Kirk J. Wojno

The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

The Utility of Basal Cell—specific Anti-cytokeratin Antibody (34βe12) in the Diagnosis of Prostate Cancer: A Review of 228 Cases

Basal cell-specific anti-cytokeratin antibody (34βE12) decorates the basal cells of benign prostatic epithelium by standard immunohistochemical techniques, whereas adenocarcinoma of the prostate lacks immunoreactivity with this antibody. We reviewed our experience with this antibody to determine its utility in the diagnosis of adenocarcinoma of the prostate as well as its pattern of usage at a tertiary medical center. In all, 7,242 prostate specimens from 5.262 men were seen at Johns Hopkins Hospital between 1/89 and 4/93. Immunostaining for basal cell-specific cytokeratin (34βE12) was originally used for diagnostic purposes in 289 questionable areas from 228 cases; 45% of these cases were seen in consultation. The distribution of cases using 34βE12 was 52% needle biopsies, 32% transurethral prostatic resections (TURPs), 13% radical prostatectomies, and 3% open enucleations. These procedures constituted 2.8% of all needle biopsies, 7.2% of all TURPs, 1.7% of all radical prostatectomies, and 3.5% of all enucleations seen during this time period. For this study the hematoxylin and eosin stain was reviewed without knowledge of the original diagnosis, a diagnosis was favored, the 34βE12 stain was examined, and a final diagnosis was determined. The 34βE12 stain established (14%), confirmed (58%), or changed (2%) our favored diagnoses, while 18% remained or became equivocal. The 34βE12 stain was of no use in 8% of the cases, yet we felt we were still able to render a final diagnosis even without the help of the stain. The differential diagnoses in the questionable foci using 34βE12 were cancer versus focus of atypical glands (44%), adenosis (39%), prostatic intraepithelial neoplasia (PIN) (8%), basal cell hyperplasia (5%), and atrophy (4%). However, 34βE12 was used in only 15–20% of all cases of adenosis and basal cell hyperplasia and in < 2% of PIN and atrophy cases seen during this time. Reasons for equivocal results were loss of suspicious glands on cut downs used for staining (49%), too few glands to rely on negative staining (23%), technical problems (15%), limited number of positive staining glands in a small focus (7%), and cautery artifact (6%). Although equivocal cases tended to have fewer negative stained glands than cases diagnosed with cancer, there was no minimum number of negative stained glands required to establish a diagnosis of cancer. From these data we conclude that 34βE12 staining is a useful tool in confirming, establishing, or changing the diagnosis in questionable foci seen in the everyday practice of surgical pathology. We feel that it is most useful in the workup of foci of atypical glands on needle biopsy and in differentiating low-grade adenocarcinoma from adenosis on TURP. Staining with 34βE12 is a cost-effective means to work up a needle biopsy as compared with ultrasound-guided re-biopsy.

The Relationship Between Prostatic Intraepithelial Neoplasia and Prostate Cancer: Critical Issues

AbstractPurpose: Prostatic intraepithelial neoplasia (PIN) is often considered to be a premalignant lesion and the main precursor of invasive carcinoma of the prostate. We evaluated the evidence for and against PIN as a premalignant lesion and determined guidelines for the clinical management of PIN.Materials and Methods: Literature analysis of histopathological, morphometric, phenotypic and molecular genetic evidence of progression and of clinical findings regarding PIN was done. Literature searches were performed on MEDLINE with relevant key words.Results: PIN, like prostate cancer, occurs most frequently in the peripheral zone of the prostate and is usually located in close proximity to prostate cancer. The relative PIN and prostate cancer volumes vary inversely. Prostate specific antigen in cases of PIN appears to be intermediate between prostate cancer and normal levels, although this elevation may be explained by concomitant prostate cancer or benign prostatic hyperplasia. Deoxyribonucleic acid ploi...

