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1.  Rb Loss is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma 
Purpose
Small cell neuroendocrine carcinoma of the prostate is likely to become increasingly common with recent advances in pharmacologic androgen suppression. Thus, developing molecular markers of small cell differentiation in prostate cancer will be important to guide diagnosis and therapy of this aggressive tumor.
Experimental Design
We examined the status of RB1, TP53 and PTEN in prostatic small cell and acinar carcinomas via immunohistochemistry (IHC), copy number alteration analysis and sequencing of formalin fixed paraffin-embedded specimens.
Results
We found Rb protein loss in 90% (26/29) of small cell carcinoma cases with RB1 allelic loss in 85% (11/13) of cases. Of acinar tumors occurring concurrently with prostatic small cell carcinoma, 43% (3/7) showed Rb protein loss. In contrast, only 7% (10/150) of primary high grade acinar carcinomas, 11% (4/35) of primary acinar carcinomas with neuroendocrine differentiation, and 15% (2/13) of metastatic castrate resistant acinar carcinomas showed Rb protein loss. Loss of PTEN protein was seen in 63% (17/27) of small cell carcinomas, with 38% (5/13) showing allelic loss. By IHC, accumulation of p53 was observed in 56% (14/25) of small cell carcinomas, with 60% (6/10) of cases showing TP53 mutation.
Conclusions
Loss of RB1 by deletion is a common event in prostatic small cell carcinoma and can be detected by validated IHC assay. As Rb protein loss rarely occurs in high grade acinar tumors, these data suggest that Rb loss is a critical event in the development of small cell carcinomas and may be a useful diagnostic and potential therapeutic target.
doi:10.1158/1078-0432.CCR-13-1982
PMCID: PMC3931005  PMID: 24323898
Prostatic adenocarcinoma; small cell carcinoma; tumor suppressor; RB1; TP53; PTEN
2.  Proposed Morphologic Classification of Prostate Cancer With Neuroendocrine Differentiation 
On July 31, 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of neuroendocrine differentiation in prostate cancer. The committee consisted of genitourinary oncologists, urologists, urological surgical pathologists, basic scientists, and translational researchers, with expertise in this field. It was concluded that the proceedings of the meeting should be reported in 2 manuscripts appealing to different target audiences, one to focus on surgical pathology and the other to review the molecular aspects of this disease. New clinical and molecular data emerging from prostate cancers treated by contemporary androgen deprivation therapies, as well as primary lesions, have highlighted the need for refinement of diagnostic terminology to encompass the full spectrum of neuroendocrine differentiation. It is envisioned that specific criteria associated with the refined diagnostic terminology will lead to clinically relevant pathologic diagnoses that will stimulate further clinical and molecular investigation and identification of appropriate targeted therapies.
doi:10.1097/PAS.0000000000000208
PMCID: PMC4112087  PMID: 24705311
small cell carcinoma; Paneth cell like; large cell neuroendocrine carcinoma; carcinoid; prostate adenocarcinonma
3.  Multiple cores of Gleason score 6 correlate with favourable findings at radical prostatectomy 
BJU international  2013;111(8):E306-E309.
Objective
To establish whether the good prognosis of Gleason score 6 (GS6) is maintained in the setting of multiple involved cores.
Patients and Methods
In total, 6156 men (from 1 April 2000 to 30 April 2007) with GS6 on biopsy underwent radical prostatectomy (RP) at our institution.
The number of positive cores was correlated with the outcome at RP.
Results
More positive cores correlated with less organ-confined disease (P < 0.001), positive margins (P < 0.012), increasing RP grade (P < 0.001) and increased seminal vesicles/lymph node involvement (P = 0.012).
For men with data available, the actuarial risk of being biochemically free of disease at 5 years was 93.2% when ≤6 cores were positive (812 men followed to 5 years) vs 89.1% if >6 cores were positive (41 men followed to 2 years) (P = 0.6).
Although the predicted ‘cure rate’ of >75% probability of a tumour showing no evidence of biochemical recurrence at 10 years after RP was statistically different between cases with ≤6 vs >6 positive cores (P < 0.0001), the outcome in both groups was still favourable (90.5% vs 84%).
Partin-like tables were generated factoring in the number of positive cores to predict organ-confined disease as a guide for urologists to perform nerve-sparing surgery.
For example, with T1c disease, there was a ≥75% probability of organ-confined disease with one to three positive cores regardless of prostate-specific antigen (PSA) level, and the same probability was present with four to six positive cores and a PSA level of 0–4 ng/mL.
Conclusion
A low Gleason score on biopsy is a powerful prognostic finding, such that this favourable outcome is maintained even in the setting of multiple positive cores with GS6.
doi:10.1111/j.1464-410X.2012.11680.x
PMCID: PMC3978182  PMID: 23350787
Gleason score 6; needle biopsy; radical prostatectomy
4.  Change in Prostate Cancer Grade Over Time in Men Followed Expectantly for Stage T1c Disease 
The Journal of urology  2008;179(3):901-905.
Purpose
We assessed whether the Gleason grade changes in men followed expectantly with nonpalpable prostate cancer diagnosed on needle biopsy (stage T1c).
Materials and Methods
We studied 241 men with stage T1c prostate cancer who were treated expectantly with repeat yearly needle biopsy sampling to assess for cancer progression. Following the initial cancer diagnosis all men had at least 1 other biopsy demonstrating cancer.
Results
Median patient age was 66 years. The number of biopsies showing cancer over time was 2 in 119 (49.4%), 3 in 74 (30.7%), 4 in 33 (13.7%) and 5 or greater in 15 (6.2%). The average followup for those without progression was 32.3 months. Of 241 cases 45 (18.7%) showed a significant change in grade from Gleason score 6 or less to Gleason score 7 or greater (Gleason score 7 in 41 cases, Gleason score 8 in 4 cases). Of 45 (53.5%) cases 24 that showed progression did so within 24 months of diagnosis.
