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The treatment of prostate cancer has made tremendous advances over the past decade. Once a certain death sentance, improved detection and treatment modalities have given afflicted men a fighting chance to lead a relatively normal life after the diagnosis.

Prostate Cancer General Information



Androgen Receptor
Atypical Small Acinar Proliferation (ASAP)
Biopsy Tumor Volume
Chromosomal abnormalities
Cysteine Protease Protein 32
Estrogen receptor
Extraprostatic Extension
Gleason Patterns
Lymph Nodes
Matrix Metalloproteinase
Radiation Resistant Foci of Cancer
Vascular Invasion



External Beam Radiation Therapy


Commonly Used Terms  
Internet Links  

PROGNOSIS Stage-see American Joint Committee on Cancer TNM staging below
Incidentally detected prostate cancer in cystoprostatectomies: Pathological and morphometric comparison with clinically detected cancer in totally embedded specimens.

Montironi R, Mazzucchelli R, Santinelli A, Scarpelli M, Beltran AL, Bostwick DG.

Hum Pathol. 2005 Jun;36(6):646-54. Abstract quote  

Summary There are limited data regarding the pathological features of incidentally detected prostate cancer. Examination of cystoprostatectomy specimens obtained during bladder cancer treatment affords a unique opportunity to examine incidentally detected prostate cancer and determine its relationship with clinically detected prostate cancer obtained during radical prostatectomy.

We compared the pathological findings of incidentally detected prostate cancer in 132 consecutive cystoprostatectomy specimens from patients treated for bladder cancer with a consecutive series of 228 radical prostatectomy specimens from patients treated for prostate cancer. All specimens were totally embedded and whole-mounted. Karyometry was evaluated in select subsets of patients from the study groups.

Incidentally detected cancer was found in 42% of cystoprostatectomy specimens, and the cancers were of lower Gleason score and lower pathological stage with fewer positive surgical margins than in clinically detected cancers in age-matched radical prostatectomies. High-grade prostatic intraepithelial neoplasia (PIN) was present in 82% of radical prostatectomy specimens, in 70% of cystoprostatectomies with incidentally detected prostate cancer, and in 54% of cystoprostatectomies without prostate cancer. Mean nuclear and nucleolar area was lower in incidentally detected cancer and PIN when compared with clinically detected cancer and PIN, respectively, similar to the results with proliferative indices.

We conclude that incidentally detected cancer is less aggressive than clinically detected cancer.
Natural history of early, localized prostate cancer.

Johansson JE, Andren O, Andersson SO, Dickman PW, Holmberg L, Magnuson A, Adami HO.

Department of Urology, Orebro University Hospital, Orebro, Sweden.
JAMA. 2004 Jun 9;291(22):2713-9. Abstract quote  

CONTEXT: Among men with early prostate cancer, the natural history without initial therapy determines the potential for survival benefit following radical local treatment. However, little is known about disease progression and mortality beyond 10 to 15 years of watchful waiting.

OBJECTIVE: To examine the long-term natural history of untreated, early stage prostatic cancer.

DESIGN: Population-based, cohort study with a mean observation period of 21 years.

SETTING: Regionally well-defined catchment area in central Sweden (recruitment March 1977 through February 1984).

PATIENTS: A consecutive sample of 223 patients (98% of all eligible) with early-stage (T0-T2 NX M0 classification), initially untreated prostatic cancer. Patients with tumor progression were hormonally treated (either by orchiectomy or estrogens) if they had symptoms.

MAIN OUTCOME MEASURES: Progression-free, cause-specific, and overall survival.

RESULTS: After complete follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P =.01).

CONCLUSION: Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

Early detection of prostate cancer.

Scardino PT.

Urol Clin North Am 1989;16:635–55.

Only 30% of men diagnosed with PCa will ultimately die of their disease and at autopsy up to 71% of men between the ages of 80 and 89 harbor latent PCa

Clinical significance of minimal prostatic adenocarcinoma found on needle biopsy

Am J Clin Pathol 2000;114:896-909
Urology 1999;54:528-532
Amount of tumor in the needle biopsy does not influence grading error-this error is more likely to occur as a result of sampling error and prostate cancer heterogeneity

Most common problem in needle biopsy is undergrading. NOTE, a small amount of tumor in needle biopsy is not equivalent to low-grade tumor. However, minimal high grade (Gleason score of 7 or higher) carcinoma in the needle biopsy was predictive of high grade carcinoma in the whole gland in 79% of cases

A small amount of carcinoma in the needle biopsy does not predict a small amount of cancer in the entire gland, even if 6 core biopsy specimens are obtained. These 6 biopsies only sample 0.03% of all prostate gland tissue

Perineural Invasion and MIB-1 Positivity in Addition to Gleason Score Are Significant Preoperative Predictors of Progression After Radical Retropubic Prostatectomy for Prostate Cancer.

Sebo TJ, Cheville JC, Riehle DL, Lohse CM, Pankratz VS, Myers RP, Blute ML, Zincke H.

Departments of Laboratory Medicine and Pathology (T.J.S., J.C.C., D.L.R.), Health Sciences Research (C.M.L., V.S.P.), and Urology (R.P.M., M.L.B., H.Z.), Mayo Clinic, Rochester, Minnesota, U.S.A.


Am J Surg Pathol 2002 Apr;26(4):431-9 Abstract quote

We assessed the use of clinical stage, serum prostate specific antigen, DNA ploidy, proliferation, and traditional histologic findings from the biopsy to predict prostate cancer progression after radical retropubic prostatectomy. Between 1995 and 1998, 454 consecutive patients with cancer on biopsy were treated by radical retropubic prostatectomy.

Preoperative serum prostate specific antigen, clinical stage, Gleason score, percentage of cores and surface area positive for cancer, perineural invasion, and DNA ploidy and MIB-1 immunostain quantitation by image analysis were evaluated in a multivariate Cox proportional hazards regression model to predict cancer progression. Cancer progression was defined as a postoperative serum prostate specific antigen level of >/=0.4 ng/mL, local recurrence, or systemic progression. Mean follow-up was 3.4 years (range 17 days to 5.8 years). Cancer progression was observed in 73 patients with a mean time to progression of 2.1 years (range 33 days to 5.1 years). Gleason score (p <0.001), MIB-1 cancer proliferation (p = 0.008), and perineural invasion (p = 0.008) were significantly associated with progression. Patients with cancer Gleason scores of 7 and >7 had a 2.5-fold and nearly 4-fold increased risk, respectively, of cancer progression compared with patients with cancer Gleason scores of </=6. Patients with perineural invasion at biopsy were twice as likely to progress compared with patients without perineural invasion. Each 1-unit increase in MIB-1 on the natural logarithmic scale increased the risk of cancer progression by 64%.

Cancer progression models that include serum prostate specific antigen and clinical stage may require revision to incorporate perineural invasion and MIB-1 proliferative activity in addition to Gleason score.

Current Thoughts on the Role of the Androgen Receptor and Prostate Cancer Progression.

Setlur SR, Rubin MA.

From the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and Harvard Medical School, Boston, Massachusetts.

Adv Anat Pathol. 2005 Sep;12(5):265-270. Abstract quote  

Androgens play a central role in the development and maintenance of prostate tissue. Treatment of prostate cancer by androgen ablation either surgically or biochemically results in massive cell death and tumor regression. However, this is often followed by the onset of aggressive disease, which is fatal. Various studies have been conducted to understand the mechanism leading to the establishment of aggressive disease following treatment.

An interesting comprehensive study recently conducted by Chen et al shows the increase in androgen receptor (AR) transcript to be the key factor in disease recurrence following treatment. This up-regulation in the AR levels is shown to increase sensitivity to low levels of androgen, leading to ligand-dependent downstream gene expression and tumor recurrence. A "mass action" model has been proposed to explain this phenomenon. Moreover, the increase in mRNA levels has been shown to facilitate conversion of classic antagonists to agonists of hormones action by the recruitment of a subset of co-activators to the promoters of AR-responsive genes.

This study underscores the importance of ARs in the establishment of prostate cancer and offers several insights into the mechanism by which tumors recur following androgen ablation. The study also prompts several questions about the reason behind the observed up-regulation and also the mechanism by which classic antagonists are rendered agonistic. The need for the design of novel therapeutic analogues is also emphasized.

High Level of Androgen Receptor Is Associated With Aggressive Clinicopathologic Features and Decreased Biochemical Recurrence-free Survival in Prostate: Cancer Patients Treated With Radical Prostatectomy.

Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G.

*Department of Pathology and the daggerScott Department of Urology, Baylor College of Medicine, Houston, TX.
Am J Surg Pathol. 2004 Jul;28(7):928-934. Abstract quote  

BACKGROUND:: Prostate cancer (PCa) is androgen dependent and is regulated by androgen/androgen receptor (AR) signaling pathway. However, the clinical significance of AR is in question. In this regard, we have correlated levels of AR expression with some well-established clinical and pathologic parameters and assessed the prognostic value of AR expression in PCa patients treated with radical prostatectomy.

DESIGN:: A total of 640 cases treated with radical prostatectomy were used to build tissue microarrays. Normal prostate tissue, benign prostatic hyperplasia, and index tumor were cored in triplicate (0.6 mm). An array (2 mm) of 177 metastatic PCa was built as well. Slides were immunostained with an antibody to AR and Ki-67 and digitized. Correlations between AR expression and clinicopathologic variables were analyzed by the Spearman test. Biochemical recurrence-free survival analysis was performed using Kaplan-Meier analysis, and Cox proportional hazard regression was used to determine the probability of disease recurrence.

RESULTS:: AR was found in epithelial nuclei of both benign and cancer tissues. AR index was higher in normal prostate tissues than that in PCa and benign prostatic hyperplasia and decreased in metastases than PCa. High level of AR expression was correlated with clinical stage, lymph node status, extracapsular extension, seminal vesicle invasion, and Gleason score. High levels of AR status also correlated with high Ki-67 index (r = 0.211, P = 0.0000). By Kaplan-Meier actuarial model, high expression of AR was predictive of a higher probability of recurrence (P = 0.0046, hazards ratio 2.72 [confidence interval 1.28-4.011]). By multivariate analysis, a high level of AR expression was an independent prognostic indicator of biochemical recurrence-free survival (P = 0.0042; hazards ratio 2.422 [confidence interval 1.32-4.44]).

CONCLUSIONS:: High levels of AR are associated with increased proliferation, markers of aggressive disease and are predictive of decreased biochemical recurrence-free survival independently. This confirms the role of AR in tumor growth and progression in hormonally naive PCa.
Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care.

Epstein JI, Herawi M.

Department of Pathology, The Johns Hopkins University School of Medicine, The James Brady Urological Institute, The Johns Hospital, Baltimore, Maryland 21231, USA.
J Urol. 2006 Mar;175(3 Pt 1):820-34. Abstract quote  

PURPOSE: We identified information critical for patient treatment on prostate needle biopsies diagnosed with prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma.

MATERIALS AND METHODS: A search was performed using the MEDLINE database and referenced lists of relevant studies to obtain articles addressing the significance of finding PIN or atypical foci suspicious for carcinoma on needle biopsy.

RESULTS: There were certain results concerning PIN. 1) Low grade PIN should not be documented in pathology reports due to poor interobserver reproducibility and a relatively low risk of cancer following re-biopsy. 2) The expected incidence of HGPIN on needle biopsy is between 5% and 8%. 3) Although the diagnosis of HGPIN is subjective, interobserver reproducibility for its diagnosis is fairly high among urological pathologists, and yet only moderate among pathologists without special expertise in prostate pathology. 4) The median risk recorded in the literature for cancer following the diagnosis of HGPIN on needle biopsy is 24.1%, which is not much higher than the risk reported in the literature for repeat biopsy following a benign diagnosis. 5) The majority of publications that compared the risk of cancer in the same study following a needle biopsy diagnosis of HGPIN to the risk of cancer following a benign diagnosis on needle biopsy show no differences between the 2 groups. 6) Clinical and pathological parameters do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. 7) A major factor contributing to the decreased incidence of cancer following a diagnosis of HGPIN on needle biopsy in the contemporary era is related to increased needle biopsy core sampling, which detects many associated cancers on initial biopsy, such that re-biopsy, even with good sampling, does not detect many additional cancers. 8) It is recommended that men do not need routine repeat needle biopsy within the first year following the diagnosis of HGPIN, while further studies are needed to confirm whether routine repeat biopsies should be performed several years following a HGPIN diagnosis on needle biopsy. There were certain results concerning atypical glands suspicious for carcinoma. 1) An average of 5% of needle biopsy pathology reports are diagnosed as atypical glands suspicious for carcinoma. 2) Cases diagnosed as atypical have the highest likelihood of being changed upon expert review and urologists should consider sending such cases for consultation in an attempt to resolve the diagnosis as definitively benign or malignant before subjecting the patient to repeat biopsy. 3) Ancillary techniques using basal cell markers and AMACR (alpha-methyl-acyl-coenzyme A racemase) can decrease the number of atypical diagnoses, and yet one must use these techniques with caution since there are numerous false-positive and false-negative results. 4) The average risk of cancer following an atypical diagnosis is approximately 40%. 5) Clinical and pathological parameters do not help predict which men with an atypical diagnosis have cancer on repeat biopsy. 6) Repeat biopsy should include increased sampling of the initial atypical site, and adjacent ipsilateral and contralateral sites with routine sampling of all sextant sites. Therefore, it is critical for urologists to submit needle biopsy specimens in a manner in which the sextant location of each core can be determined. 7) All men with an atypical diagnosis need re-biopsy within 3 to 6 months.

CONCLUSIONS: It is critical for urologists to distinguish between a diagnosis of HGPIN and that of atypical foci suspicious for cancer on needle biopsy. These 2 entities indicate different risks of carcinoma on re-biopsy and different recommendations for followup.

Survivin and Bcl-2 expression in prostatic adenocarcinomas.

Kaur P, Kallakury BS, Sheehan CE, Fisher HA, Kaufman RP Jr, Ross JS.

Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
Arch Pathol Lab Med. 2004 Jan;128(1):39-43. Abstract quote  

CONTEXT: Dysregulated cell proliferation caused by inhibitors of programmed cell death (apoptosis) contributes to tumor progression and spread. Aberrant expression of Bcl-2, the most notable inhibitor of apoptosis, has been well characterized in several human malignancies. Recent studies have described a novel apoptosis inhibitor, survivin, in human carcinomas, although its exact role remains to be characterized.

OBJECTIVE: The purpose of this study was to evaluate the immunohistochemical expression of Bcl-2 and survivin proteins in prostate cancer and to correlate the results with clinicopathologic variables.

DESIGN: Formalin-fixed, paraffin-embedded tissue sections from 138 cases of prostatic adenocarcinomas (PACs) were immunostained by an automated method using specific antibodies against survivin and Bcl-2. Staining was semiquantitatively scored based on both intensity and distribution, and results were correlated with morphologic and prognostic variables.

RESULTS: Of the 138 PACs tested, 113 (82%) expressed survivin. We found no correlation between survivin expression and prognostic variables, including grade, stage, DNA content (ploidy), and recurrence. Bcl-2 expression was positive in 95 (69%) of these 138 cases and correlated with nondiploid DNA content. Fourteen (50%) of 28 nondiploid PACs expressed Bcl-2, compared to 17 (25%) of 68 diploid tumors (P =.02). A trend for association of Bcl-2 expression with tumor stage was noted as follows: 21 (39%) of 54 advanced-stage PACs expressed Bcl-2, in comparison with 20 (24%) of 84 low-stage tumors (P =.07). On univariate analysis, 25 (48%) of the 52 PACs that recurred expressed Bcl-2, as compared with 16 (19%) of the 86 nonrecurrent PACs (P <.001). No correlation was noted between survivin and Bcl-2 expression.

CONCLUSION: Survivin is expressed in a majority of PACs and is not a prognosis-related marker, but may be a potential target for apoptosis-based therapy. Overexpression of Bcl-2 correlates with other prognostic variables and predicts disease recurrence of PACs. These data also suggest that survivin and Bcl-2 may regulate cell proliferation and cell death through different mechanisms.

A streamlined three-dimensional volume estimation method accurately classifies prostate tumors by volume.

Chen ME, Johnston D, Reyes AO, Soto CP, Babaian RJ, Troncoso P
Am J Surg Pathol. 2003 Oct;27(10):1291-301. Abstract quote  

SUMMARY: Prostate tumor volume has been suggested to be an important pathologic variable that predicts for clinical significance and outcome. However, the determination of tumor volume using standard methods such as computerized planimetry or image analysis is labor intensive. We studied whether length (L), width (W), and height (number of cross sections x sectional thickness, CST) of a tumor focus could be used to estimate prostate tumor volume. We studied 1091 tumor foci from 365 selected serially sectioned radical prostatectomy specimens. We randomly divided the specimens into evaluation (182 specimens) and validation (183 specimens) groups. After analyzing the evaluation group, we derived the formula 0.4 (slope of the regression line) x L x W x CST to estimate volume.

We then tested whether our three-dimensional volume estimation formula could accurately classify tumor volume for specimens in the validation set as insignificant (</=0.5 cm3) or significant (>0.5 cm3), and also into a five-category tumor volume scheme. Our three-dimensional estimate accurately classified tumors into insignificant and significant total volume categories in 94.0% of cases and into the five-category scheme in 85.8% cases.

These accuracy rates were significantly better than rates for other methods. The three-dimensional estimate is an accurate and straightforward method for assessing prostate tumor volume.
Predicting Tumor Volume in Radical Prostatectomy Specimens From Patients With Prostate Cancer

Lori E. Eichelberger, MD, Michael O. Koch, MD, Joanne K. Daggy, MS, Thomas M. Ulbright, MD, John N. Eble, MD, and Liang Cheng, MD
Am J Clin Pathol 2003:120:386-391 Abstract quote

Tumor volume has prognostic value in numerous malignant neoplasms; however, the determination of tumor volume in prostatic adenocarcinoma remains problematic. We tested the hypothesis that the diameter of the largest focus of carcinoma in whole-mount prostate sections predicts the volume of adenocarcinoma in the entire prostate.

We evaluated 184 radical prostatectomy specimens by whole-mount processing of the entire prostate. The maximum diameter of the largest focus of carcinoma was measured directly on glass slides. Tumor volume in the entire prostate was calculated by the grid method. The maximum tumor diameter ranged from 0.1 to 4.1 cm (median, 1.6 cm). The total tumor volume ranged from 0.1 to 12.5 cm 3 (median, 1.6 cm 3 ). There were significant correlations between maximum tumor diameter and tumor volume (Spearman correlation coefficient = 0.84; P < .0001), surgical margin status ( P < .001), perineural invasion ( P < .001), serum prostate-specific antigen level at diagnosis ( P = .004), Gleason score ( P = .004), and pathologic stage ( P < .0001).

Maximum tumor diameter is a predictor of tumor volume and might be useful for the assessment of tumor volume in routinely processed prostatectomy specimens.

Multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population.

Bismar TA, Lewis Jr JS, Vollmer RT, Humphrey PA.


Am J Surg Pathol 2003 Apr;27(4):432-40 Abstract quote

The capacity of perineural invasion by carcinoma in prostate needle biopsy tissue to independently predict pathologic stage in radical prostatectomy tissues remains uncertain.

We sought to determine, in a prostate specific antigen-based screening population, the ability of needle biopsy histologic grade, tumor extent, and perineural invasion to independently predict pathologic stage and margin status in the whole prostate gland. Perineural invasion, Gleason grade, percentage Gleason pattern 4/5 carcinoma, and multiple measures of needle biopsy tumor extent, including number of positive cores, percentage of positive cores, total percentage of carcinoma, greatest percentage of carcinoma in a single core, and total carcinoma length in millimeters, were captured for 215 men from a prostate specific antigen-based screening program diagnosed with prostate cancer in a median of six procured needle biopsy cores. Pathologic stage and surgical margin status were evaluated in corresponding completely embedded radical prostatectomy specimens. A logistic regression model was used to relate the endpoints of extraprostatic extension by carcinoma and/or positive margins to needle biopsy tissue findings.

In univariate analyses, total percentage of carcinoma (p = 0.003), greatest percentage of carcinoma in a single core (p = 0.004), total tumor length in millimeters (p = 0.009), and fraction of positive cores (p = 0.02) were all significantly associated with extraprostatic (pT3) carcinoma, whereas all five measures of carcinoma extent in needle biopsy tissue were related to positive margins. Correlation coefficient determinations showed that all five measures of needle biopsy carcinoma extent were highly interrelated. In multivariate analyses, total percentage of carcinoma was significantly related to pathologic T stage (p = 0.003) and positive margins (p = 0.0002).

In a multivariate model with the radical prostatectomy whole gland endpoint of either pT3 disease or positive margins, fraction of positive cores (p = 0.00001) was the only variable with significant predictive value. Perineural invasion by carcinoma in needle biopsy tissue was detected in 11% of cases.

Neither presence nor absence of perineural carcinoma nor number nor percentage of positive nerves related to pathologic stage in univariate or multivariate analyses. Amount of carcinoma in prostate needle biopsy tissue, using multiple measurements but not perineural invasion, is a significant histologic attribute predictive of pathologic stage and margin status for men with prostate specific antigen screening detected prostatic carcinoma. Reporting of several measures of carcinoma extent in needle biopsy tissue is recommended.

Percent of cancer in the biopsy set predicts pathological findings after prostatectomy.

Grossklaus DJ, Coffey CS, Shappell SB, Jack GS, Chang SS, Cookson MS.

Department of Urologic Surgery and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.


J Urol 2002 May;167(5):2032-5; discussion 2036 Abstract quote

PURPOSE: The ability to use pretreatment variables to identify patients with organ confined prostate cancer continues to challenge physicians. We examined information available preoperatively, including prostate needle biopsy, clinical stage and preoperative prostate specific antigen (PSA), and evaluated these data based on pathological variables after radical retropubic prostatectomy.

MATERIALS AND METHODS: We reviewed results in 135 consecutive patients who underwent radical retropubic prostatectomy at a single institution. Needle biopsy information, such as the number of cores, percent of tumor per biopsy set, laterality of positive cores and Gleason sum, were compared with pathological data on the radical retropubic prostatectomy specimen, including pathological stage, Gleason sum and tumor volume. Clinical data, including biopsy information and pathological findings, were compared using univariate and multivariate models.

RESULTS: Overall total PSA, percent of tumor in the biopsy and bilateral positive cores directly correlated with tumor volume (p <0.01). Also, increasing PSA, increasing percent of tumor in the biopsy and bilateral positive cores were associated with increased risks of extracapsular extension (p <0.01).

CONCLUSIONS: From the information readily available from prostate needle biopsy these results suggest that percent of tumor in the biopsy is a useful predictor of pathological stage and tumor volume. Furthermore, including percent of tumor in the biopsy set and bilateral disease with traditional variables such as serum PSA and clinical stage may improve pretreatment tumor staging. This finding adds additional credence to the inclusion of percent of tumor in the biopsy set in models for the preoperative prediction of pathological stage and should be factored into discussions with patients on treatment options.

The Influence of Percentage of Preradiation Needle Biopsies With Adenocarcinoma and Total Radiation Dose on the Pathologic Response of Unfavorable Prostate Adenocarcinoma

Neal S. Goldstein, MD
Larry L. Kestin, MD
Frank A. Vicini, MD
and Alvaro A. Martinez, MD

Am J Clin Pathol 2002;117:927-934 Abstract quote

We studied relationships among clinicopathologic factors in 78 patients with unfavorable prostate adenocarcinoma treated in a dose-escalation radiation therapy (RT) study using pre- and 18-month protocol post-RT biopsy specimens. Pre-RT factors analyzed were serum prostate-specific antigen (PSA) level, Gleason score, and percentage of needle cores with adenocarcinoma; post-RT factors were percentage of needle cores with adenocarcinoma and amount of radiation effect on the adenocarcinoma.

Of 78 patients, 42 (54%) had residual adenocarcinoma in the post-RT biopsy specimen. Lower total RT dose and dose per implant and greater serum PSA level were associated with an increasing percentage of needle cores with residual post-RT adenocarcinoma. Lower RT dose, an increasing percentage of pre-RT needle cores with adenocarcinoma, and a greater serum PSA level were associated with an increasing percentage of post-RT needle cores with no to moderate RT effect scores in adenocarcinoma.

The mean percentage of pre-RT and post-RT needle cores with adenocarcinoma was greater in patients with post-RT biopsy specimens with no to moderate RT effect.


Down-regulation of CEACAM1 in human prostate cancer: Correlation with loss of cell polarity, increased proliferation rate, and Gleason grade 3 to 4 transition.

Busch C, Hanssen TA, Wagener C, oBrink B.

Department of Pathology, University Hospital, Tromso, Norway, Department of Clinical Chemistry, University Hospital Eppendorff, Hamburg, Germany, Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden.

Hum Pathol 2002 Mar;33(3):290-8 Abstract quote

Many cancers have altered expression of various cell adhesion molecules. One of these is CEACAM1, which has been found to be downregulated in several carcinomas, including prostate cancer.

We explored its immunohistochemical expression in a set of 64 total prostatectomy specimens and compared it with that of the epithelial cell adhesion molecule E-cadherin and occludin, a tight junction-associated molecule. The luminal surface of the epithelial cells of normal prostate glands and ducts showed a dense expression of CEACAM1. This pattern prevailed in prostate cancer of Gleason grades 1 to 3 as long as the cells maintained their polarity and formed individual glands. With "fusion" of glands (ie, in the transition to Gleason grade 4), the expression of CEACAM1 was lost in polygonal nonpolar cells and was lost or focally very weak in cells lining a lumen in the cribriform complexes. E-cadherin, which outlined the basolateral cell membranes of contacting neighboring epithelial cells was also downregulated in prostate carcinomas. However, the loss of E-cadherin expression in higher grades was gradual and not related to the Gleason 3 to >4 transition. Occludin was also lost in polygonal (ie, unpolarized) cells of Gleason grades 4 and 5, but remained expressed in all cells facing a lumen in all grades of cancer, which CEACAM1 was not.

In conclusion, downregulation of CEACAM1 as well as that of occludin in prostate cancer is associated with loss of cell polarity. It coincides with the formation of the complex glandular architecture of Gleason grade 4 pattern or complete loss thereof in Gleason grade 5 patterns. The proliferative activity, measured as Ki67 labeling index, showed a fourfold increase in the carcinoma cells with lost CEACAM1 expression, supporting previous observations that CEACAM1 regulates cell proliferation. Immunohistochemical analysis of CEACAM1 expression patterns may be useful in assessment of the malignant potential of prostate carcinoma.


Aneusomy of chromosomes 7, 8, and 17 and amplification of HER-2/neu and epidermal growth factor receptor in Gleason score 7 prostate carcinoma: A differential fluorescent in situ hybridization study of Gleason pattern 3 and 4 using tissue microarray

Marek Skacel, MD
Adrian H. Ormsby, MBChB
James D. Pettay
Evangelos K. Tsiftsakis, MD
Louis S. Liou, MD, PhD
Eric A. Klein, MD
Howard S. Levin, MD
Craig D. Zippe, MD
Raymond R. Tubbs, DO

Hum Pathol 32:1392-1397. Abstract quote

Recent evidence shows that the proportion of poorly differentiated prostate carcinoma (Gleason pattern [GP] 4/5) is a surrogate factor for biochemical failure after radical prostatectomy (RP). However, little is known about specific molecular and cytogenetic changes in this aggressive component of localized prostate cancer.

We constructed a tissue microarray containing areas of GP 3 and 4 from formalin-fixed radical prostatectomy specimens of 39 patients with Gleason score 7 carcinoma (50% GP 4), known pathologic staging parameters (stage < T3b), and biochemical failure data (mean follow-up, 30 months; range, 5 to 74 months). Interphase fluorescent in situ hybridization (FISH) was performed on 5-µm microarray sections using pericentromeric probes to chromosomes 7, 8, and 17 and probes for the HER-2/neu and epidermal growth factor receptor (EGFR) genes.