A MODEL FOR THE NUMBER OF CORES PER PROSTATE BIOPSY BASED ON PATIENT AGE AND PROSTATE GLAND VOLUME

PURPOSE The systematic sextant biopsy is currently the gold standard for the tissue diagnosis of prostate cancer. However, it is unknown whether this 6 core approach provides optimal sampling of all prostate glands in men of all ages. The goal of the current study was to determine the appropriate number of cores per prostate biopsy based on patient age and prostate gland volume. MATERIALS AND METHODS Patient age and tumor volume doubling time were used to calculate life threatening, clinically significant tumor volumes at diagnosis for 5-year intervals of patient age. A mathematical model was created to determine the minimum number of cores necessary to identify these life threatening tumor volumes in prostate glands 10 to 80 cm.3 without detecting clinically insignificant cancers. RESULTS Younger men and men with larger prostate glands require more than 6 cores to ensure the diagnosis of life threatening prostate cancer. These prostates are currently under sampled by sextant biopsy. In a select group of older men who require fewer than 6 cores sextant biopsy may over sample these prostates and lead to over treatment. CONCLUSIONS The standard sextant biopsy provides optimal sampling of only a minority of prostate glands. An approach to prostate biopsy based on patient age and prostate gland volume maximizes the detection of clinically significant prostate cancer.

DETERMINATION OF THE "REFLEX RANGE" AND APPROPRIATE CUTPOINTS FOR PERCENT FREE PROSTATE- SPECIFIC ANTIGEN IN 413 MEN REFERRED FOR PROSTATIC EVALUATION USING THE AxSYM SYSTEM

OBJECTIVES Prostate-specific antigen (PSA) exists in the serum in two clinically important molecular forms: free PSA and PSA complexed to alpha 1-antichymotrypsin. Total PSA approximates the sum of the free and complexed forms. Preliminary investigations have illustrated the potential benefits of using percent free PSA to enhance the clinical utility of PSA in distinguishing benign prostate disease from prostate cancer. The current study defines the optimal range of total PSA for measuring percent free PSA (reflex range) and generates appropriate cutpoints for percent free PSA within this range. METHODS A total of 413 patients, 225 (54%) with benign prostate disease (mean age, 67 years) and 188 (46%) with prostate cancer (mean age, 66 years), who had PSA values between 2.0 and 20.0 ng/mL participated in the investigation. All patients underwent a sextant biopsy to establish the diagnosis. The serum specimens were assayed with the AxSYM PSA assay (total PSA) and AxSYM Free PSA assay (Abbott Laboratories; Abbott Park, IL). Percent free PSA was calculated for all patients. Receiver operating characteristic (ROC) curves were generated for various ranges of total PSA to determine the reflex range that maximized the increase in sensitivity and specificity of percent free PSA over total PSA. Within the optimal range, the ROC curves were utilized to generate cutpoints for percent free PSA to be used in clinical practice. RESULTS The appropriate reflex range for the utility of percent free PSA was 3.0 to 10.0 ng/mL. The appropriate cutpoint for percent free PSA when the total PSA value was 3.0 to 4.0 ng/mL to achieve 90% sensitivity for the detection of prostate cancer was 0.19. This approach resulted in a biopsy rate of 73% and a cancer detection rate of 44% in men with a total PSA value between 3.0 and 4.0 ng/mL. The appropriate cutpoint for percent free PSA when the total PSA value was 4.1 to 10.0 ng/mL to ensure 95% sensitivity for detection of prostate cancer was 0.24. Within the range of 4.1 to 10.0 ng/mL, this approach resulted in 13% fewer negative biopsies and failure to detect 5% of the cancers. CONCLUSIONS Percent free PSA should be utilized in patients with a total serum PSA value between 3.0 and 10.0 ng/mL. In patients with a total PSA value between 3.0 and 4.0 ng/mL, percent free PSA enhanced the detection of prostate cancer (improving sensitivity). In patients with a total PSA concentration ranging from 4.1 to 10.0 ng/mL, negative biopsies were eliminated (improving specificity).

Decreased Galectin-3 Expression in Prostate Cancer

Galectin‐3 is a carbohydrate‐binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin‐3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples.