Conclusions
Within the first 3 years after diagnosis of Gleason score 6 prostate cancer, there is a relatively low risk of grade progression. Within the first 3 years, our data suggest that in most cases tumor grade did not evolve but rather that the higher grade component was not initially sampled since most grade changes occurred relatively soon after biopsy. Grade progression does appear to occur in some men with long-term followup who had multiple biopsies showing Gleason score 6 followed by higher grade cancer.
doi:10.1016/j.juro.2007.10.062
PMCID: PMC4251426  PMID: 18207195
prostatic neoplasms; disease progression
5.  UTILITY OF GATA3 IMMUNOHISTOCHEMISTRY IN DIFFERENTIATING UROTHELIAL CARCINOMA FROM PROSTATE ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMAS OF THE UTERINE CERVIX, ANUS, AND LUNG 
Distinguishing invasive high-grade urothelial carcinoma (UC) from other carcinomas occurring in the genitourinary tract may be difficult. The differential diagnosis includes high-grade prostatic adenocarcinoma, spread from an anal squamous cell carcinoma (SCC), or spread from a uterine cervical SCC. In terms of metastatic UC, the most common problem is differentiating spread of UC to the lung versus a primary pulmonary SCC. Immunohistochemistry (IHC) for GATA binding protein 3 (GATA3), thrombomodulin (THROMBO), and Uroplakin III was performed on a tissue microarray (TMA) containing 35 cases of invasive high-grade UC. GATA3 IHC was also performed on TMAs containing 38 high-grade (Gleason score 8) prostatic adenocarcinomas, representative tissue sections from 15 invasive anal SCCs, representative tissue sections from 19 invasive cervical SCCs, and TMAs with 12 invasive cervical carcinomas of the cervix [SCC (n=10), SCC with neuroendocrine features (n=1), adenosquamous carcinoma (n=1)]. Additionally, GATA3 IHC was performed on representative tissue sections from 15 pulmonary UC metastases and a TMA with 25 SCCs of the lung and 5 pulmonary non-small cell carcinomas with squamous features. GATA3, THROMBO, and Uroplakin III were positive in 28 (80%), 22 (63%), and 21 (60%) cases of high-grade UC, respectively. All GATA3 positive staining was non-focal, 25 (89%) cases demonstrated moderate-strong staining, and 3 (11%) cases demonstrated weak staining. Of the 7 cases that failed to express GATA3, 5 were positive for THROMBO and/or Uroplakin III, while 2 cases were negative for all 3 markers. None of 38 high-grade prostatic adenocarcinomas were positive for GATA3. Weak GATA3 staining was present in occasional basal cells of benign prostate glands, in a few benign atrophic glands, and in urothelial metaplasia. Of the 15 cases of anal SCCs, 2 (7%) cases showed focal weak staining and 1 (3%) case showed focal moderate staining. Weak staining was also rarely observed in the benign anal squamous epithelium. Of the 31 uterine cervical carcinomas, 6 (19%) showed weak GATA3 staining (3 non-focal, 3 focal) and 2 (6%) demonstrated focal moderate staining. Twelve (80%) of the metastatic UC to the lung were positive for GATA3 with 11 cases showing diffuse moderate or strong staining and 1 case showing focal moderate staining. None of the pulmonary SCC or non-small cell carcinomas with squamous features were GATA3 positive. GATA3 IHC is a sensitive marker for UC and positive staining in UC is typically non-focal and moderate or strong in intensity. GATA3 is also highly specific in excluding high-grade prostate adenocarcinoma. Although some cervical and anal SCCs can be GATA3 positive, unlike in UC, staining is more commonly focal and weak. GATA3 is also a useful maker when diagnosing metastatic UC to the lung.
doi:10.1097/PAS.0b013e318260cde7
PMCID: PMC3444740  PMID: 22982890
6.  DO ADENOCARCINOMAS OF THE PROSTATE WITH GLEASON SCORE (GS) ≤6 HAVE THE POTENTIAL TO METASTASIZE TO LYMPH NODES? 
Although rare, there are cases within reported series of men with GS≤6 in radical prostatectomies that have pelvic lymph node (LN) metastases. However, there are no studies as to whether pelvic LN metastases occur in tumors GS≤6 using the International Society of Urological Pathology (ISUP) updated Gleason scoring system. We performed a search of the radical prostatectomy databases at 4 large academic centers for cases of GS≤6. Only prostatectomies submitted and embedded in entirety with pelvic lymph node dissections were included. A combined total of 14,123 cases were identified out of which 22 cases had a positive LN. Histopathology review of 19 cases (3 cases unavailable for review) showed higher grade than originally reported by the pathologists in all cases. Of the 17 pre-ISUP reviewed cases, 2 were upgraded to 4+3=7 with both cribriform and poorly formed glands. One case was upgraded to 4+3=7 with tertiary pattern five displaying cribriform glands, poorly formed glands, and cords of single cells. Eleven cases were upgraded to 3+4=7 with glomeruloid structures and small to large cribriform glands (1 of these also had ductal adenocarcinoma features). Two cases had tertiary pattern 4 with small cribriform glands. One case had a prominent colloid component that would currently be graded as 4+5=9 due to large cribriform glands and solid sheets of cells within mucin. Of the two post-ISUP cases, one demonstrated tertiary pattern 4 and the other showed Gleason score 3+4=7 with irregular cribriform glands. Under-grading primarily accounts for LN positivity with GS ≤6, which has decreased significantly since the adoption of the ISUP grading system in 2005. Out of over 14,000 totally embedded RPs from multiple institutions, there was not a single case of a GS≤6 tumor with LN metastases. In contrast to prevailing assumptions, Gleason score ≤6 tumors do not appear to metastasize to lymph nodes. Rather, Gleason patterns 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease.
doi:10.1097/PAS.0b013e3182556dcd
PMCID: PMC3421030  PMID: 22531173
Gleason score; radical prostatectomy; lymph node metastases
7.  Low Prostate-specific Antigen and No Gleason Score Upgrade Despite More Extensive Cancer During Active Surveillance Predicts Insignificant Prostate Cancer at Radical Prostatectomy 
Urology  2012;80(4):883-888.