Low-level amplification of HER-2/neu was found in 26% of cases (3 to 5 signals per nucleus, corrected for chromosome 17 aneusomy). Aneusomy of chromosomes 7, 8, and 17 was identified in 21%, 15%, and 5% of cases, respectively. All aberrations occurred almost exclusively in GP 4 carcinoma (8 of 8 aneusomies 7, 2 of 2 trisomies 17, 9 of 10 HER-2/neu amplifications, and 5 of 6 aneusomies 8; P < .001). The presence of HER-2/neu amplification was associated with high tumor volume (>2.0 cm3, P = 0.004). Among patients with negative surgical margins, gain of chromosome 7 was associated with biochemical failure after RP (P = .004, log-rank). Amplification of the EGFR gene occurred in only 1 case (3%). Significant differences in HER-2/neu amplification and gain of chromosomes 7, 8, and 17 were detected between GP 4 prostate carcinoma and GP 3. The frequency of aberrations increased with tumor volume.

Chromosome 7 abnormalities may play an important role in cancer progression in margin-negative patients. EGFR amplification was rare, suggesting that this oncogene is not altered at the gene copy number level.

Expression of cysteine protease protein 32 in prostatic adenocarcinoma correlates with tumor grade.

Anwar S, Ambros RA, Jennings TA, Ross JS, Beza A, Mian B, Nazeer T.

Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
Arch Pathol Lab Med. 2004 Jun;128(6):649-52. Abstract quote  

CONTEXT: Controlled cell death is mediated by apoptosis-specific genes, tumor suppressor genes, and oncogenes. The caspase family is a group of at least 15 known cysteine proteases that serve as initiator and effector molecules of the apoptosis pathway. On activation, caspases cause cell shrinkage, condensation of chromatin, fragmentation of DNA, and the formation of blebs in the cytoplasmic membrane.

OBJECTIVES: The patterns of cysteine protease protein (CCP) 32 (caspase-3) expression have been determined in normal human tissues and a variety of tumors, and have been shown to correlate with the outcome in breast cancer and linked to resistance to chemotherapy in other tumors. This study was performed to determine whether CPP32 is expressed in prostatic adenocarcinoma and to define its relationship with outcome variables.

DESIGN: Formalin-fixed, paraffin-embedded radical prostatectomy specimens from 211 patients with prostatic adenocarcinoma were evaluated for CPP32 expression by immunohistochemistry. Hematoxylin-eosin-stained slides were reviewed, and tumors were graded based on the Gleason grading system. Tumors were scored for CPP32 expression semiquantitatively, based on the staining intensity and distribution patterns. These results were compared with Gleason grade and clinical and pathologic stages.

RESULTS: One hundred thirty-three (63%) of 211 cases showed high expression of CPP32, whereas expression was low in 78 (37%) cases. One hundred three (49%) of 211 cases had a high Gleason score (7 and above). Of 103 cases with a high Gleason score, 74 (72%) showed high CPP32 expression. Strong cytoplasmic staining for CPP32 in high-grade tumors was statistically significant (P =.01). Also, by linear regression analysis a significant correlation was seen between the Gleason score and the cytoplasmic CPP32 expression (P =.001). Expression of CPP32 did not correlate with either clinical stage (P =.28) or pathologic stage (P =.60); however, this study included very few patients with stage IV disease.

CONCLUSION: The correlation between CPP32 and high tumor grade suggests a CPP32-related high turnover rate in high-grade prostatic adenocarcinoma. Moreover, strong correlation with Gleason grade, a powerful predictor of disease progression and overall survival, suggests potential usefulness of CPP32 as a prognostic factor, especially in limited biopsy samples.

E-cadherin expression in prostate cancer: A broad survey using high-density tissue microarray technology

Mark A. Rubin, MD Neil R. Mucci, BS Jay Figurski, BS Alice Fecko, BA Kenneth J. Pienta, MD Mark L. Day, PhD

Hum Pathol 2001;32:690-697. Abstract quote

E-cadherin is a calcium 2+–dependent cell-adhesion molecule that determines epithelial development in the embryo and maintains adult differentiated epithelium and homeostasis. Aberrant or decreased expression has been reported to be associated with prostate carcinoma progression. The degree of E-cadherin expression in prostate cancer remains controversial. Some studies have reported decreased expression of E-cadherin as tumors advance and metastasize. Other studies have not demonstrated this relationship.

To address these variations, we undertook a study to systematically evaluate E-cadherin expression in a broad range of prostate tissue. Benign prostate, clinically localized prostate cancer, and hormone-refractory metastatic prostate cancer were analyzed under uniform conditions using high-density tissue microarrays (TMA).

Formalin-fixed, paraffin-embedded prostate carcinoma from men with clinically localized prostate carcinoma and autopsy material from men who died of widely metastatic, hormone-refractory prostate carcinoma were arrayed into 6 high-density TMA blocks. Benign and atrophic prostate tissue and high-grade prostatic intraepithelial neoplasia (PIN) were also included from the clinically localized cases. Immunohistochemistry was performed using the immunoglobulin G1 mouse monoclonal antibody (HECD-1; Zymed, San Francisco, CA). Membranous staining was recorded as low (aberrant) or high (normal). E-cadherin expression was considered aberrant if less than 70% of the cells had strong membranous staining. A total of 1,220 prostate TMA samples were analyzed. High (normal) E-cadherin expression was seen in 87% of 757 benign, 80% of 41 high-grade PIN, 82% of 325 prostate carcinoma and 90% of 97 hormone-refractory prostate carcinoma TMA samples. Mean E-cadherin expression was determined for each of the 128 clinically localized prostate cancer cases. Aberrant E-cadherin expression showed a statistical trend toward an association with positive surgical margins (P = .012), higher Gleason score (P = .18), and prostate-specific antigen (PSA) failure (Kaplan-Meier analysis, log-rank P = .09). There was a statistically significant association between aberrant E-cadherin expression and larger tumor size (P = .01). No significant associations were seen with extraprostatic extension and seminal vesicle invasion.

The current study shows a broad-spectrum approach to evaluating E-cadherin protein expression in prostate carcinoma. Clinically localized prostate tumors, treated with surgery alone, show a high level of E-cadherin expression. Aberrant expression was identified in tumors with positive surgical margins, higher Gleason score, and a higher rate of PSA failure. However, these trends were not statistically significant. A statically significant association between aberrant E-cadherin expression and larger tumor size was identified. In the metastatic hormone-refractory prostate tumors, E-cadherin expression was vastly expressed, and only rare cases had aberrant expression. Therefore, the findings of this study are most consistent with a transient down-regulation of E-cadherin in localized prostate cancer. Metastatic prostate cancer shows strong E-cadherin expression as determined by anti-E-cadherin antibody HECD-1.


Prostate carcinoma expression of estrogen receptor-beta as detected by PPG5/10 antibody has positive association with primary Gleason grade and Gleason score.

Torlakovic E, Lilleby W, Torlakovic G, Fossa SD, Chibbar R.

Departments of Pathology and Oncology, Norwegian Radium Hospital, Oslo, Norway, and the Department of Pathology, Royal University Hospital, Saskatoon, Canada.

Hum Pathol 2002 Jun;33(6):646-51 Abstract quote

The objective of this study was to study the expression of estrogen receptor-beta (ER-beta) in prostatic adenocarcinoma and correlate it with Gleason grade and clinical outcome. Immunohistochemical evaluation was performed on prostate needle biopsies from 53 patients (T1-T3pN0M0).

ER-beta and ER-alpha transcripts were also studied by semiquantitative reverse transcriptase polymerase chain reaction in PC-3 and LNCaP prostate carcinoma cell lines. ERbeta was expressed in 93% of adenocarcinomas and was positively associated with primary Gleason grade (P = 0.028 for percentage of positive cells and P = 0.046 using a semiquantitative scale) and Gleason score (P = 0.010 for percentage of positive cells and P = 0.014 using a semiquantitative scale). ER-beta expression in the benign epithelium of prostates with adenocarinoma was detected in 92% of cases and in the stroma in 47% of cases. A trend for longer time to treatment failure was noted for cases with low ER-beta expression after curatively intended radiotherapy (P = 0.082). PC-3, an aggressive prostate cancer cell line with invasive properties in nude mice, expressed higher levels of ER-beta than LNCaP, a nonmetastasizing cell line, whereas no difference for ER-alpha transcripts could be observed.

Our findings suggest that ER-beta, as detected by PPG5/10 antibody, may have a role in the process of dedifferentiation of prostate adenocarcinomas, with higher levels present in less differentiated tumors.

Radial Distance of Extraprostatic Extension Measured by Ocular Micrometer is an Independent Predictor of Prostate-specific Antigen Recurrence: A New Proposal for the Substaging of pT3a Prostate Cancer.

Departments of *Pathology and Laboratory Medicine parallelUrology, Indiana University School of Medicine, Indianapolis, Indiana daggerDepartment of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center double daggerChang Gung University College of Medicine, Kaohsiung, Taiwan section signDepartment of Biostatistics, Yale University, New Haven, CT.


Am J Surg Pathol. 2007 Feb;31(2):311-318. Abstract quote

Extraprostatic extension is an unfavorable prognostic factor for prostate cancer. Consequently, it has been assigned to pT3a in the current 2002 tumor, lymph node, metastasis staging system.

The aim of our study is to analyze the extent of extraprostatic extension by 8 quantitative methods and to determine which is best for substaging of pT3a tumors.

We studied 83 patients with extraprostatic extension after radical prostatectomy for clinically localized prostatic adenocarcinoma. The extent of extraprostatic extension was evaluated using 8 quantitative methods. Univariate and multivariate analyses were performed to determine which measurement best predicts prostate-specific antigen (PSA) recurrence. In the univariate analysis, the radial distance of extraprostatic tumor measured by ocular micrometer was associated with PSA recurrence (P=0.02). No significant association was observed between PSA recurrence and other measurements of extraprostatic extension, including focal versus established extraprostatic extension using Epstein's criterion, focal versus established extraprostatic extension using Wheeler's modified criterion, the number of extraprostatic neoplastic glands, unilateral versus bilateral involvement, circumferential length of extraprostatic tumor, unifocal versus multifocal involvement, and volume of extraprostatic tumor.

In the multivariate analysis, radial distance remained an independent predictor of PSA recurrence (hazard ratio, 2.4; 95% confidence interval, 1.12-5.01; P=0.02). The radial distance of the extraprostatic extension measured by ocular micrometer is an independent prognostic factor for pT3 prostate cancer. Two-year and 4-year PSA recurrence-free survival was 62% and 35%, respectively, for those patients with radial distance <0.75 mm, as compared with 35% and 18%, respectively, for those with radial distance >/=0.75 mm.

We recommend reporting this parameter routinely for radical prostatectomy specimens. The strength of its prognostic value for PSA recurrence makes it a potential criterion for incorporation into a future tumor, lymph node, metastasis staging system.
Preoperative prediction of Gleason grade in radical prostatectomy specimens: the influence of different Gleason grades from multiple positive biopsy sites.

Poulos CK, Daggy JK, Cheng L.

1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Mod Pathol. 2004 Oct 08 Abstract quote

The Gleason score of prostate adenocarcinomas is an important preoperative predictor of cancer behavior, and is used to help guide treatment. In the setting of more than two positive biopsy sites, pathologists usually grade the tumor at each site separately, and the Gleason score may differ from each positive site.

This study seeks to determine if the highest Gleason score in all biopsy sites, or the Gleason score in the site with the highest tumor volume on the needle biopsy is the best predictor of final Gleason score in the radical prostatectomy specimens. Various preoperative biopsy findings were analyzed. All 151 patients had at least two positive biopsy sites and underwent radical prostatectomy. Primary and secondary Gleason pattern grades were assigned for each positive biopsy site. The tumor volume in the needle biopsy site was defined by the percentage of areas of biopsy cores involved by cancer. The radical prostatectomy specimens were completely embedded and processed in the whole-mount method. The Gleason score from both the biopsy site with the highest Gleason score and the biopsy site with the highest tumor volume on the needle biopsy correlated equally well with final Gleason score at radical prostatectomy (Spearman correlation coefficient =0.54 for both, P<0.001). The Gleason score from both the biopsy site with the highest Gleason score and the biopsy site with the highest tumor volume on the needle biopsy also correlated with primary Gleason pattern grade at radical prostatectomy (Spearman correlation coefficient =0.53 for both, P<0.001). Secondary Gleason pattern grade from the biopsy site with the highest tumor volume on the needle biopsy correlated with secondary Gleason pattern grade at radical prostatectomy slightly better than those from the biopsy site with the highest Gleason score (Spearman correlation coefficient, 0.32 vs 0.24; both P<0.001).

Our data indicate that the highest Gleason score from all sites and the Gleason score from the site with the highest tumor volume on the needle biopsy are equally and significantly predictive of final Gleason score on radical prostatectomy. Both methods of prediction are significantly predictive of primary and secondary Gleason pattern grade on radical prostatectomy.

We recommend that the highest Gleason score from all positive biopsy sites should be used when assigning an initial score using needle biopsies.

The Prognostic Significance of Tertiary Gleason Pattern 5 in Radical Prostatectomy Specimens

Mosse, Claudio A MD, PHD; Magi-Galluzzi, Cristina MD; Tsuzuki, Toyonori MD; Epstein, Jonathan I MD

From the Department of Pathology, Johns Hopkins Hospital, Baltimore, MD.

American Journal of Surgical Pathology : Volume 28(3) March 2004 pp 394-398 Abstract quote

In the Gleason grading system for prostatic cancer only the two most prevalent patterns are reported, although a third (tertiary) pattern grade may be present.

We compared the pathologic stage of 227 radical prostatectomies with tertiary pattern 5 to the pathologic stage of 604 radical prostatectomies lacking a tertiary component. Gleason score 3 + 4 tumors with a tertiary pattern of 5 were more likely to present with higher stage disease than those Gleason score 3 + 4 tumors without a tertiary component ( P = 0.012) and at a stage similar to Gleason score 3 + 5 tumors. Gleason score 4 + 3 tumors with a tertiary pattern of 5 were less likely to be organ-confined than Gleason score 4 + 3 tumors ( P = 0.02) and less likely to have lymph node metastases than Gleason score 4 + 4 tumors ( P = 0.027).

