6 (15%) had cancer. Of the 1 5 patients with a family history of cancer, 6 (40%) were found to have cancer on biopsy (P = 0.05). Of the 23 patients with cancer, 3 were lost to follow-up, 1 was treated with hormones, and 3 chose watchful waiting. The remaining 16 patients underwent radical prostatectomy and had diverse pathologic findings. Tumor volume ranged from 0.01 to 6.35 cc. Pathologic stage was pT2 in 9 cases and pT3 in 7 cases (2 with positive pelvic lymph nodes). In 14 men, serum PSA values were available: of 4 men with PSA greater than 10 ng/mL, all had Stage pT3, and of 10 men with PSA less than 10 ng/mL, 3 had Stage pT3.
CONCLUSIONS: Young men who are candidates for radical prostatectomy have potentially curable disease, particularly if PSA at the time of diagnosis is less than 10 ng/mL.
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Capsular invasion-There is no true capsule of the prostate. Instead there is a condensation of fibromuscular tissue the edge of the prostate which acts as a physiologic barrier.
Gleason's Grading/Scoring (Adapted from Urologic Pathology. The Prostate 1977:171-198)
Grade Description 1 Single, separate, uniform glands in closely packed masses with a definite, usually rounded, edge limiting the area of tumor 2 Single, separate, slightly less uniform glands, loosely packed (separated by small amounts of stroma) with less sharp edge 3a Single, separate, much more variable glands, may be closely packed but usually irregularly separated; ragged, poorly defined edge 3b Like 3a, but very small glands or tiny cell clusters 3c Sharply and smoothly circumscribed rounded masses of papillary or loose cribriform tumor (papillary intraductal tumor) 4a Raggedly outlined, raggedly infiltrating, fused glandular tumor 4b Like 4a, with large pale cells (hypernephroid) 5a Sharply circumscribed, rounded masses of almost solid cribriform tumor, usually with central necrosis (comedocarcinoma) 5b Ragged masses of anaplastic carcinoma with only enough gland formation or vacuoles to identify it as adenocarcinoma
Prostate Specific Antigen (PSA)
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