OBJECTIVE
To identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance.
METHODS
Parameters evaluated at diagnosis and at biopsy reclassification included serum prostate-specific antigen, prostate-specific antigen density, number of positive cores, maximum percent involvement of cancer per core, and any interval negative biopsies. Gleason upgrading at biopsy reclassification was also assessed to predict insignificant cancer.
RESULTS
Mean time between diagnosis and radical prostatectomies was 30.3 months with a median of 3 biopsies (range 2–9). Nineteen of 67 (28.4%) had clinically insignificant cancer at radical prostatectomy. In the entire group, there were no variables significantly associated with insignificant cancer at radical prostatectomy. In a subgroup analysis of 37 patients without Gleason pattern 4/5 at biopsy reclassification, 16/37 (43.2%) showed insignificant cancer at radical prostatectomy. In this subgroup, prostate-specific antigen at diagnosis was significantly lower in men with insignificant cancer (3.7 ng/mL) vs significant cancer (5.4 ng/mL) (P = .0005). With prostate-specific antigen <4 ng/mL at diagnosis or at biopsy reclassification, 12/13 (92.3%) men showed insignificant cancer, whereas only 4/24 (16.7%) men with prostate-specific antigen >4 ng/mL both at diagnosis and at biopsy reclassification showed insignificant cancer.
CONCLUSION
Most men with biopsy reclassification while on active surveillance have significant disease at radical prostatectomy, justifying their treatment. Low prostate-specific antigen at diagnosis or at biopsy reclassification can predict a high probability of insignificant cancer in the absence of Gleason pattern 4/5 on biopsy. These men may be candidates for continuing active surveillance.
doi:10.1016/j.urology.2012.05.045
PMCID: PMC3715088  PMID: 22921697
8.  Adjuvant Leuprolide With or Without Docetaxel in Patients With High-Risk Prostate Cancer After Radical Prostatectomy (TAX-3501) 
Cancer  2013;119(20):3610-3618.
BACKGROUND
The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting.
METHODS
TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n = 228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of ≤60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value.
RESULTS
Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3–3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457–546 days). The nomogram’s predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P < .00001).
CONCLUSIONS
TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible.
doi:10.1002/cncr.28270
PMCID: PMC4124610  PMID: 23943299
prostate cancer; adjuvant therapy; docetaxel; leuprolide; testosterone recovery
9.  Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy 
BJU international  2012;110(8):1122-1128.
OBJECTIVE
To investigate preoperative characteristics that distinguish favourable and unfavourable pathological and clinical outcomes in men with high biopsy Gleason sum (8 – 10) prostate cancer to better select men who will most benefit from radical prostatectomy (RP).
PATIENTS AND METHODS
The Institutional Review Board-approved institutional RP database (1982 – 2010) was analysed for men with high-Gleason prostate cancer on biopsy; 842 men were identified.
The 10-year biochemical-free (BFS), metastasis-free (MFS) and prostate cancer-specific survival (CSS) were calculated using the Kaplan – Meier method to verify favourable pathology as men with Gleason <8 at RP or ≤ pT3a compared with men with unfavourable pathology with Gleason 8 – 10 and pT3b or N1.
Preoperative characteristics were compared using appropriate comparative tests.
Logistic regression determined preoperative predictors of unfavourable pathology.
RESULTS
There was favourable pathology in 656 (77.9%) men. The 10-year BFS, MFS and CSS were 31.0%, 60.9% and 74.8%, respectively.
In contrast, men with unfavourable pathological findings had significantly worse 10-year BFS, MFS and CSS, at 4.3%, 29.1% and 52.3%, respectively (all P < 0.001).
In multivariable logistic regression, a prostate-specific antigen (PSA) concentration of > 10 ng/mL (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.38 – 3.62, P = 0.001), advanced clinical stage (≥ cT2b; OR 2.55, 95% CI 1.55 – 4.21, P < 0.001), Gleason pattern 9 or 10 at biopsy (OR 2.55, 95% CI 1.59 – 4.09, P < 0.001), increasing number of cores positive with high-grade cancer (OR 1.16, 95% CI 1.01 – 1.34, P = 0.04) and > 50% positive core involvement (OR 2.25, 95% CI 1.17 – 4.35, P = 0.015) were predictive of unfavourable pathology.
CONCLUSIONS
Men with high-Gleason sum at biopsy are at high risk for biochemical recurrence, metastasis and death after RP; men with high Gleason sum and advanced pathological stage (pT3b or N1) have the worst prognosis.
Among men with high-Gleason sum at biopsy, a PSA concentration of > 10 ng/mL, clinical stage ≥ T2b, Gleason pattern 9 or 10, increasing number of cores with high-grade cancer and > 50% core involvement are predictive of unfavourable pathology.