However, Gleason score 4 + 4 with a tertiary pattern of 5 were indistinguishable from Gleason score 4 + 4 tumors. The relative effects of a tertiary pattern of 5 were greatest when the primary and secondary stages were low but become obscured by the already aggressive nature of advanced primary and secondary patterns.

Therefore, except for very high-grade tumors, tertiary scoring of prostatic adenocarcinoma at radical prostatectomy should be reported as it has prognostic significance.

Accuracy of gleason grading by practicing pathologists and the impact of education on improving agreement.

Mikami Y, Manabe T, Epstein JI, Shiraishi T, Furusato M, Tsuzuki T, Matsuno Y, Sasano H.

Hum Pathol. 2003 Jul;34(7):658-65. Abstract quote

The aims of this study were to evaluate the accuracy of Gleason grading for prostatic adenocarcinoma among practicing pathologists in Japan and to determine the influence of education on this accuracy.

Using a case-oriented approach, 16 hematoxylin and eosin-;stained glass slides with consensus scores established by 4 urologic pathologists were reviewed by 91 pathologists, divided into 2 groups. In group A, average agreements with consensus scores before and after an educational lecture were 55.7% (n = 17) and 68.4% (n = 25), and average kappa values were 0.43 and 0.67, respectively. Twelve pathologists reviewed slides twice in a different order, with average agreements of 59.5% and 77.6%, and average kappa values of 0.48 and 0.69 before and after the lecture, yielding a statistically significant improvement. In group B, the average agreement before providing an atlas with a tutorial was 61.3% (n = 61), and the kappa value was 0.44. In the second round, the average agreement was 74.5% (n = 39), and the kappa value was 0.68. Among 39 pathologists who reviewed slides twice, the average agreement in the first round was 58.8%, and the kappa value was 0.42. Improvement of both the average agreement and the kappa value were statistically significant. The average improvement in kappa values among participants who reviewed slides twice was 0.22 in group A and 0.27 in group B, a difference that is not statistically significant. Combining both groups, the incidence of concordant scores for 16 cases rose from 58.9% to 75.4%, an average increase of 16.5%. The undergrading of score 5-7 lesions was significantly reduced, from 36.3% to 14.2%. With respect to demographic factors, pathologists signing out more than 5000 cases per year showed a better agreement than those with more than 1000 cases per year (48.9% versus 78.8%; P = 0.031).

These results indicate that the general agreement of Gleason scores among practicing pathologists in Japan was comparable with those in the Western countries as reported in the literature. Although this requires further improvement, both the lecture and the printed material had a similar influence on the degree of improvement.

The Prognostic Significance of Tertiary Gleason Patterns of Higher Grade in Radical Prostatectomy Specimens A Proposal to Modify the Gleason Grading System

Chin-Chen Pan, M.D.; Steven R. Potter, M.D.; Alan W. Partin, M.D., Ph.D.; Jonathan I. Epstein, M.D.

From the Departments of Urology (S.R.P., A.W.P., J.I.E.) and Pathology (C.-C.P., J.I.E.), The Johns Hopkins University School of Medicine, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD, U.S.A. .

Am J Surg Pathol 2000;24:563-569 Abstract quote

The Gleason grading system of prostatic adenocarcinoma does not account for the existence of a tertiary (third most prevalent) pattern, and there are no studies concerning the latter's prognostic influence.

The authors analyzed 114 radical prostatectomies with small tertiary components, which mostly occupied less than 5% of whole tumors. These specimens were compared with a prostatectomy database comprised of 2,276 cases without a tertiary component.

The pathologic stages of ``typical'' Gleason score 5 to 6 tumors (Gleason scores 2 + 3 = 5, 3 + 2 = 5, 3 + 3 = 6), which contained tertiary patterns 4 or 5, were significantly higher than those of ``typical'' Gleason score 5 to 6 tumors without pattern 4 (p = 0.018) but lower than those of ``typical'' Gleason score 7 tumors (p = 0.021; Gleason scores, 3 + 4 = 7, 4 + 3 = 7). Typical Gleason score 7 tumors with a tertiary pattern 5 showed significantly worse pathologic stages than typical Gleason score 7 tumors (p = 0.008) without pattern 5 and were not different statistically from typical Gleason score 8 (Gleason score, 4 + 4 = 8) tumors. Both typical Gleason score 5 to 6 and 7 tumors with tertiary components revealed significantly higher progression rates than typical Gleason score 5 to 6 tumors (p <0.0001) and Gleason score 7 tumors (p = 0.003) without tertiary components, and progressed like typical Gleason score 7 and 8 tumors respectively.

Tertiary high-grade components have an adverse impact on biologic behavior. The authors propose that the Gleason system for radical prostatectomy specimens be modified to take into account small volumes of patterns 4 and 5, which are important prognostically.

Primary Gleason Pattern as a Predictor of Disease Progression in Gleason Score 7 Prostate Cancer A Multivariate Analysis of 823 Men Treated With Radical Prostatectomy

C. M. Herman, etal.

Am J Surg Pathol 2001;25:657-660 Abstract quote

Gleason score (GS) is a powerful predictor of disease progression in men with prostate cancer (PCa). The majority of clinically localized prostate cancers, however, are moderately (GS5/6) or moderate to poorly (GS7) differentiated tumors with indeterminate prognosis. Differences in disease progression between patients with GS5/6 and GS7 tumors suggest the presence of any component of high-grade tumor (Gleason pattern [GP] 4/5) worsens prognosis markedly. Indeed, McNeal et al. have shown that quantification of GP4/5 provides prognostic information beyond the standard GS. Few investigators have analyzed whether primary and secondary GPs are important prognostically within GS7 PCa.

All 823 whole-mount radical prostatectomy specimens with GS7 from a single surgeon (P.T.S.) were analyzed. Tumors were either 3+4 or 4+3, and primary GP was assigned by the same pathologist (T.M.W.). A total of 643 patients with 3+4 tumors and 180 patients with 4+3 tumors were studied.

Statistical analysis using the log-rank test showed a significant difference in recurrence-free survival between patients with primary GP4 and those with GP3 (p <0.0001). However, in multivariate analysis with preoperative prostate-specific antigen, total tumor volume, surgical margin status, and the presence or absence of seminal vesicle involvement, extraprostatic extension, and lymph node metastasis, the primary GP did not retain independent significance (p = 0.0557). GS7 PCa is a heterogeneous group of tumors.

In this cohort of men with GS7 tumors treated by radical retropubic prostatectomy, primary GP showed a significant correlation with other histologic and clinical predictors of disease progression; however, it was not independently predictive of disease progression in multivariate analysis (p = 0.76).

Spread of Prostate Carcinoma to the Perirectal Lymph Node Basin: Analysis of 112 Rectal Resections Over a 10-year Span for Primary Rectal Adenocarcinoma.

Murray SK, Breau RH, Guha AK, Gupta R.

*Department of Pathology, Capital Health and daggerDalhousie University Medical School, Halifax, Nova Scotia, Canada.
Am J Surg Pathol. 2004 Sep;28(9):1154-1162. Abstract quote  

We recently identified metastatic prostate carcinoma (PCA) within perirectal lymph nodes (PLNs) from 2 patients undergoing abdominoperineal resection (APR) for rectal adenocarcinoma (RA).

As this phenomenon has not been addressed by any studies in the literature and because these positive PLNs had the potential to be mistakenly diagnosed as metastatic RA, we were prompted to undertake a retrospective study of rectal resections for RA to determine the frequency of PCA metastasizing to the PLNs in this patient population. The laboratory information system of the Department of Pathology, Capital Health, Halifax, Nova Scotia was searched for lymph node (LN)-positive RAs resected by low anterior resection or APR in male patients between January 1, 1992 and December 31, 2002. The hematoxylin and eosin slides were retrieved and reviewed, comparing the histology of the primary rectal tumor with that of the LN metastases in each case. Metastases having a different histologic appearance than the primary rectal tumor or having a pattern suggestive of metastatic PCA were analyzed by immunohistochemistry to detect prostate specific antigen (PSA), prostatic acid phosphatase (PAP), cytokeratin 7 (CK7), cytokeratin 20 (CK20), and carcinoembryonic antigen in LN metastases and in each RA. The presence or absence of mucin in the tumors was assessed by staining with Alcian blue, periodic acid-Schiff (PAS) +/- diastase, and modified PANFOPAS (2-hydroxy-3-naphthoic acid hydrazide/fast black B/saponification/periodic acid-Schiff).

The study identified 112 cases of RA with positive LNs. Of those, 5 of 112 (4.5%) were identified as having metastatic PCA within the PLNs. All five were positive for PSA and PAP and only one case had rare CK20-positive tumor cells. The primary RAs were all diffusely positive for CK20 and carcinoembryonic antigen. Two cases of metastatic PCA expressed colonic type/acetylsialomucin, which was also seen in well-differentiated primary RAs. These 5 patients had a mean age of 76.8 years (range, 68-82 years). Four (80%) underwent APR while one (20%) underwent a low anterior resection. The mean number of LNs identified per case was 14 (range, 5-26). The mean number of LNs per case with metastatic PCA was 7.6 (range, 1-18). The majority of the LNs were under 1.0 cm in diameter. Two cases (40%) were associated with significant extranodal extension of PCA. The PLNs were mistakenly diagnosed as being involved by RA 40% of the time. On follow-up, 2 patients (40%) had died with progressive pelvic tumor, while 3 patients (60%) were alive, including 2 who, as a result of the study, were referred to the urology service for management. Both of these patients were subsequently started on medical (anti-androgen) therapy and 1 additionally had bilateral orchiectomy. In 4 of the patients, the serum PSA after the rectal resection ranged from 2.5 to 13.5 ng/mL. In 1 patient, the serum PSA was markedly elevated (5961 ng/mL), and this patient was subsequently identified on bone scan as having extensive skeletal metastases.

This study identified a subset (4.5%) of patients with RA and PLNs positive for PCA. PCA may extend to the PLN basin and therefore influence the management of patients with rectal tumors and the staging, LN dissection, and management of patients with PCA. Moreover, the LNs were incorrectly diagnosed as metastatic RA 40% of the time, emphasizing the need to consider the differential diagnosis of metastatic PCA when evaluating PLNs. The diagnosis of metastatic PCA can be confirmed using an immunohistochemical panel consisting of PSA, PAP, CK20, and carcinoembryonic antigen along with mucin stains in some cases.

In patients undergoing APR for RA, there should be preoperative screening for PCA as it will not be possible to do a digital rectal examination or transrectal ultrasound post-APR, and a prostate biopsy, if necessary, would have to be done via the more difficult transperineal approach.

Incidence, Location, and Significance of Periprostatic and Periseminal Vesicle Lymph Nodes in Prostate Cancer

Pulin S. Kothari, M.D. ; Peter T. Scardino, M.D. ; Makoto Ohori, M.D. ; Michael W. Kattan, Ph.D. ; Thomas M. Wheeler, M.D.

From the Department of Pathology (P.S.K., T.M.W.), Baylor College of Medicine, Houston, Texas; and the Department of Urology (P.T.S., M.O., M.W.K.), Memorial Sloan Kettering Cancer Center, New York, NY, U.S.A.

Am J Surg Pathol 2001;25:1429-1432 Abstract quote

Pelvic lymph node metastases in prostate cancer (PCa) carry an ominous prognosis. Periprostatic/periseminal vesicle (PP/PSV) lymph nodes are present in some individuals, but their incidence and involvement by metastases are unknown.

A total of 832 of 1233 (67.5%) patients who underwent radical retropubic prostatectomy for clinically localized PCa at the Methodist Hospital from 1983 to 1998 by one surgeon (P.T.S.) had whole-mount slides available for review. Of these, 92 (11.1%) had received preoperative therapy (radiation in 48 [5.8%], hormonal in 44 [5.3%]). Slides were examined with the naked eye by placing them on a white illuminated background, and any area suggestive of a lymph node in PP/PSV fat was confirmed microscopically and assessed for the presence of metastases.

Thirty-seven of 832 patients (4.4%) had 39 PP/PSV lymph nodes—one bilateral, one with two ipsilateral lymph nodes, and the rest solitary. Sizes ranged from 0.7 to 4.5 mm (mean 1.8 mm). Distribution was 2 of 39 (5.1%) apical, 3 of 39 (7.7%) mid, 17 of 39 (43.6%) base, and 17 of 39 (43.6%) seminal vesicle. Five patients (0.6%) had metastatic PCa to the PP/PSV lymph nodes. All five patients were of advanced pathologic T stage [one pT3a (extraprostatic extension) and four pT3b (seminal vesicle invasion)]. Only two of those five (40%) had metastases (all ipsilateral) to pelvic lymph nodes. In three of five (60%) the metastases were isolated to the PP/PSV lymph nodes. Metastases were to the lymph nodes in the periseminal vesicle fat in four of five (80%) of the cases and in the fat surrounding the base of the prostate in one of five (20%). Four of five (80%) patients recurred. Histologic grade (Gleason score), tumor volume, and failure (recurrence) rates were significantly different between the five patients with metastases and the 32 patients without metastases to the PP/PSV lymph nodes (p <0.0001, p <0.0001, and p = 0.005, respectively). However, there was no evidence that an individual patient's probability of having a PP/PSV lymph node increased with resection of the neurovascular bundle (p = 0.7698).

PP/PSV lymph nodes are uncommon, but based upon these limited data, it appears that patients with metastases limited to PP/PSV lymph nodes have a poor prognosis (similar to pelvic lymph node metastases) and should be included in the American Joint Committee on Cancer (AJCC) Staging Manual to indicate “N1” if positive for metastases.

Closest Distance Between Tumor and Resection Margin in Radical Prostatectomy Specimens: Lack of Prognostic Significance.

Emerson RE, Koch MO, Daggy JK, Cheng L.