Magnetic resonance imaging anatomy of the female urethra: A direct histologic comparison**

Objective To define the urethral structures visible on magnetic resonance imaging (MRI) relevant to stress urinary incontinence. Methods The urethra and surrounding tissues were harvested from 13 female cadavers (ages 21–81) and fixed in 10% buffered formalin. High-resolution T1- and T2-weighted images were obtained at 1.5 tesla. Mallory trichrome-stained histologic sections were prepared in corresponding planes from the cadaveric specimens. Immunohistologic stains for smooth muscle (actin) and vascular endothelium (CD-34 and factor VIII) were obtained on two specimens. Histology and MRI were compared using side-by-side correlation of projected images and by superimposing projected images. Comparison was also made to a non-cadaveric urethral MRI of a 29-year-old woman and to the MRI of another specimen imaged pre- and post-fixation. Results Distinct layers of the cadaveric urethra were seen best on proton density and T2-weighted images. From the center to the periphery, a series of concentric rings were visible: an inner bright ring, the mucosa; a dark ring, the submucosa; an outer bright ring, the smooth muscle of the urethra in a loose connective tissue matrix; and a peripheral dark ring, the striated urogenital sphincter muscle of the urethra in dense connective tissue. No significant alterations were caused by fixation. These cadaveric images matched the non-cadaveric MRI of the 29-year-old woman. Conclusion The internal urethral anatomy visible on high-resolution MRI can be identified and confirmed histologically, and these findings may form the basis for future anatomic investigation of stress urinary incontinence and other urethral abnormalities.

Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Age-specific distribution of serum prostate-specific antigen in a community-based study of African-American men

OBJECTIVES Previous studies have observed higher age-specific serum prostate-specific antigen (PSA) values in African-American (AA) men without prostate cancer compared to white men, leading some to recommend race-specific PSA reference ranges for the early detection of prostate cancer. The primary objective of the Flint Mens Health Study was to determine age-specific PSA reference values in a community-based sample of AA men, aged 40 to 79 years. METHODS A probability sample of 943 AA men was selected from households in Genesee County, Michigan. Men without a prior history of prostate cancer/surgery were invited to participate in a prostate cancer screening protocol, consisting of measurement of serum total PSA, free/total PSA ratio, and digital rectal examination. Sextant biopsies were recommended, based on total PSA greater than 4.0 ng/mL and/or an abnormal digital rectal examination. RESULTS From the sample of 943 men, 732 were eligible, 432 had blood drawn for PSA testing, and 374 completed all phases of the clinical examination. The 95th percentile PSA values were estimated to range from 2.36 ng/mL for men in the fifth decade to 5.59 ng/mL for men in the eighth decade. The 95th percentile values for age-specific PSA were comparable to those observed in a similar study of white men in Olmsted County, Minnesota. The median and 5th percentile values for free/total PSA did not vary significantly across age. CONCLUSIONS The minor differences in PSA reference ranges between AA and white men may not be of sufficient magnitude to recommend the use of race-specific PSA reference ranges for screening.

8p22> loss concurrent with 8c gain is associated with poor outcome in prostate cancer

OBJECTIVES A critical issue in the management of prostate cancer is the ability to distinguish patients at risk of disease recurrence. The aim of this study was to determine whether specific physical alterations of chromosome 8 may be associated with disease recurrence and poor outcome using postoperative prostate-specific antigen (PSA) values as surrogate end points. METHODS To test this hypothesis, we examined paired normal and tumor radical prostatectomy tissues from 25 patients with prostate cancer for chromosome 8 alterations using dual fluorescence in situ hybridization with a fluorescein-labeled 8p22-specific (8p) cosmid probe and a rhodamine-labeled 8-centromere-specific (8c) probe. The probes were enumerated in 200 nuclei per tissue. RESULTS Of the 25 tumors examined, 22 demonstrated distinct classes of genetic alterations, or nuclear types, including disomy for 8p and 8c (1 tumor), loss of 8p and disomy for 8c (10 tumors), or loss of 8p concurrent with gain of 8c (11 tumors). The presence of even a small population of tumor nuclei characterized by the loss of 8p concurrent with the gain of 8c was correlated with poor tumor grade (P = 0.009), preoperative PSA values 11 ng/mL or higher (P = 0.022), high tumor stage (P = 0.086), and detectable, rising postoperative PSA values (P = 0.086). These observations are consistent with the hypothesis that a gain of chromosome 8 is associated with poor outcome in prostate cancer. CONCLUSIONS 8p loss concurrent with 8c gain may successfully predict disease recurrence and poor clinical outcome before the observation of detectable postoperative PSA values in patients with prostate cancer.