doi:10.1111/j.1464-410X.2012.10986.x
PMCID: PMC4124597  PMID: 22373045
prostate cancer; high-risk; Gleason sum; outcomes
10.  Implication of Cell Kinetic Changes during the Progression of Human Prostatic Cancer1 
The daily percentage of cells proliferating and dying were determined for normal, premalignant, and cancerous prostatic cells within the prostate as well as for prostatic cancer cells in lymph node, sort tissue, and bone metastases from untreated and hormonally failing patients. These data demonstrate that normal prostatic glandular cells have an extremely low but balanced rate of cell proliferation and death (i.e., both <0.20%/day). This results in a steady-state, self-renewing condition in which there is no net growth, although the glandular cells are continuously being replaced (i.e., turnover) every 500 ± 79 days. Transformation of these cells into high-grade prostatic intraepithelial neoplastic cells initially involves an unbalanced increase in the daily percentage of cells proliferating versus dying, such that net continuous growth occurs (i.e., mean doubling time, 154 ± 22 days). As these early proliferation lesions continue to grow into late stage high-grade prostatic intraepithelial neo-plastic cells, the daily percentage of cells dying increases further to a point equaling the daily percentage of proliferation. This results in cessation of net growth while inducing a 6-fold increase in the turnover time of these cells (i.e., 56 ± 12 days), increasing their risk of further genetic changes. The transition of late stage high-grade prostatic intraepithelial neoplastic cells into localized prostatic cancer cells involves no further increase in proliferation but a decrease in death resulting in net continuous growth of localized prostatic cancers with a mean doubling time of ≥475 days. As compared to localized prostatic cancer cells, metastatic prostatic cancer cells within lymph nodes or bones of untreated patients have an increase in daily rate of proliferation coupled with a reduction in their daily percentage of cell death, producing net growth rates with a mean doubling time of 33 ± 4 days and 54± 5 days, respectively. Remarkably, there is no further increase in proliferation in hormonally failing patients, but instead an increase in the daily percentage of androgen-independent prostatic cancer cells dying within sort tissue or bone metastases. These changes result in doubling times which are two to three times longer (i.e., 126 ± 21 and 94 ± 15 days) in these lymph node and bone meta-static sites, respectively, compared to similar sites in hormonally untreated patients. These data demonstrate that the daily percentage of proliferation for either androgen-dependent or -independent metastatic prostatic cancer cells is remarkably low (i.e., <3.0%/day), consistent with why antiproliferative chemotherapy has been of such limited value against such metastatic cells. These results also suggest that prostatic carcinogenesis starts in the second to third decade of life and may require over 50 years for progression to pathologically detectable metastatic disease.
PMCID: PMC4086477  PMID: 9816006
11.  Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors 
Alterations in methylation of CpG dinucleotides at the 5 position of deoxycytidine residues (5mC) are a hallmark of cancer cells, including testicular germ cell tumors. Virtually all testicular germ cell tumors are believed to be derived from intratubular germ cell neoplasia unclassified (IGCNU), which is thought to arise from primordial germ cells. Prior studies revealed that seminomas contain reduced levels of global DNA methylation as compared with nonseminomatous germ cell tumors. Smiraglia et al have proposed a model whereby seminomas arise from IGCNU cells derived from primordial germ cells that have undergone 5mC erasure, and nonseminomas arise from IGCNU cells derived from primordial germ cells that have already undergone de novo methylation after the original erasure of methylation and contain normal 5mC levels. Yet the methylation status of IGCNU has not been determined previously. We used immunohistochemical staining against 5mC to evaluate global methylation in IGCNU and associated invasive testicular germ cell tumors. Strikingly, staining for 5mC was undetectable (or markedly reduced) in the majority of IGCNU and seminomas, yet there was robust staining in nonseminomatous germ cell tumors. The lack of staining for 5mC in IGCNU and seminomas was also found in mixed germ cell tumors containing both seminomatous and nonseminomatous components. Lack of 5mC staining was not related to a lack of the maintenance methyltransferase (DNA methyltransferase 1) protein. We conclude that testicular germ cell tumors are derived in most cases from IGCNU cells that have undergone developmentally programmed 5mC erasure and that the degree of subsequent de novo methylation is most closely related to the differentiation state of the neoplastic cells. That is, IGCNU cells and seminoma cells remain unmethylated, whereas all other histological types appear to arise after de novo methylation.
doi:10.1038/modpathol.2008.127
PMCID: PMC4086525  PMID: 18622385
seminoma; nonseminomatous germ cell tumors; IGCNU; global methylation
12.  Pathological Examination of Radical Prostatectomy Specimens in Men with Very Low Risk Disease at Biopsy Reveals Distinct Zonal Distribution of Cancer in Black American Men 
The Journal of urology  2013;191(1):60-67.
Purpose
Of men with very low risk prostate cancer at biopsy recent evidence shows that black American men are at greater risk for adverse oncologic outcomes after radical prostatectomy. We studied radical prostatectomy specimens from black and white men at very low risk to determine whether there are systematic pathological differences.
Materials and Methods
Radical prostatectomy specimens were evaluated in men with National Comprehensive Cancer Network® (NCCN) very low risk prostate cancer. At diagnosis all men underwent extended biopsy sampling (10 or more cores) and were treated in the modern Gleason grade era. We analyzed tumor volume, grade and location in 87 black and 89 white men. For each specimen the dominant nodule was defined as the largest tumor with the highest grade.
Results
Compared to white men, black men were more likely to have significant prostate cancer (61% vs 29%), Gleason 7 or greater (37% vs 11%, each p <0.001) and a volume of greater than 0.5 cm3 (45% vs 21%, p = 0.001). Dominant nodules in black men were larger (median 0.28 vs 0.13 cm3, p = 0.002) and more often anterior (51% vs 29%, p = 0.003). In men who underwent pathological upgrading the dominant nodule was also more frequently anterior in black than in white men (59% vs 0%, p = 0.001).
Conclusions
Black men with very low risk prostate cancer at diagnosis have a significantly higher prevalence of anterior cancer foci that are of higher grade and larger volume. Enhanced imaging or anterior zone sampling may detect these significant anterior tumors, improving the outcome in black men considering active surveillance.