From the Departments of *Pathology and Laboratory Medicine and daggerUrology, and double daggerDivision of Biostatistics, Indiana University School of Medicine, Indianapolis, IN.
Am J Surg Pathol. 2005 Feb;29(2):225-229. Abstract quote

Complete removal of the tumor by surgery offers the best chance for cancer cure; however, many prostate cancer patients who have negative surgical margins at radical prostatectomy will still experience local and distant tumor recurrence. In other organs, the closest distance between tumor and resection margin has prognostic significance. This has not been adequately studied in prostatectomy specimens.

We undertook a prospective study of 278 consecutive margin-negative whole-mount prostatectomy cases. The anatomic location and closest distance between tumor and resection margin, measured with an ocular micrometer, were analyzed. All the slides were reviewed by a single pathologist, and data were collected prospectively. The closest distance between tumor and resection margin ranged from 0.02 to 5.0 mm (mean, 0.7 mm; median, 0.5 mm) and correlated with patient age (P = 0.03), prostate weight (P = 0.002), Gleason score (P = 0.001), pathologic stage (P = 0.01), tumor volume (P < 0.001), and perineural invasion (P < 0.001).

The closest distance between tumor and resection margin was not a significant predictor of PSA recurrence in univariate or multivariate logistic regression; and we do not, therefore, advocate reporting the closest distance between tumor and resection margin as a standard part of the surgical pathology report on prostatectomy specimens.

Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer.

Ross JS, Kaur P, Sheehan CE, Fisher HA, Kaufman RA Jr, Kallakury BV.

Departments of Pathology and Laboratory Medicine (JSR, PK, CES, BVSK) and Surgery (Urology.

Mod Pathol 2003 Mar;16(3):198-205 Abstract quote

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading the structural support network for normal and malignant cells, promoting neoplastic cell invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) maintain connective tissue integrity by modulating MMP activity.

Formalin-fixed paraffin-embedded tissue sections from 138 prostatic adenocarcinomas (PACs) were immunostained by a combined automated/manual method using monoclonal antibodies against MMP2 and TIMP2. Immunoreactivity was semiquantitatively scored based on stain intensity and distribution, and results were correlated with Gleason grade, pathologic stage, ploidy status, and disease recurrence. One hundred five of 138 (76%) and 113/138 (82%) PACs expressed MMP2 and TIMP2, respectively.

Co-expression was observed in 94/138 (68%) of PACs (P =.01), correlated with advanced tumor stage (P =.05), and tended to be associated with disease recurrent cases (P =.07). TIMP2 expression individually correlated with advanced tumor stage (P =.04) and reached near significance with disease recurrence (P =.06). MMP2 expression was also more frequent in recurrent PACs, although this value did not reach statistical significance (P =.07). However, on multivariate analysis, only pathologic stage (P =.009) and ploidy status (P =.03) independently predicted disease recurrence. In conclusion, MMP2 and TIMP2 are co-expressed in a majority of PACs and correlate with prognostic variables.

Interestingly, contrary to the previously documented anti-tumor effects of TIMPs, TIMP2 expression appears to have a tumor-promoting role in PACs and warrants further investigation.


Neurologic complications of prostate cancer.

Benjamin R.

Keck School of Medicine of the University of Southern California, Los Angeles, USA.

Am Fam Physician 2002 May 1;65(9):1834-40 Abstract quote

Neurologic complications continue to pose problems in patients with metastatic prostate cancer. From 15 to 30 percent of metastases are the result of prostate cancer cells traveling through Batson's plexus to the lumbar spine. Metastatic disease in the lumbar area can cause spinal cord compression. Metastasis to the dura and adjacent parenchyma occurs in 1 to 2 percent of patients with metastatic prostate cancer and is more common in those with tumors that do not respond to hormone-deprivation therapy. Leptomeningeal carcinomatosis, the most frequent form of brain metastasis in prostate cancer, has a grim prognosis.

Because neurologic complications of metastatic prostate cancer require prompt treatment, early recognition is important. Physicians should consider metastasis in the differential diagnosis of new-onset low back pain or headache in men more than 50 years of age.

Spinal cord compression requires immediate treatment with intravenously administered corticosteroids and pain relievers, as well as prompt referral to an oncologist for further treatment.


Loss of p53 and c-myc Overrepresentation in Stage T2-3N1-3M0 Prostate Cancer are Potential Markers for Cancer Progression

Junqi Qian, M.D., Kiyoshi Hirasawa, M.D., David G. Bostwick, M.D., Erik J. Bergstralh, M.S., Jeff M. Slezak, M.S., Kari L. Anderl, B.S., Thomas J. Borell, B.S., Michael M. Lieber, M.D. and Robert B. Jenkins, M.D., Ph.D.

Department of Laboratory Medicine and Pathology (JQ, DGB, TJB, KLA, RBJ), Department of Urology (KH, MML), and Section of Biostatistics (EJB, JMS), Mayo Clinic, Rochester, Minnesota.

Mod Pathol 2002;15:35-44 Abstract quote

To determine whether genetic changes are markers of cancer progression and patient survival in Stage T2–3N1–3M0 prostatic carcinoma, we compared 26 patients who died of tumor relapse after prostatectomy and lymphadenectomy (case group) with 26 matched patients who were alive at the time of the matched case’s death (control group).

Nine unmatched cases were also included in this study. In 37 cases, paired primary tumors (119 foci) and lymph node metastases (114 foci) were available for study. Fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, and 17 and region-specific probes for D7S486 (7q31), c-myc (8q24), LPL (8p22), and p53 (17p13) was performed on available primary carcinomas and lymph node metastases. In primary tumor foci, +7q31, -8p22, +c-myc, substantial additional increases of myc (AI-c-myc), and -p53 were observed in 65%, 74%, 43%, 29%, and 31% of foci, respectively. AI-c-myc was strongly associated with higher cancer Gleason score (P = .003). Heterogeneity of genetic changes was frequently observed among multiple cancer foci. Lymph node metastases of prostate cancer usually shared genetic changes with paired primary tumors. In addition, the genetic change pattern with -8p, +c-myc or AI-c-myc, +7q, and +p53 was slightly higher in lymph node metastases (22%) than in primary tumors (6%) (P = .08). In matched case and control patients, simultaneous gain of 7q31 (+7q31) and CEP7 (+CEP7) was identified in 59% and 68% of specimens for case and control groups, respectively (P = .48). Loss of 8p22 (-8p22) was identified in 77% and 69% of specimens for case and control groups, respectively (P = 1.0). Simultaneous gain of c-myc (+c-myc) and CEP8 (+CEP8) without overt additional increase of c-myc copy number relative to CEP8 copy number, was identified in 38% and 54% of specimens for case and control groups, respectively (P = .27). AI-c-myc was identified in 54% and 23% of specimens for case and control groups, respectively (odds ratio = 3.0, P = .06). Loss of p53 (-p53) was identified in 46% and 15% of specimens for case and control groups, respectively (odds ratio = 4.0, P = .04).

Our results indicate that FISH anomalies are very common in both primary tumors and lymph node metastases of Stage T2–3N1–3M0 prostate cancer; that AI-c-myc is associated with higher cancer Gleason score; that AI-c-myc and -p53 are associated with prostate cancer progression and are potential markers of survival in Stage T2–3N1–3M0 prostate cancer; and that lymph node metastases usually have similar or additional genetic changes compared with primary tumors, and multiple lymph node metastases usually have similar genetic changes.


High-grade Prostatic Intraepithelial Neoplasia on Needle Biopsy: Risk of Cancer on Repeat Biopsy Related to Number of Involved Cores and Morphologic Pattern.

Bishara T, Ramnani DM, Epstein JI.

*Pee Dee Pathology Associates, Florence, SC; daggerVirginia Urology Center, Richmond, VA; and double daggerJohns Hopkins Medical Institutions, Baltimore, MD.
Am J Surg Pathol. 2004 May;28(5):629-633. Abstract quote  

The importance of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on needle biopsy is its association with synchronous invasive carcinoma. The relevance of this relationship has been called into question in recent years.

In our study, we examined whether the histologic subtype of HGPIN (ie, tufting, micropapillary, cribriform, flat) and/or the number of core biopsies involved by HGPIN was predictive of a subset of men who were at higher risk of having invasive carcinoma on follow-up biopsies.

We examined 200 sets of needle biopsies with a diagnosis of isolated HGPIN. Patient age ranged from 46 to 90 years (mean 66.4 years). The breakdown of the histologic subtypes of HGPIN is as follows: tufting 59%, micropapillary 34.3%, cribriform 6.2%, and flat 0.5%. A total of 132 patients (66%) had follow-up biopsies. Prostatic adenocarcinoma was identified in 28.8% of patients with 89.5% of cancers identified on the first two follow-up biopsies. For men that had two or more cores with HGPIN on the initial biopsy, 35.9% eventually had cancer on follow-up whereas men with only single core involvement had cancer in 22% of cases. Men with tufting/flat HGPIN on the initial biopsy had cancer on follow-up in 31.9% of cases, whereas the micropapillary/cribriform subtype was associated with cancer in 22% of follow-up biopsies. The histologic findings on the first repeat biopsy can be quite informative as to the risk of synchronous invasive carcinoma. Of the men with HGPIN on the first repeat biopsy, 32% eventually had cancer on follow-up. Additionally, if multiple cores were involved by HGPIN on the first repeat biopsy, the risk of finding cancer was 50%, regardless of single or multiple core involvement on the initial biopsy. Men with a benign diagnosis on the first repeat biopsy had a 14% risk of having cancer on follow-up.

These data indicate that the multiple core involvement by HGPIN, both on initial and first repeat biopsy, defines a subset of men that are at increased risk of harboring synchronous invasive carcinoma. The histologic subtype of PIN does not appear to be as informative

Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate.

Keetch DW, Humphrey P, Stahl D, Smith DS, Catalona WJ.

Division of Urologic Surgery, Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.

J Urol 1995 Aug;154(2 Pt 1):347-51 Abstract quote

PURPOSE: We evaluate the significance of grade and extent of isolated prostatic intraepithelial neoplasia in prostate needle biopsies as a predictor of cancer on repeat biopsy.

MATERIALS AND METHODS: We reviewed our experience with 58 men 50 years or older who had isolated prostatic intraepithelial neoplasia on initial prostate needle biopsy during a prostate specific antigen (PSA) based screening trial for prostate cancer. All 58 men underwent repeat biopsy to follow the initial findings of prostatic intraepithelial neoplasia. We assessed the relationship of patient age, digital rectal examination, serum PSA concentration, PSA density, prostatic intraepithelial neoplasia grade, number of foci of neoplasia and linear extent of prostatic intraepithelial neoplasia in the initial biopsy specimen to the finding of cancer on the repeat biopsy. We also compared the cancer detection rate in the 58 men with and 427 without prostatic intraepithelial neoplasia in the same screening trial.

RESULTS: Of 21 men with low grade and 37 with high grade prostatic intraepithelial neoplasia 4 (19%) and 19 (51%), respectively, had cancer on repeat biopsy (p < 0.02), compared to 82 of 427 (19%) without cancer or prostatic intraepithelial neoplasia on the initial biopsy. High grade prostatic intraepithelial neoplasia was a significant predictor of malignancy on repeat biopsy (p < 0.05). The number of foci of neoplasia and the linear extent of prostatic intraepithelial neoplasia on initial biopsy were not predictive of cancer on repeat biopsy.

CONCLUSIONS: Our results demonstrate that the presence of high grade prostatic intraepithelial neoplasia is a strong predictor of prostate cancer in men with elevated serum PSA concentrations and they should be followed with repeat biopsy.

Repeat biopsy strategy in patients with atypical small acinar proliferation or high grade prostatic intraepithelial neoplasia on initial prostate needle biopsy.

Borboroglu PG, Sur RL, Roberts JL, Amling CL.

Department of Urology, Naval Medical Center-San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-1005, USA.

J Urol 2001 Sep;166(3):866-70 Abstract quote

PURPOSE: Isolated high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation on prostate biopsy increases the risk of identifying cancer on repeat biopsy. We report the results of repeat prostate biopsy for high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation, and propose an optimal repeat biopsy strategy.

MATERIALS AND METHODS: Of 1,391 men who underwent standard systematic sextant biopsy of the prostate 137 (9.8%) had isolated high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation, including 100 who underwent repeat prostate biopsy within 12 months of the initial biopsy.

RESULTS: Adenocarcinoma was detected in 47 of the 100 patients who underwent repeat biopsy. The initial biopsy site of high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation matched the sextant location of cancer on repeat biopsy in 22 cases (47%). Repeat biopsy directed only to the high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation site on initial biopsy would have missed 53% of cancer cases. In 12 of the 47 men (26%) cancer was limited to the side of the prostate contralateral to the side of high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation. Of the 31 patients with cancer in whom the transition zone was sampled cancer was limited to the transition zone in 4 (13%) and evident at other biopsy sites in 13 (42%). The only significant predictor of positive repeat biopsy was mean prostate specific antigen velocity plus or minus standard error (1.37 +/- 1.4 versus 0.52 +/- 0.8 ng./ml. per year, p <0.001).

CONCLUSIONS: Patients with isolated high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation on prostate biopsy are at 47% risk for cancer on repeat biopsy. The optimal repeat biopsy strategy in this setting should include bilateral biopsies of the standard sextant locations. We also strongly recommend that transition zone sampling should be considered.


The histology of radiation therapy effect on prostate adenocarcinoma as assessed by needle biopsy after brachytherapy boost. Correlation with biochemical failure.

Goldstein NS, Martinez A, Vicini F, Stromberg J.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

Am J Clin Pathol 1998 Dec;110(6):765-75 Abstract quote

Brachytherapy boost with external radiation therapy (RT) allows safer delivery to the prostate than conventional techniques.

We measured the degree of radiation effect of adenocarcinoma cells in post-RT biopsy specimens and the association with biochemical failure.