doi:10.1016/j.juro.2013.06.021
PMCID: PMC4042393  PMID: 23770146
prostate; prostatic neoplasms; African Americans; risk; neoplasm grading
13.  Immunohistochemical Panel to Identify the Primary Site of Invasive Micropapillary Carcinoma 
Invasive micropapillary carcinoma (IMC) is generally an aggressive morphologic variant that has been described in the bladder, lung, breast, salivary gland, gastrointestinal tract, and ovary. Given the morphologic similarities between IMCs arising from different organ systems and the high propensity of this histologic subtype for lymphatic metastasis, it may be necessary to use immunohistochemical (IHC) markers to determine the primary site of an IMC. Few studies have compared the IHC profiles of IMCs originating from different sites. We tested a panel of 11 IHC markers for their ability to distinguish urothelial, lung, breast, and ovarian IMC using a tissue microarray constructed with primary tumor tissue from 47 patients with IMC (13 bladder, 6 lung, 16 breast, and 12 ovarian). For each tumor, correct classification as IMC was verified by reverse polarity MUC1 expression. We found that immunostaining for uroplakin, CK20, TTF-1, estrogen receptor (ER), WT-1 and/or PAX8, and mammaglobin was the best panel for determining the most likely primary site of IMC. The best markers to identify urothelial IMC were uroplakin and CK20, whereas p63, high molecular weight cytokeratin, and thrombomodulin were less sensitive and specific. Lung IMC was uniformly TTF-1 positive. Breast IMC was ER positive, mammaglobin positive, and PAX8/WT-1 negative, while ovarian IMC was ER positive, mammaglobin negative, and PAX8/WT-1 positive. In the metastatic setting, or when IMC occurs without an associated in situ or conventional carcinoma component, staining for uroplakin, CK20, TTF-1, ER and WT-1, and/or PAX8, and mammaglobin is the best panel for accurately classifying the likely primary site of IMC.
doi:10.1097/PAS.0b013e3181962dcd
PMCID: PMC3484367  PMID: 19238079
micropapillary carcinoma; urothelial; bladder; breast; lung; ovary; immunohistochemistry
14.  Interobserver Variability in Histologic Evaluation of Radical Prostatectomy Between Central and Local Pathologists: Findings of TAX 3501 Multinational Clinical Trial 
Urology  2010;77(5):1155-1160.
OBJECTIVES
To determine the agreement between the local pathologist findings and central pathologist findings using data from the TAX 3501 trial. TAX 3501 was a randomized, multinational trial comparing the outcomes of patients with high-risk prostate cancer treated with androgen deprivation with or without docetaxel after radical prostatectomy (RP). Patient eligibility was determined by a minimal 5-year progression-free survival estimate of 60% using Kattan’s nomogram.
METHODS
The pathologic findings were reassessed in 257 consecutive RP specimens by 2 central pathologists and compared with the local pathologist data.
RESULTS
For the Gleason score, agreement was found in 181 (70%) of 257 cases, upgrading in 57 (75%), and downgrading in 25% of the RP specimens The most frequent upgrade was from Gleason score 7 to 8 or 9 and downgrading from Gleason score 8 to 7. Of the upgrades and downgrades, 37% and 21% were of 2 Gleason score points, respectively. For the tumor extent, agreement was found in 179 (70%) of 256 specimens, with upstaging in 70 (91%) and downstaging in 9%. The most frequent upstage was from focal to extensive extraprostatic extension (45%). For seminal vesicle invasion, agreement was found for 238 (93%) of 256 RP specimens Almost equal rates of underdiagnosing and overdiagnosing seminal vesicle invasion was observed. For margin status, agreement was present for 229 (89%) of 256 cases. The central pathologist review led to reclassification as a positive margin in 17 cases and a negative margin in 10. For lymph node status, 2 (1%) of 210 RP specimens had positive nodes identified only by the central pathologist. Agreement was observed in 154 negative and 54 positive cases.
CONCLUSIONS
Significant interobserver variations were found between the central and local pathologists. From the central pathologist review, the progression-free survival estimates were altered in 31 patients (13%), including 22 who were reassigned a greater risk estimate, rendering them study eligible. Thus, interobserver variability affected prognostication and trial accrual.
doi:10.1016/j.urology.2010.08.031
PMCID: PMC3449146  PMID: 21146858
15.  Prognostic Gleason grade grouping: data based on the modified Gleason scoring system 
BJU international  2013;111(5):753-760.
Objective
• To investigate pathological and short-term outcomes since the most recent Gleason system modifications by the International Society of Urological Pathology (ISUP) in an attempt to divide the current Gleason grading system into prognostically accurate Gleason grade groups.
Patients and Methods
• We queried the Johns Hopkins Radical Prostatectomy Database (1982–2011), approved by the institutional review board, for men undergoing radical prostatectomy (RP) without a tertiary pattern since 2004 and identified 7869 men.
• Multivariable models were created using preoperative and postoperative variables; prognostic grade group (Gleason grade ≤6; 3 + 4; 4 + 3; 8; 9–10) was among the strongest predictors of biochemical recurrence-free (BFS) survival.
Results
• Significant differences were noted among the Gleason grade groups at biopsy; differences were noted in the race, PSA level, clinical stage, number of positive cores at biopsy and the maximum percentage of positive cores among the Gleason grade groups at RP.
• With a median (range) follow-up of 2 (1–7) years, 5-year BFS rates for men with Gleason grade ≤6, 3 + 4, 4 + 3, 8 and 9–10 tumours at biopsy were 94.6, 82.7, 65.1, 63.1 and 34.5%, respectively (P < 0.001 for trend); and 96.6, 88.1, 69.7, 63.7 and 34.5%, respectively (P < 0.001), based on RP pathology.
Conclusions
• The 2005 ISUP modifications to the Gleason grading system for prostate carcinoma accurately categorize patients by pathological findings and short-term biochemical outcomes but, while retaining the essence of the Gleason system, there is a need for a change in its reporting to more closely reflect tumour behaviour.
• We propose reporting Gleason grades, including prognostic grade groups which accurately reflect prognosis as follows: Gleason score ≤6 (prognostic grade group I); Gleason score 3+4=7 (prognostic grade group II); Gleason score 4+3=7 (prognostic grade group III); Gleason score 4+4=8 (prognostic grade group (IV); and Gleason score 9–10 (prognostic grade group (V).
doi:10.1111/j.1464-410X.2012.11611.x
PMCID: PMC3978145  PMID: 23464824
Gleason grade; prostate carcinoma; radical prostatectomy
16.  Serum prostate-specific antigen (PSA) concentration is positively associated with rate of disease reclassification on subsequent active surveillance prostate biopsy in men with low PSA density 
BJU international  2013;113(4):561-567.
Objective
To investigate the association between serum prostate-specific antigen (PSA) concentration at active surveillance (AS) entry and disease reclassification on subsequent AS biopsy (‘biopsy reclassification’) in men with low PSA density (PSAD).
To investigate whether a clinically meaningful PSA threshold for AS eligibility/ineligibility for men with low PSAD can be identified based on risk of subsequent biopsy reclassification.
Patients and Methods
We included men enrolled in the Johns Hopkins AS Study (JHAS) who had a PSAD of <0.15 ng/mL/g (640 men).
We estimated the incidence rates (IRs; per 100 person years) and hazard ratios (HR) of biopsy reclassification (Gleason score ≥ 7, any Gleason pattern 4 or 5, ≥3 positive cores, or ≥50% cancer involvement/biopsy core) for categories of serum PSA concentration at the time of entry into AS.
We generated predicted IRs using Poisson regression to adjust for age and prostate volume, mean percentage free PSA (ratio of free to total PSA) and maximum percentage biopsy core involvement with cancer.
Results
The unadjusted IRs (per 100 person years) of biopsy reclassification across serum PSA concentration at entry into JHAS showed, in general, an increase; however, the pattern was not linear with higher IRs in the group ≥ 4 to <6 ng/mL (14.2, 95% confidence interval [CI] 11.8–17.2%) when compared with ≥ 6 to <8 ng/mL (8.4, 95% CI 5.7–12.3%) but almost similar IRs when compared with the group ≥ 8 to <10 ng/mL (14.8, 95% CI 8.4–26.1%).
The adjusted predicted IRs of reclassification showed a similar non-linear increase in IRs, whereby the rates around 4 ng/mL were similar to the rates around 10 ng/mL.
Conclusion
Risk for biopsy reclassification increased non-linearly across PSA concentration in men with low PSAD, whereby no obvious clinically meaningful threshold could be identified. This information could be incorporated into decision-making for AS. However, longer follow-up times are needed to warrant final conclusions.
doi:10.1111/bju.12131
PMCID: PMC3978167  PMID: 23746233
active surveillance; PSA; patient selection
17.  Pathological Outcomes in Men with Low Risk and Very Low Risk Prostate Cancer: Implications on the Practice of Active Surveillance 
The Journal of urology  2013;190(4):1218-1222.
Purpose
We assessed oncologic outcomes at surgery in men with low risk and very low risk prostate cancer who were candidates for active surveillance.
Materials and Methods
In a prospectively collected institutional database, we identified 7,486 subjects eligible for active surveillance who underwent radical retropubic prostatectomy. Candidates were designated as being at low risk (stage T1c/T2a, prostate specific antigen 10 ng/ml or less, and Gleason score 6 or less) or very low risk (stage T1c, prostate specific antigen density 0.15 or less, Gleason score 6 or less, 2 or fewer positive biopsy cores, 50% or less cancer involvement per core) based on preoperative data. Adverse findings were Gleason score upgrade (score 7 or greater) and nonorgan confined cancer on surgical pathology. The relative risk of adverse findings in men at low risk with very low risk disease was evaluated in a multivariate model using Poisson regression.
Results
A total of 7,333 subjects met the criteria for low risk disease and 153 had very low risk disease. The proportion of subjects at low risk found to have Gleason score upgrade or nonorgan confined cancer on final pathology was 21.8% and 23.1%, respectively. Corresponding values in those at very low risk were 13.1% and 8.5%, respectively. After adjusting for age, race, year of surgery, body mass index, and prostate specific antigen at diagnosis, the relative risk of Gleason score upgrade in men with low risk vs very low risk disease was 1.89 (95% CI 1.21–2.95). The relative risk of nonorgan confined cancer was 2.06 (95% CI 1.19–3.57).
Conclusions
Men with very low risk prostate cancer were at significantly lower risk for adverse findings at surgery compared to those with low risk disease. These data support the stratification of low risk cancer when selecting and counseling men who may be appropriate for active surveillance.
doi:10.1016/j.juro.2013.04.071
PMCID: PMC3978170  PMID: 23643603
prostate; prostatic neoplasms; risk; disease progression; treatment outcome
18.  Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance 
BJU international  2013;111(7):1037-1045.
Objective
To assess the performance of multiparametric magnetic resonance imaging (MRI) in identifying pathological-index (path-index) lesions, defined as cancer present in the same prostate sextant in two separate surveillance biopsies, in men followed within an active surveillance (AS) programme for low-risk prostate cancer (CaP) with extended follow-up.
Materials and Methods
A total of 50 men, representing >215 person-years of follow-up in an AS programme, who were referred for prostate MRI were randomly chosen to have their images reviewed by a radiologist with expertise in prostate MRI, who was blinded to biopsy results.
Index lesions on MRI were defined as a single suspicious lesion ≥10 mm or >2 lesions in a given prostate sextant. Lesions on MRI were considered suspicious if ≥2 abnormal parameters co-registered anatomically. Path-index lesions were defined as cancer present in a given prostate sextant on two separate biopsy sessions.
Sensitivity and specificity were calculated to test the performance of MRI for identifying path-index lesions.
Clinical and pathological features were compared between men with and without a MRI-index lesion.
Results
A total of 31 path-index and 13 MRI-index lesions were detected in 22 and 10 patients, respectively.
Multiparametric MRI demonstrated excellent specificity and negative predictive value (0.974 and 0.897, respectively) for the detection of path-index lesions. Sensitivity (0.19) and positive predictive value (0.46) were considerably lower.
Patients with an index lesion on MRI were younger and less likely to have met the ‘Epstein’ criteria for very low-risk CaP.
Compared with men without an MRI lesion, a significant increase in biopsy reclassification was noted for men with a MRI lesion (40 vs 12.5%, P = 0.04).
Conclusions
A non-suspicious MRI was highly correlated with a lack of path-index lesions in an AS population.