Forty-six patients with T2b-3c adenocarcinomas underwent 18-month post-RT biopsies, of whom 22 had adenocarcinoma. All biopsy specimens without obvious adenocarcinoma were stained with antibodies to prostate-specific antigen and keratins AE1/AE3 and 34 beta E12. The RT effect to adenocarcinoma cells was scored by adding the scores of the nuclear and cytoplasmic changes. Each adenocarcinoma was assigned 2 scores; the most-common and the least-amount RT effect. Treatment for 7 of the 46 patients failed; 6 of these had residual adenocarcinoma on the post-RT biopsy specimen. Sixteen of 22 patients with adenocarcinoma on the post-RT biopsy specimen did not experience biochemical failure. The presence of adenocarcinoma on the post-RT biopsy specimen was significantly associated with failure. The mean most-common RT-effect score for the 16 patients without failure was 5.2 compared with 4.2 for the 6 patients with failure. The mean least-amount RT-effect score in patients without failure was 4.4 compared with 2.8 (range, 2-4; SD, 0.75) in the failure group.

These relatively radiation-resistant foci may be the source of failure. Scoring the RT-effect of adenocarcinoma in post-RT biopsy specimens may be clinically useful in predicting subsequent biochemical failure.

Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients.

Crook J, Malone S, Perry G, Bahadur Y, Robertson S, Abdolell M.

Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

Int J Radiat Oncol Biol Phys 2000 Sep 1;48(2):355-67 Abstract quote

PURPOSE: Postradiotherapy (RT) prostate biopsies are prone to problems in interpretation. False negatives due to sampling error, false positives due to delayed tumor regression, and indeterminate biopsies showing radiation effect in residual tumor of uncertain viability are common occurrences.

METHODS AND MATERIALS: A cohort of 498 men treated with conventional RT from 06/87-10/96 were followed prospectively with systematic transrectal ultrasound (TRUS)-guided post-RT prostate biopsies, starting 12-18 months after RT. If there was residual tumor but further decline in serum prostate-specific antigen (PSA), biopsies were repeated every 6-12 months. Patients with negative biopsies were rebiopsied at 36 months. Residual tumor was evaluated for RT effect and proliferation markers. The 498 men had 978 biopsies. Median time of the first biopsy (n = 498) was 13 months, biopsy #2 (n = 342) 28 months, biopsy #3 (n = 110) 36 months, biopsy #4 (n = 28) 44 months, and biopsy #5 (n = 4) 55 months. Median follow-up is 54 months (range 13-131). One hundred seventy-five patients (34%) had prior hormonal therapy for a median of 5 months (range 1-60).

RESULTS: Clinical stage distribution was T1b: 46; T1c: 50; T2a: 115; T2b/c: 170; T3: 108; T4: 11; Tx: 1. Distribution by Gleason score was: 28% Gleason score 2-4; 42%: 5-6; 18%: 7; and 12%: 8-10. Seventy-one men have died, 26 of prostate cancer and 45 of other causes. Actuarial failure-free survival by T stage at 5 years is T1b: 78%; T1c: 76%; T2a: 60%; T2b/c: 55%; T3: 30%; and T4: 0%. Actuarial freedom from local failure at 5 years is T1b: 83%; T1c: 88%; T2a: 72%; T2b/c: 66%; T3: 58%; and T4: 0%. The proportion of indeterminate biopsies decreases with time, being 33% for biopsy 1, 24% for biopsy 2, 18% for biopsy 3, and 7% for biopsy 4. Thirty percent of indeterminate biopsies resolved to NED status, regardless of the degree of RT effect, 18% progressed to local failure, and 34% remained as biopsy failures with indeterminate status within the time frame of this report. Positive staining for proliferation markers was associated with both subsequent local failure and also any type of failure. In multivariate analysis, only PSA nadir (p = 0.0002) and biopsy status at 24-36 months (p = 0. 0005) were independent predictors of outcome.

CONCLUSIONS: Post-RT prostate biopsies are not a gold standard of treatment efficacy, but are an independent predictor of outcome. Positive immunohistochemical staining for markers of cellular proliferation is associated with subsequent local failure. Indeterminate biopsies, even when showing marked RT effect, cannot be considered negative.

Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy?

Koppie TM, Grossfeld GD, Nudell DM, Weinberg VK, Carroll PR.

Department of Urology, University of California-San Francisco, USA

J Urol 2001 Jul;166(1):111-5 Abstract quote

PURPOSE: External beam radiotherapy may be given after radical prostatectomy as adjuvant (immediate) or therapeutic (delayed) treatment, the latter in response to evidence of disease recurrence. In patients receiving delayed radiotherapy the necessity of a positive anastomotic biopsy before treatment remains unclear. We determined whether a positive anastomotic biopsy predicted the response to radiation in this setting.

MATERIALS AND METHODS: We reviewed the records of 67 patients who received radiotherapy for biochemical or biopsy proved recurrent prostate cancer after radical prostatectomy. Patients underwent surgery at our institution or its affiliated hospitals, or were referred to our institution for radiotherapy. All patients had a negative metastatic evaluation before receiving radiotherapy. Biochemical failure after radiotherapy was defined as serum prostate specific antigen (PSA) 0.2 ng./dl. or greater on 2 or more consecutive occasions. Biochemical recurrence-free survival was calculated using the Kaplan-Meier method. Independent predictors of PSA failure after radiotherapy were identified using the multivariate Cox proportional hazards model.

RESULTS: Of the 67 patients evaluated 33 and 34 received radiotherapy for biochemical failure and biopsy proved local recurrence, respectively. The 3-year recurrence-free survival rate was 49% in patients treated for biochemical failure and 39% in those with biopsy proved local recurrence. There was no significant difference in PSA-free survival in these 2 groups. Only pre-radiotherapy PSA 1 ng./dl. or greater (p = 0.02) and seminal vesicle invasion (p = 0.02) were significant independent predictors of biochemical failure.

CONCLUSIONS: A positive anastomotic biopsy did not predict an improved outcome after radiotherapy following radical prostatectomy. Anastomotic biopsy was associated with a longer time to salvage radiotherapy. However, this delay did not translate into worse disease-free outcomes in patients who underwent anastomotic biopsy. High pre-radiotherapy PSA greater than 1 ng./ml. was the most significant predictor of biochemical failure after therapeutic radiotherapy. Decisions regarding local radiation therapy after radical prostatectomy may be made without documenting recurrent local disease.

Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma.

Roma AA, Magi-Galluzzi C, Kral MA, Jin TT, Klein EA, Zhou M.

1Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
Mod Pathol. 2006 Mar;19(3):392-8 Abstract quote.  

Lymphangiogenesis, detected by antibodies specific for lymphatic endothelial cells, has been associated with regional lymph node metastases and poor prognosis in carcinomas of head and neck, breast and uterine cervix, but remains largely uninvestigated in prostate adenocarcinoma.

We evaluated the lymphatic vessel density and lymphatic vessel invasion by prostate cancer cells in the intratumoral, peritumoral and normal prostate tissue compartments in cancer-bearing prostate glands and correlated them with lymph node metastases, Gleason score and other pathological parameters. Lymphatic vessels were detected by immunohistochemical stain using an antibody specific for the lymphatic endothelial cells (clone D2-40) on 33 radical prostatectomies.

In all, 26 patients had lymph node dissection, and 14 of them had lymph node metastasis. The lymphatic vessel density and lymphatic vessel invasion were then recorded for each of the three compartments microscopically. Lymphatic vessel density in the intratumoral, peritumoral and normal prostate compartments was 0.91+/-0.80, 1.54+/-0.68 and 1.58+/-0.96/mm(2), respectively. The intratumoral lymphatic vessel density was significantly lower than that of the peritumoral and normal prostate compartments, and the latter two were not significantly different. The lymphatic vessel density of the three compartments was not significantly different between cases with and without lymph node metastasis. The peritumoral lymphatic vessel density correlated inversely with the Gleason score. Lymphatic vessel invasion was present in significantly higher percentage of cases with lymph node metastasis (9/14, 62.3%), as compared to those without lymph node metastasis (1/12, 8.3%, P<0.01). The peritumoral lymphatic vessel invasion had a better correlation with the presence of lymph node metastases than intratumoral lymphatic vessel invasion. There is no evidence of lymphangiogenesis in prostate adenocarcinoma.

Peritumoral lymphatic vessel invasion correlates with regional lymph node metastases, suggesting that the peritumoral lymphatic vessels are functionally important and identification of lymphatic vessel invasion in this compartment implies a high probability of regional lymph node metastases.

Lymphovascular Invasion as a Predictor of Disease Progression in Prostate Cancer

Christopher M. Herman, M.D.; George E. Wilcox, M.D.; Michael W. Kattan, Ph.D.; Peter T. Scardino, M.D.; Thomas M. Wheeler, M.D.

From the Departments of Pathology and the Scott Department of Urology Baylor College of Medicine, The Methodist Hospital, Houston, Texas (C.M.H., G.E.W., T.M.W.) and the Department of Urology Memorial Sloan Kettering Cancer Center, New York, New York, U.S.A. (M.W.K., P.T.S.).

Am J Surg Pathol 2000;24:859-863 Abstract quote

The biologic heterogeneity of prostate cancer (PCa) is evident from the large discrepancy between incidence rates and disease progression and tumor-related deaths. One of the challenges in treating patients with PCa lies in developing nomograms to identify patients who might benefit from adjuvant therapies. Lymphovascular invasion (LVI) is among the variables in PCa recommended to be reported by the Cancer Committee of the College of American Pathologists (CAP), yet few studies have evaluated the prognostic significance and prevalence of LVI in PCa.

In the present study, whole-mount specimens from 263 patients with pT3N0 PCa treated by radical prostatectomy by a single surgeon were evaluated for the presence, location, and number of foci of LVI.

Foci of LVI were identified in 91 patients. In cases with LVI the number of foci ranged from 1 to 40 with the majority of patients having 1 or 2 foci. LVI was found to be a significant predictor of disease progression in univariate analysis (p <0.0001) and was significantly related to Gleason sum (p <0.001), extra prostatic extension (focal vs established; p = 0.033), and seminal vesicle involvement (p <0.001). Furthermore, in multivariate analysis, LVI was a significant independent predictor of disease progression as well (p = 0.0014).

These findings support the CAP recommendations and provide merit for the inclusion of LVI in nomograms to predict disease recurrence in PCa.

20-year outcomes following conservative management of clinically localized prostate cancer.

Albertsen PC, Hanley JA, Fine J.

Division of Urology, University of Connecticut Health Center, Farmington, CT 06030-3955, USA.
JAMA. 2005 May 4;293(17):2095-101. Abstract quote  

CONTEXT: The appropriate therapy for men with clinically localized prostate cancer is uncertain. A recent study suggested an increasing prostate cancer mortality rate for men who are alive more than 15 years following diagnosis.

OBJECTIVE: To estimate 20-year survival based on a competing risk analysis of men who were diagnosed with clinically localized prostate cancer and treated with observation or androgen withdrawal therapy alone, stratified by age at diagnosis and histological findings.

DESIGN, SETTING, AND PATIENTS: A retrospective population-based cohort study using Connecticut Tumor Registry data supplemented by hospital record and histology review of 767 men aged 55 to 74 years with clinically localized prostate cancer diagnosed between January 1, 1971, and December 31, 1984. Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years.

MAIN OUTCOME MEASURES: Probability of mortality from prostate cancer or other competing medical conditions, given a patient's age at diagnosis and tumor grade.

RESULTS: The prostate cancer mortality rate was 33 per 1000 person-years during the first 15 years of follow-up (95% confidence interval [CI], 28-38) and 18 per 1000 person-years after 15 years of follow-up (95% CI, 10-29). The mortality rates for these 2 follow-up periods were not statistically different, after adjusting for differences in tumor histology (rate ratio, 1.1; 95% CI, 0.6-1.9). Men with low-grade prostate cancers have a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6 deaths per 1000 person-years; 95% CI, 2-11). Men with high-grade prostate cancers have a high probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8-10, 121 deaths per 1000 person-years; 95% CI, 90-156). Men with Gleason score of 5 or 6 tumors have an intermediate risk of prostate cancer death.

CONCLUSION: The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis, which does not support aggressive treatment for localized low-grade prostate cancer.

Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy.

Zietman AL, Thakral H, Wilson L, Schellhammer P.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

J Urol 2001 Nov;166(5):1702-6 Abstract quote

PURPOSE: The long natural history of early stage prostate cancer is well recognized and a conservative approach to the treatment of elderly men is often encouraged. We assessed the ability of patients and physicians to adhere to a policy of watchful waiting in the prostate specific antigen (PSA) era.

MATERIALS AND METHODS: We retrospectively reviewed the records of all 199 men with stages T1-2 prostate cancer and PSA less than 20 ng./ml. who in our practice elected watchful waiting. Median followup in the population overall was 3.4 years. We performed Kaplan-Meier actuarial analysis of overall and disease specific survival, and most pertinent survival free from therapy. A questionnaire was administered to record the attitude of patients who ultimately proceeded to treatment to determine how therapy was triggered.

RESULTS: Median patient age was 71 years and median PSA was 6.6 ng./ml. The tumor was impalpable in 52% of patients, Gleason sum was 6 or less in 80% and 11% used some form of herbal remedy or nutritional supplementation. Of the 37 men who died during observation, including 35 of co-morbid illness, only 6 underwent treatment. Overall survival at 5 and 7 years was 77% and 63% but disease specific survival was 98% and 98%, respectively. A total of 64 patients underwent treatment and actuarial freedom from treatment was 56% at 5 years, including 51% and 73% in those younger and older than 75 years at diagnosis. The likelihood of being alive and free from treatment was 43% at 5 years and 26% at 7. Of the 63 men treated 48 (76%) underwent radical therapy (brachytherapy in 17, external beam radiotherapy in 29 and prostatectomy in 2), while only 24% received androgen deprivation. The median PSA increase from diagnosis to treatment in treated patients was 2.9 ng./ml., and it was 0.9 ng./ml. from diagnosis to the last followup in those not treated. Of the treated patients 81% believed that the physician had initiated therapy due to a PSA increase or a nodule. However, physicians recorded having advocated treatment in only 24% of cases.

CONCLUSIONS: When patients do not die of co-morbid illness, they are likely to proceed to therapy well within the first decade after diagnosis (57% by 5 years and 74% by 7). Therapy was usually definitive (radical) and triggered by slight, inevitable PSA increases. The patient perception was that the physicians initiated therapy in response to increasing PSA. However, the physicians more often perceived that treatment was initiated by patients. Therefore, watchful waiting in the PSA era often represents radical therapy delayed by a few years.


Survivin expression is associated with features of biologically aggressive prostate carcinoma.

Shariat SF, Lotan Y, Saboorian H, Khoddami SM, Roehrborn CG, Slawin KM, Ashfaq R.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-91120, USA.
Cancer. 2004 Feb 15;100(4):751-7. Abstract quote

BACKGROUND: Survivin counteracts cell death and controls mitotic progression. The objectives of the current study were to compare the expression patterns of survivin in normal prostate, primary prostate carcinoma, and lymph node tissues involved with prostate carcinoma and to determine whether the expression of survivin is associated with prostate carcinoma characteristics and progression.

METHODS: Immunohistochemical staining for survivin and for transforming growth factor beta1 (TGF-beta1) and its receptors (types I and II; TGF-betaR1 and TGF-betaR2, respectively) was carried out on archival specimens from 114 consecutive patients who underwent radical prostatectomy (median follow-up, 64.8 months). Punch biopsies of the index carcinoma and normal tissue from each specimen were sectioned onto a single slide and stained. The authors also evaluated the expression of survivin in normal and malignant lymph node tissue from eight patients.

RESULTS: Survivin was expressed in 41 of 114 normal prostate specimens (36%) from prostates that contained carcinoma, in 81 of 114 primary prostate carcinoma specimens (71%), in 3 of 8 normal lymphoid specimens (38%), and in 7 of 8 prostate carcinoma lymphoid specimens (88%). Survivin expression was associated with higher final Gleason sum (P = 0.001), loss of TGF-betaR1 and TGF-betaR2 expression (P = 0.041 and P = 0.008, respectively), and an increased risk of biochemical progression on univariate analysis (P = 0.0441). Among patients who had disease progression, survivin was expressed more commonly in those who had tumors with features of aggressive behavior.

CONCLUSIONS: The expression of survivin gradually increased from normal prostate tissue, to low-grade primary carcinoma, to high-grade primary carcinoma and was highest in lymph node metastases. Survivin expression was associated further with alteration of the TGF-beta pathway and with overall and aggressive biochemical progression after radical prostatectomy.
Surgery Radical prostatectomy is often combined with modalities listed below

Prospective patient-reported continence after laparoscopic radical prostatectomy.

Olsson LE, Salomon L, Nadu A, Hoznek A, Cicco A, Saint F, Chopin D, Abbou CC.

Service d'Urologie, Hopital Henri-Mondor, Creteil, France

Urology 2001 Oct;58(4):570-2 Abstract quote

Objectives. To perform a prospective study using confidential patient-completed questionnaires about their urinary habits before and after laparoscopic radical prostatectomy. Published reports on urinary continence after radical prostatectomy vary depending on the definitions of urinary continence and methods of data collection.

Methods. From May 1998 to February 2000, 228 men underwent laparoscopic radical prostatectomy for clinically localized prostate cancer. The patients were given questionnaires before surgery and at 1, 3, 6, and 12 months postoperatively.

Results. Before surgery, no patient reported incontinence. At 1, 3, 6, and 12 months postoperatively, perfect diurnal urinary control (no pads, no leakage at all) was reported in 9.9%, 28.6%, 57.4%, and 56.8% of patients, respectively. No pads were used in 18.8%, 58.4%, 68.9%, and 78.4% at 1, 3, 6, and 12 months, respectively. No patient reported use of more than 1 pad daily at 6 months of follow-up.

Conclusions. Continence after laparoscopic radical prostatectomy is comparable to the results after traditional radical retropubic prostatectomy. Ongoing use of the laparoscopic route for treating clinically localized prostate cancer is warranted.

Laparoscopic radical prostatectomy: is it feasible and reasonable?

Cadeddu JA, Kavoussi LR.

Department of Urology, Section of Minimally Invasive Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.

Urol Clin North Am 2001 Aug;28(3):655-61 Abstract quote

Laparoscopic radical prostatectomy is an extremely challenging procedure for even experienced laparoscopic surgeons, and it is not practical to expect most urologists to learn the technique. Nevertheless, it is a feasible procedure and has short-term results comparable with conventional radical prostatectomy. For LRP to be an acceptable and reasonable alternative, the oncologic results must be equivalent to the results of RRP, and significant advantages is morbidity (hospital stay, pain, incontinence, impotence) must be attained; otherwise, the steep learning curve and the additional expense of the procedure make it difficult to justify as an alternative therapeutic modality. Beside a reduction in the transfusion rate, no other significant advantages of LRP over radical prostatectomy have been demonstrated definitively to date.

As a result, the role of LRP in the management of prostate cancer remains investigational, and patients should be informed appropriately. The oncologic results and low morbidity of nerve-sparing RRP set a high standard for a laparoscopic technique to equal.

Long-term results of treatment for prostate carcinoma by staging pelvic lymph node dissection and definitive irradiation using low-dose rate temporary iridium-192 interstitial implant and external beam radiotherapy.

Puthawala AA, Nisar AM, Austin PA, Cherlow JM, Perley JM, Shanberg AM, Sawyer DE, Ingram JE, Baghdassarian R, Wachs BH, Perley JE, Londrc A, Espinoza-Ferrel T.

Department of Radiation Oncology, Long Beach Memorial Medical Center, Long Beach, California.

Cancer 2001 Oct 15;92(8):2084-94 Abstract quote

BACKGROUND: The objective of this study was to evaluate long-term treatment outcome of definitive irradiation by using temporary interstitial implant and limited dose of external beam radiotherapy in treatment of localized prostate carcinoma.

METHODS: In total, 536 patients with biopsy-proven adenocarcinoma of the prostate, classification T1-T3, underwent staging pelvic lymph node dissection and brachytherapy delivering an average tumor dose of 30 grays (Gy), supplemented by external beam radiation therapy for an additional dose of 36 Gy delivered over 4 weeks. One hundred of 536 (18%) patients had pathologic D1 disease. A total of 181 patients had undergone transurethral prostatectomy before the treatment. Repeat prostate biopsy was performed on 132 patients 18 or more months after treatment. None of the patients received neoadjuvant or adjuvant hormone therapy.

RESULTS: Cumulative disease free survival (DFS) including biochemical DFS at 10 and 15 years for classification T1B,C was 78% and 72%; for T2A, 78% and 78%; for T2B,C, 68% and 66%; and for T3A-C, 45% and 45%, respectively. Cause specific survival for the entire group at 10 and 15 years was 89% and 87%, respectively. Severe complications occurred only in the early developmental phase of the study.

CONCLUSIONS: In univariate analysis, the clinical stage, histologic grade, pretreatment PSA level, lymph node status, and results of repeat posttreatment biopsy were all independently significant prognostic factors. However, the authors' study indicates that in multivariate analysis, only two factors emerged with statistical significance-the status of pelvic lymph nodes and the results of posttreatment biopsy. This signifies the importance of local tumor control to achieve ultimate cure and the importance of assessment of pelvic lymph nodes before definitive local therapy other than radical prostatectomy, especially in the high-risk group.

A centralized comparison of radical perineal and retropubic prostatectomy specimens: is there a difference according to the surgical approach?

Korman HJ, Leu PB, Huang RR, Goldstein NS.

Department of Urology, William Beaumont Hospital, Royal Oak, Michigan, USA.

J Urol 2002 Sep;168(3):991-4 Abstract quote

PURPOSE: We performed a central review of pathology specimens from radical perineal and radical retropubic prostatectomies performed by a single surgeon. We determined whether differences exist in the 2 approaches in regard to the ability to obtain adequate surgical margins around the tumor and adequate extracapsular tissue around the prostate, and avoid inadvertent capsular incision.

MATERIALS AND METHODS: The review included whole mount prostates from 60 patients who underwent radical retropubic prostatectomy and 40 who underwent radical perineal prostatectomy. The pathologist (N. S. G.) was blinded to the surgical approach. All prostatectomies were consecutive and performed by the same surgeon (H. J. K.). To ensure consistency of the pathological measurements patients were excluded from analysis if they had undergone preoperative androgen ablation or a nerve sparing procedure, leaving 45 retropubic and 27 perineal prostatectomy specimens for further evaluation. Pertinent clinical parameters were assessed and a detailed pathological analysis of each specimen was performed.

RESULTS: In the retropubic and perineal groups 78% of the tumors were organ confined (stage pT2) with extracapsular extension (stage pT3) in the majority of the remaining patients. There was no significant difference in the positive margin rate for the retropubic and perineal procedures (16% and 22%, p = 0.53) or for Gleason 6 and 7 tumors only in the 2 groups (10% and 17%, respectively, p = 0.47). The capsular incision rate was 4% in each group. The distance of the tumor from the posterolateral margins and the amount of extracapsular tissue excised were equivalent in each group. Subgroups of patients with a prostate of less than 50 gm. and containing only low grade, low stage neoplasms were also analyzed. Subgroup analysis showed no difference in any variable.

CONCLUSIONS: Radical perineal prostatectomy is comparable to radical retropubic prostatectomy for obtaining adequate surgical margins, avoiding inadvertent capsular incisions and excising adequate extracapsular tissue around tumor foci. Additional patient accrual and prostate specific antigen followup would further help validate the similar efficacy of the 2 surgical approaches as treatment for prostate cancer.


Incidence of Cancer and Mortality Following {alpha}-Tocopherol and {beta}-Carotene Supplementation: A Postintervention Follow-up.

The ATBC Study Group.

ATBC Study Group Authors: Jarmo Virtamo, MD, Pirjo Pietinen, DSc, Jussi K. Huttunen, MD, Pasi Korhonen, PhD, Nea Malila, MD, and Mikko J. Virtanen, MSc, National Public Health Institute, Helsinki, Finland.

JAMA. 2003 Jul 23;290(4):476-485. Abstract quote

CONTEXT: In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, alpha-tocopherol supplementation decreased prostate cancer incidence, whereas beta-carotene increased the risk of lung cancer and total mortality. Postintervention follow-up provides information regarding duration of the intervention effects and may reveal potential late effects of these antioxidants.

OBJECTIVE: To analyze postintervention effects of alpha-tocopherol and beta-carotene on cancer incidence and total and cause-specific mortality.

DESIGN, SETTING, AND PARTICIPANTS: Postintervention follow-up assessment of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April 30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001]) of 25 563 men. In the ATBC Study, 29 133 male smokers aged 50 to 69 years received alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5 to 8 years. End point information was obtained from the Finnish Cancer Registry and the Register of Causes of Death. Cancer cases were confirmed through medical record review.

MAIN OUTCOME MEASURES: Site-specific cancer incidence and total and cause-specific mortality and calendar time-specific risk for lung cancer incidence and total mortality.

RESULTS: Overall posttrial relative risk (RR) for lung cancer incidence (n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among recipients of beta-carotene compared with nonrecipients. For prostate cancer incidence (n = 672), the RR was 0.88 (95% CI, 0.76-1.03) for participants receiving alpha-tocopherol compared with nonrecipients. No late preventive effects on other cancers were observed for either supplement. There were 7261 individuals who died by April 30, 2001, during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05) for alpha-tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12) for beta-carotene recipients vs nonrecipients. Regarding duration of intervention effects and potential late effects, the excess risk for beta-carotene recipients was no longer evident 4 to 6 years after ending the intervention and was primarily due to cardiovascular diseases.

CONCLUSIONS: The beneficial and adverse effects of supplemental alpha-tocopherol and beta-carotene disappeared during postintervention follow-up. The preventive effects of alpha-tocopherol on prostate cancer require confirmation in other trials. Smokers should avoid beta-carotene supplementation.

Neoadjuvant Androgen Ablation Combined with External-Beam Radiation Therapy and Permanent Interstitial Brachytherapy Boost in Localized Prostate Cancer.

Sylvester J, Blasko JC, Grimm PD, Meier R, Goy B, Colburn G, Cavanagh W.

Seattle Prostate Institute, Seattle, Washington.

Mol Urol 1999;3(3):231-236 Abstract quote

Androgen ablation therapy has been combined with permanent interstitial brachytherapy in order to downsize the gland prior to seed implantation. It also has been employed in an attempt to improve the effectiveness of therapy in patients with a poor prognosis.

We report on 50 patients consecutively treated and prospectively followed. All received neoadjuvant hormonal therapy (NHT) and 45 Gy of external-beam therapy to a limited pelvic field, followed by permanent implantation of (125)I or (103)Pd seeds. The median follow-up is 42.1 months (range 9.0-90.8 months). The prostate specific antigen (PSA) progression-free survival rate (<1.0 ng/mL) was 76% at 5 years (Kaplan-Meier method). Local control was achieved in 100% of the patients and distant disease-free survival in 85%. High-risk patients treated contemporaneously with these patients, who received external-beam radiation and a seed boost without NHT, had a 62% rate of 5-year PSA progression-free survival.

Although the modest improvement in PSA progression-free survival is not statistically significant at 5 years (P = 0.5), the patients treated with NHT in addition to combined radiotherapy presented with significantly higher serum PSA concentrations (mean 21.0 ng/mL; median 17.0 ng/mL) than those treated with combination radiotherapy alone (mean 15.6 ng/mL; median 10.6 ng/mL) and thus had a worse prognosis.

Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent development.

Lieberman R.

Prostate and Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA

Urology 2001 Aug;58(2 Suppl 1):83-90 Abstract quote

Prostate cancer chemoprevention is defined as the administration of natural and synthetic agents that inhibit >/=1 steps in the natural history of prostate carcinogenesis.

The goal is to find agents that modulate the progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and systemic disease. Another important goal for chemoprevention is the maintenance of an androgen-sensitive clinical state and delay of the emergence of androgen independence. There is a strong rationale for androgen deprivation therapy (ADT) as a chemoprevention strategy for prostate cancer based on evidence from epidemiologic, experimental, molecular pathophysiologic, and randomized, controlled clinical trials. This includes the fact that HGPIN, the most likely precursor of invasive cancer, is androgen dependent and responds to ADT. Although the large, phase-3 Prostate Cancer Prevention Trial (PCPT) of finasteride versus placebo has established the feasibility and role of ADT for primary prevention, nevertheless, limitations of the anticipated treatment-effect size (eg, 25% reduction) and the potential for selection of androgen resistance provide incentive for finding other effective chemopreventive agents. The availability of novel noncytotoxic pharmaceutical and natural products in clinical development create opportunities for improving the therapeutic index through the principles of combination therapy.