Multiparametric MRI may be useful in both the selection and monitoring of patients undergoing AS.
doi:10.1111/j.1464-410X.2012.11641.x
PMCID: PMC3978179  PMID: 23464904
prostate cancer; surveillance; magnetic resonance imaging; sensitivity and specificity
19.  Association of [-2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer 
The Journal of urology  2012;188(4):1131-1136.
Purpose
Previous studies have suggested an association between [-2]proPSA expression and prostate cancer detection. Less is known about the utility of this marker in following prostate cancer patients on active surveillance. Thus, our objective was to examine the relationship between [-2]proPSA and biopsy results in men enrolled in an active surveillance program.
Materials and Methods
In 167 men from our institutional active surveillance program, we used Cox proportional hazards models to examine the relationship between [-2]proPSA and annual surveillance biopsy results. The outcome of interest was biopsy reclassification (Gleason score ≥7, or >2 positive biopsy cores, or >50% involvement of any core with cancer). We also examined the association of biopsy results with total PSA, %fPSA, [-2]proPSA/%fPSA, and the Beckman Coulter Prostate Health Index [phi=([-2]proPSA/fPSA) x (tPSA)½].
Results
While on active surveillance (median time from diagnosis 4.3 years), 63 (37.7%) men demonstrated biopsy reclassification based on the above criteria, including 28 (16.7%) of whom had reclassification based on Gleason score upgrading (Gleason score≥7). Baseline and longitudinal %fPSA, %[-2]proPSA, [-2]proPSA/%fPSA, and phi measurements were significantly associated with biopsy reclassification, and %[-2]proPSA and phi provided the greatest predictive accuracy for high-grade cancer.
Conclusions
In men on active surveillance, measures based on [-2]proPSA such as phi, appear to provide improved prediction of biopsy reclassification during follow-up. Additional validation is warranted to determine whether clinically useful thresholds can be defined, and to better characterize the role of %[-2]proPSA and phi in conjunction with other markers in monitoring patients enrolled in active surveillance.
doi:10.1016/j.juro.2012.06.009
PMCID: PMC3976250  PMID: 22901577
proPSA; PSA; prostate cancer; biopsy; active surveillance
20.  A Broad Survey of Cathepsin K Immunoreactivity in Human Neoplasms 
Cathepsin K is consistently and diffusely expressed in alveolar soft part sarcoma (ASPS) and a subset of translocation renal cell carcinomas (RCCs). However, cathepsin K expression in human neoplasms has not been systematically analyzed. We constructed tissue microarrays (TMA) from a wide variety of human neoplasms, and performed cathepsin K immunohistochemistry (IHC). Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC. In contrast to carcinomas, cathepsin K labeling was relatively common (54.6%) in the 414 mesenchymal lesions studied, including granular cell tumor, melanoma, and histiocytic lesions, but not paraganglioma, all of which are in the morphologic differential diagnosis of ASPS. Cathepsin K IHC can be helpful in distinguishing ASPS and translocation RCC from some but not all of the lesions in their differential diagnosis.
doi:10.1309/AJCPDTRTO2Z4UEXD
PMCID: PMC3957187  PMID: 23355199
Cathepsin K; TFE3; TFEB; Immunohistochemistry
21.  An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011 
BJU international  2012;111(1):10.1111/j.1464-410X.2012.11324.x.
Objective
To update the 2007 Partin tables in a contemporary patient population.
Patients and Methods
The study population consisted of 5,629 consecutive men who underwent RP and staging lymphadenectomy at the Johns Hopkins Hospital between January 1, 2006 and July 30, 2011 and met inclusion criteria.
Polychotomous logistic regression analysis was used to predict the probability of each pathologic stage category: organ-confined disease (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+) based on preoperative criteria.
Preoperative variables included biopsy Gleason score (6, 3+4, 4+3, 8, and 9–10), serum PSA (0–2.5, 2.6–4.0, 4.1–6.0, 6.1–10.0, greater than 10.0 ng/mL), and clinical stage (T1c, T2c, and T2b/T2c).
Bootstrap re-sampling with 1000 replications was performed to estimate 95% confidence intervals for predicted probabilities of each pathologic state.
Results
The median PSA was 4.9 ng/mL, 63% had Gleason 6 disease, and 78% of men had T1c disease.
73% of patients had OC disease, 23% had EPE, 3% had SV+ but not LN+, and 1% had LN+ disease. Compared to the previous Partin nomogram, there was no change in the distribution of pathologic state.
The risk of LN+ disease was significantly higher for tumours with biopsy Gleason 9–10 than Gleason 8 (O.R. 3.2, 95% CI 1.3–7.6).
The c-indexes for EPE vs. OC, SV+ vs. OC, and LN+ vs. OC were 0.702, 0.853, and 0.917, respectively.
Men with biopsy Gleason 4+3 and Gleason 8 had similar predicted probabilities for all pathologic stages.
Most men presenting with Gleason 6 disease or Gleason 3+4 disease have <2% risk of harboring LN+ disease and may have lymphadenectomy omitted at RP.
Conclusions
The distribution of pathologic stages did not change at our institution between 2000–2005 and 2006–2011.