The emergence of new powerful tools, such as gene chip complementary DNA microarrays for multiplex gene expression profiling, will accelerate the identification of new molecular targets and the design of rational combinations. Several agent classes have a strong basis for combination with ADT, including antiproliferatives, antioxidant micronutrients (selenium), antiestrogens, and nonsteroidal anti-inflammatory drugs (selective cyclooxygenase-2 inhibitors).

A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy.

Lee WR, Hall MC, McQuellon RP, Case LD, McCullough DL.

Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem, NC, USA

Int J Radiat Oncol Biol Phys 2001 Nov 1;51(3):614-23 Abstract quote

Purpose: To prospectively assess the health-related quality of life (HRQOL) and changes in HRQOL during the first year after 3 different treatments for clinically localized prostate cancer.

Methods and Materials: Ninety men with T1-T2 adenocarcinoma of the prostate were treated with curative intent between May 1998 and June 1999 and completed a quality-of-life Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire before treatment (T0) and 1 month (T1), 3 months (T3), and 12 months (T12) after treatment. Forty-four men were treated with permanent source interstitial brachytherapy (IB), 23 received external beam radiotherapy (EBRT), and 23 men were treated with radical prostatectomy (RP). The mean age of the entire study population was 65.9 years (median 67, range 42-79). The mean pretreatment prostate-specific antigen level of the entire study population was 6.81 ng/mL (median 6.25, range 1.33-19.6). The Gleason score was

Results: A comparison of the demographic characteristics of the 3 treatment groups demonstrated significant differences. The men treated with RP were significantly younger than the men in either the IB or EBRT group (median age 61.0 RP, 67.1 IB, 68.8 EBRT; p = 0.0006). The men in the IB group were more likely to have a Gleason score of

Conclusions: The results of this analysis suggest that significant decreases in HRQOL, as measured by the FACT-P instrument, are evident in the first month after IB or RP, but not after EBRT. One year after treatment, however, the FACT-P scores were not statistically different from the baseline measures for any group. For all treatment groups, most of the HRQOL decreases were observed in the physical, functional, and prostate cancer-specific domains. These results suggest that the HRQOL changes are likely to be treatment-specific, further emphasizing the importance of a randomized trial comparing the different treatment options in this population of men.

Prostate cancer chemoprevention: Strategies for designing efficient clinical trials.

Lieberman R.

National Cancer Institute, Rockville, Maryland 20852, USA.

Urology 2001 Apr;57(4 Suppl 1):224-9 Abstract quote

A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions.

Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life.

Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3; family history of PCa; carriers of PCa susceptibility genes [ELAC2, CYP3A4, SRD5A2, etc.]; and histology such as atypia and HGPIN) that could be combined into a multivariate risk model for PCa. The probability of cancer risk (recurrence) is a key factor that impacts on the clinical trial design (power, sample size, and primary endpoint). Multivariate predictive mathematical models for biochemical recurrence after radical prostatectomy by decreasing sample size and time to clinical outcomes maximize trial efficiency and identify the patients most likely to benefit from secondary prevention.

The two large primary prevention trials, Prostate Cancer Prevention Trial/Seleninium and Vitamin E Chemoprevention Trial (PCPT/ SELECT), in low- and average-risk subjects have sample sizes of 18,000 to 32,000, with a treatment duration of 7 years to detect a 25% reduction in biopsy-proven PCa. Subjects with HGPIN have the highest known cancer risk (approximately 50% at 3 years), and thus require a small sample size (n = 450) to detect a 33% reduction in cancer incidence. A schema involving three sequential trials for agent registration is described. In summary, a CP strategy that incorporates well-defined agents, clinical and validated SE, and high-risk cohorts defined by genetic and acquired risk factors in a series of well-designed randomized controlled trials provides an efficient pathway for evaluating and approving new agents for PCa prevention.

External beam radiotherapy CA 2000;50:349-375

Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy.

Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA, Pacholke HD, Liauw SL, Katz MS, Leibel SA, Scardino PT, Slawin KM.

Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
JAMA. 2004 Mar 17;291(11):1325-32. Abstract quote

CONTEXT: Salvage radiotherapy may potentially cure patients with disease recurrence after radical prostatectomy, but previous evidence has suggested that it is ineffective in patients at the highest risk of metastatic disease progression.

OBJECTIVE: To delineate patients who may benefit from salvage radiotherapy for prostate cancer recurrence by identifying variables associated with a durable response.

DESIGN, SETTING, AND PATIENTS: Retrospective review of a cohort of 501 patients at 5 US academic tertiary referral centers who received salvage radiotherapy between June 1987 and November 2002 for detectable and increasing prostate-specific antigen (PSA) levels after radical prostatectomy.

MAIN OUTCOME MEASURE: Disease progression after salvage radiotherapy, defined as a serum PSA value > or =0.1 ng/mL above the postradiotherapy PSA nadir confirmed by a second PSA measurement that was higher than the first by any amount, by a continued increase in PSA level after treatment, or by the initiation of androgen deprivation therapy after treatment.

RESULTS: Over a median follow-up of 45 months, 250 patients (50%) experienced disease progression after treatment, 49 (10%) developed distant metastases, 20 (4%) died from prostate cancer, and 21 (4%) died from other or unknown causes. The 4-year progression-free probability (PFP) was 45% (95% confidence interval [CI], 40%-50%). By multivariable analysis, predictors of progression were Gleason score of 8 to 10 (hazard ratio [HR], 2.6; 95% CI, 1.7-4.1; P<.001), preradiotherapy PSA level greater than 2.0 ng/mL (HR, 2.3; 95% CI, 1.7-3.2; P<.001), negative surgical margins (HR, 1.9; 95% CI, 1.4-2.5; P<.001), PSA doubling time (PSADT) of 10 months or less (HR, 1.7; 95% CI, 1.2-2.2; P =.001), and seminal vesicle invasion (HR, 1.4; 95% CI, 1.1-1.9; P =.02). Patients with no adverse features had a 4-year PFP of 77% (95% CI, 64%-91%). When treatment was given for early recurrence (PSA level < or =2.0 ng/mL), patients with Gleason scores of 4 to 7 and a rapid PSADT had a 4-year PFP of 64% (95% CI, 51%-76%) and of 22% (95% CI, 6%-38%) when the surgical margins were positive and negative, respectively. Patients with Gleason scores of 8 to 10, positive margins, and receiving early salvage radiotherapy had a 4-year PFP of 81% (95% CI, 57%-100%) when the PSADT was longer than 10 months and of 37% (95% CI, 16%-58%) when the PSADT was 10 months or less.

CONCLUSIONS: Gleason score, preradiotherapy PSA level, surgical margins, PSADT, and seminal vesicle invasion are prognostic variables for a durable response to salvage radiotherapy. Selected patients with high-grade disease and/or a rapid PSADT who were previously thought to be destined to develop progressive metastatic disease may achieve a durable response to salvage radiotherapy.

20-year outcome of patients with T1-3N0 surgically staged prostate cancer treated with external beam radiation therapy.

Gray CL, Powell CR, Riffenburgh RH, Johnstone PA.

Department of Urology, Naval Medical Center San Diego, San Diego, California, USA.

J Urol 2001 Jul;166(1):116-8 Abstract quote

PURPOSE: Patients with surgically staged localized prostate cancer treated with external beam radiation therapy were retrospectively analyzed for 15 and 20-year overall and cause specific survival. The need for additional therapy was also evaluated.

MATERIALS AND METHODS: We analyzed 145 patients who received external beam radiotherapy after negative staging pelvic lymphadenectomy. Followup data were available for 129 patients. Overall and cause specific survival was calculated with the Kaplan-Meier method.

RESULTS: Median followup was 14.9 years. Actuarial overall survival at 15 and 20 years was 45.9% and 24.6%, respectively. Cause specific survival at 15 and 20 years was 64.5% and 37.7% for having all patients dying of unknown causes censored, and 54.4% and 30.1% for those dying of unknown causes categorized as having prostate cancer, respectively. Of the patients who survived 47% were on hormonal therapy.

CONCLUSIONS: Longer followup after external beam radiation therapy continues to demonstrate a decrease in cause specific survival. Many patients ultimately require hormonal therapy.

Lymph node-positive prostate cancer: evaluation of the results of the combination of androgen deprivation therapy and radiation therapy.

Buskirk SJ, Pisansky TM, Atkinson EJ, Schild SE, O'Brien PC, Wolfe JT, Zincke H.

Department of Radiation Oncology, Mayo Clinic, Jacksonville, Fla 32082, USA

Mayo Clin Proc 2001 Jul;76(7):702-6 Abstract quote

OBJECTIVE: To evaluate the outcome of patients with pathologic stage IV prostate cancer treated with androgen ablation plus external-beam radiation therapy.

PATIENTS AND METHODS: Sixty consecutive patients treated between August 1986 and February 1995 with androgen ablation plus radiation therapy for stage IV (T1-4 N1 M0) adenocarcinoma of the prostate were selected for outcome analysis in this retrospective study. Bilateral pelvic lymphadenectomy was performed in 56 patients (93%). The 4 remaining patients had pelvic adenopathy on computed tomography, which was confirmed histologically in all patients. The median pretreatment prostate-specific antigen (PSA) level was 28.8 ng/mL (mean, 55 ng/ mL; range, 0.1-428 ng/mL). All patients received radiation therapy to the prostate, and 29 (48%) had pelvic node radiation. Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology criteria of 3 successive increases in the PSA level.

RESULTS: The median follow-up duration for surviving patients was 101.1 months (range, 20-134 months). Biochemical failure with (in 2 patients) or without (in 10 patients) clinically evident disease relapse was noted in 12 patients (20%). Four additional patients (7%) had clinical relapse without biochemical failure. Local recurrences were observed in 6 patients (10%), and this clinical impression was confirmed by biopsy in 4 patients. Thirteen patients (22%) died of causes related to prostate cancer. The biochemical relapse-free, clinical disease-free, overall, and cause-specific survival rates at 5 years were 82%, 84%, 76%, and 80%, respectively.

CONCLUSIONS: This observational case series of patients treated with the combination of external-beam radiation therapy and permanent androgen ablation for pathologic stage IV prostate cancer suggests that the addition of androgen deprivation therapy to radiation therapy may improve disease outcome. In the absence of randomized trial results, these observations may be beneficial in clinical decision making.

Brachytherapy CA 2000;50:380-393

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial.

Martinez AA, Kestin LL, Stromberg JS, Gonzalez JA, Wallace M, Gustafson GS, Edmundson GK, Spencer W, Vicini FA.

Department ofRadiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

Int J Radiat Oncol Biol Phys 2000 May 1;47(2):343-52 Abstract quote

PURPOSE: We analyzed our institution's experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach.

METHODS AND MATERIALS: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) >/= 10.0 ng/ml, Gleason score >/= 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition.

RESULTS: The pretreatment PSA level was >/= 10.0 ng/ml in 51% of patients. The biopsy Gleason score was >/= 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2-4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity.

CONCLUSION: Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.

Five-year biochemical outcome following permanent interstitial brachytherapy for clinical T1-T3 prostate cancer.

Merrick GS, Butler WM, Galbreath RW, Lief JH.

Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV 26003-6300, USA.

Int J Radiat Oncol Biol Phys 2001 Sep 1;51(1):41-8 Abstract quote

PURPOSE: To evaluate 5-year biochemical disease-free outcome for men with clinical T1b-T3a NxM0 1977 American Joint Committee on Cancer (1997 AJCC) adenocarcinoma of the prostate gland who underwent transperineal ultrasound-guided permanent prostate brachytherapy.

METHODS AND MATERIALS: Four hundred twenty-five patients underwent transperineal ultrasound-guided prostate brachytherapy using either 103Pd or 125I, for clinical T1b-T3a NxM0 (1997 AJCC) adenocarcinoma of the prostate gland, from April 1995 to October 1999. No patient underwent pathologic lymph-node staging. One hundred ninety patients were implanted with either 103Pd or 125I monotherapy; 235 patients received moderate-dose external beam radiation therapy (EBRT), followed by a prostate brachytherapy boost; 163 patients received neoadjuvant hormonal manipulation, in conjunction with either 103Pd or 125I monotherapy (77 patients) or in conjunction with moderate-dose EBRT and a prostate brachytherapy boost (86 patients). The median patient age was 68.0 years (range, 48.2-81.3 years). The median follow-up was 31 months (range, 11-69 months). Follow-up was calculated from the day of implantation. No patient was lost to follow-up. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology (ASTRO) consensus definition.

RESULTS: For the entire cohort, the 5-year actuarial biochemical no evidence of disease (bNED) survival rate was 94%. For patients with low-, intermediate-, and high-risk disease, the 5-year biochemical disease-free rates were 97.1%, 97.5%, and 84.4%, respectively. For hormone-naive patients, 95.7%, 96.4%, and 79.9% of patients with low-, intermediate-, and high-risk disease were free of biochemical failure. Clinical and treatment parameters predictive of biochemical outcome included: clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, risk group, age > 65 years, and neoadjuvant hormonal therapy. Isotope choice was not a statistically significant predictor of disease-free survival for any risk group. The median postimplant PSA was < or = 0.2 for all risk groups, regardless of hormonal status. The mean posttreatment PSA, however, was significantly lower for men implanted with 103Pd (0.14 ng/mL) than for those implanted with 125I (0.25 ng/mL), p < or = 0.001.

CONCLUSION: With a median follow-up of 31 months, permanent prostate brachytherapy results in a high probability of actuarial 5-year biochemical disease-free survival (DFS) for patients with clinical T1b-T3a (1997 AJCC) adenocarcinoma of the prostate gland, with an apparent plateau on the PSA survival curve.

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