The updated Partin nomogram takes into account the updated Gleason scoring system and may be more accurate for contemporary patients diagnosed with prostate cancer.
doi:10.1111/j.1464-410X.2012.11324.x
PMCID: PMC3876476  PMID: 22834909
prostate cancer; prostatectomy; prostage-specific antigen; nomograms; staging
23.  Cytoplasmic PTEN Protein Loss Distinguishes Intraductal Carcinoma of the Prostate from High Grade Prostatic Intraepithelial Neoplasia 
Intraductal carcinoma of the prostate is a marker of aggressive disease. However, intraductal carcinoma exists on a morphologic continuum with high grade prostatic intraepithelial carcinoma (PIN) and distinguishing intraductal carcinoma from PIN is a common diagnostic dilemma with significant clinical implications. We evaluated whether immunostains for PTEN and ERG can sensitively identify intraductal carcinoma and accurately distinguish it from high grade PIN. A combined immunostain for PTEN, ERG, p63 and CK903 was developed and validated. Radical prostatectomy specimens with lesions meeting criteria for intraductal carcinoma (n=45), intraductal cribriform proliferations falling short of intraductal carcinoma (n=15), and PIN lesions (n=39) were retrospectively identified and assessed for PTEN and ERG. Cytoplasmic PTEN loss was identified in 84% (38/45) of the intraductal carcinoma and 100% (15/15) of intraductal cribriform proliferation cases. In contrast, cytoplasmic PTEN loss was never observed in PIN (0/39) (p<0.0001). Of the 53 cases of intraductal carcinoma or intraductal cribriform proliferation with cytoplasmic PTEN loss, it was homogeneously lost in 42 cases (79%). Weak, focal nuclear positivity for PTEN was retained in 31 of these 42 cases (74%). ERG expression was identified in 58% (26/45) of intraductal carcinoma and 67% (10/15) of intraductal cribriform proliferations compared to 13% (5/39) of PIN. Concordance between the PTEN/ERG status of the intraductal carcinoma lesions and the concurrent invasive carcinoma was high (>95% and p<0.0001 for each), and substantially less for PIN and the concurrent invasive tumor (83% for PTEN and 67% for ERG; p=NS for each). Cytoplasmic PTEN loss occurs in the majority of intraductal carcinoma and intraductal cribriform proliferation cases. Cytoplasmic PTEN loss was never observed in PIN (100% specificity). Our study identifies PTEN loss as a potentially useful marker to distinguish intraductal carcinoma from PIN and provides a plausible molecular explanation for why intraductal carcinoma is associated with poor prognosis.
doi:10.1038/modpathol.2012.201
PMCID: PMC3610824  PMID: 23222491
Prostatic adenocarcinoma; intraductal carcinoma; PTEN; ERG; immunohistochemistry
24.  Prognostic value of Her-2/neu and DNA Index for Progression, Metastasis and Prostate Cancer-specific Death in Men with Long-Term Follow-up after Radical Prostatectomy 
Abnormal DNA content in tumor cells represents large scale chromosomal alterations and reflects later changes of genetic instability. Her-2/neu oncogene is amplified in 20% to 30% of breast and ovarian cancer patients and is associated with poor prognosis. Therefore, we evaluated prognostic value of Her-2/neu expression and DNA content measurements in 252 clinically localized PCa patients with long-term follow-up after radical prostatectomy for progression, metastasis and PCa-specific death. Her-2/neu expression was determined by immunohistochemistry and DNA content measurements employed Feulgen-stained cancer nuclei captured using static image cytometry system. Cox proportional hazard regression & Kaplan Meir plots were used to identify significant prognostic factors for progression, metastasis and PCa-specific death. The proportions of Her-2/neu positive and high %DNA index tumors significantly increased from non-progressor to progressors without metastasis to progressors with metastasis (p<0.0001; <0.0001). Further, the proportions of Her-2/neu positive and high %DNA index tumors significantly increased from patients who died from another cause without progression to those who died from another cause with progression to those died with PCa-specific death (p=0.027; <0.0001). Her-2/neu expression and %DNA index were significant prognosticators for progression (p≤0.001), metastasis (p≤0.01) PCa-specific death (p≤0.04) in univariate analyses. Multivariately, Her-2/neu expression and %DNA index were also significant for progression (p=0.001), metastasis (p=0.001), and PCa-specific death (p=0.02). When all other clinicopathologic information is available, the increment in concordance index by addition of either Her-2/neu or DNA index was ∼2% and of both biomarkers was ∼3% for progression, metastasis and PCa-specific death free survival models. Therefore, patients with Her-2/neu positive and high %DNA index are at a higher risk for disease progression, metastasis and PCa-specific death. Further, Her-2/neu expression and %DNA index may be used with clinicopathologic parameters for prediction of long-term prognosis in PCa.
doi:10.1002/ijc.23838
PMCID: PMC2652562  PMID: 18767043
25.  Long Term Assessment of Prostate Cancer Progression Free Survival: Evaluation of Pathological Parameters, Nuclear Shape and Molecular Biomarkers of Pathogenesis 
The Prostate  2008;68(16):1806-1815.
Background
Molecular pathways of proliferation, angiogenesis, neuroendocrine differentiation, apoptosis and alterations in nuclear structure of cancer epithelial cells are important in the pathogenesis of prostate cancer (PCa). Therefore, we evaluated the prognostic value of these parameters multivariately in 105 clinically localized PCa tumors with long-term follow-up after radical prostatectomy for progression-free survival (PFS).
Method
Nuclear roundness variance (NRV) was calculated for tumor nuclei using the graphic tracing DynaCELL system. Immunohistochemistry assessed expression of Ki67, PCNA (proliferation), Chromogranin A (neuroendocrine differentiation), CD31 (angiogenesis), BCL2 (apoptosis), and Her-2/neu (oncogene) in the tumors. Cox proportional hazards regression, Spearman’s rank correlation, and Kaplan-Meier plots were employed to analyze the data.
Results
Gleason score, focal vs. non-focal extra-prostatic extension, organ confined status, NRV, Her-2/neu, CD-31 and Ki67 were univariately significant predictors of PFS. NRV was the most significant prognostic indicator with the highest concordance index (0.7) for PFS. Gleason score, NRV and Her-2/neu were multivariately significant and yielded a concordance index of 0.77.
Conclusion
Her-2/neu oncogene and NRV were shown to be significant in the prediction of PFS. The assessment of alterations in nuclear structure using NRV proved to be the most significant factor in the prediction of PFS. Integration of image analysis-based NRV and molecular biomarkers with pathologic parameters should be considered for validation in the prediction of PFS.
doi:10.1002/pros.20848
PMCID: PMC2577716  PMID: 18767028

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