To identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance.
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.
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.
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.
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.
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.
Prostatic adenocarcinoma; intraductal carcinoma; PTEN; ERG; immunohistochemistry
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.
Gleason score; radical prostatectomy; lymph node metastases
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.
The pathologic findings were reassessed in 257 consecutive RP specimens by 2 central pathologists and compared with the local pathologist data.
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.
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.
Plasmacytoid urothelial carcinoma is a rare but aggressive variant of bladder cancer with no clear therapeutic guidelines. Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been linked to oncogenesis in conventional bladder cancer. Several antineoplastic agents targeting mTOR pathway are currently available. This study assesses mTOR pathway status as well as c-myc and p27 expression. We retrieved 19 archival cases of plasmacytoid urothelial carcinoma from two institutions. Whole tissue sections were evaluated for immunoexpression of phosphatase and tensin homolog (PTEN), phosphorylated mTOR, phosphorylated protein kinase B (AKT), phosphorylated S6, c-myc, and p27. We evaluated intensity (0 to 3+) and extent (0%–100%) of expression for all markers. An H score was calculated as the sum of products of intensity and extent for each marker and used during analysis. In addition, PTEN loss was defined as absence of expression in >10% of tumor cells. We encountered PTEN loss in 28%. Higher H score for nuclear phosphorylatedAKT and a lowerHscore for phosphorylated S6 was encountered in muscle invasive tumors compared to non-muscle invasive tumors (P = .007 and P = .009, respectively). Although a trend for negative prognostic impact on overall survival for higher phosphorylated mTOR expression was noted (P = .051), markers expression levels failed to predict survival in our cohort. We found dysregulation of mTOR pathway members in urinary bladder plasmacytoid urothelial carcinoma, suggesting that the use of mTOR pathway inhibitors might be beneficial for patients with this aggressive tumor.
Mammalian target of rapamycin; PTEN; Plasmacytoid urothelial carcinoma; Bladder
To evaluate the prognostic significance of six epigenetic biomarkers (AIM1, CDH1, KIF1A, MT1G, PAK3 and RBM6 promoter hypermethlation) in a homogeneous group of prostate cancer patients, following radical prostatectomy.
Patients and Methods
Biomarker analyses were performed retrospectively on tumors from 95 prostate cancer patients all with a Gleason score of 3+4=7 and a minimum follow up period of 8 years. Using Quantitative Methylation Specific PCR (QMSP), we analyzed the promoter region of six genes in primary prostate tumor tissues. Time to any progression was the primary endpoint and development of metastatic disease and/or death from prostate cancer was a secondary endpoint. The association of clinicopathological and biomolecular risk factors to recurrence was performed using the Log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used.
At a median follow-up time of 10 years, 48 patients (50.5%) had evidence of recurrence: biochemical/PSA relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression, the significant factors were: older age, HR=0.95 (95% CI: 0.91, 1.0) (P=0.03), positive lymph nodes HR=2.11 (95%CI: 1.05, 4.26) (P=0.04) and decreased hypermethylation of AIM1 HR=0.45 (95%CI: 0.2, 1.0) (P=0.05).
Methylation status of AIM1 in the prostate cancer specimen may predict for time to recurrence in Gleason 3+4=7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.
To evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.
PATIENTS AND METHODS
We prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high-risk features.
All men underwent repeat 12-core ultrasonography-guided biopsy.
DNA methylation of glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy.
The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).
On repeat biopsy, 21/86 (24%) men had prostate cancer.
APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06–1.36), indicating APC has significantly higher NPV.
Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1.
Combining both methylation markers produced a performance similar to that of APC alone.
APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.
APC methylation provided a very high NPV with a low percentage of false-negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy.
The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.
prostate cancer; biopsy; methylation; APC; GSTP1
To investigate the outcomes and potential effect of improved longitudinal screening in men presenting with high-risk (advanced clinical stage [> T2b], Gleason score 8–10 or prostate-specific antigen [PSA] level > 20 ng/mL) prostate cancer (PC).
Patients and methods
The Institutional Review Board approved, Institutional Radical Prostatectomy Database (1992–2010) was queried for men with high-risk PC based on D’Amico criteria.
Year of surgery was divided into two cohorts: the Early PSA Era (EPE, 1992–2000) and the Contemporary PSA Era (CPE, 2001–2010).
PC features and outcomes were evaluated using appropriate comparative tests.
In total, 667 men had high-risk PC in the EPE and 764 in the CPE.
In the EPE, 598 (89.7%) men presented with one high-risk feature; 173 (29.0%) men had a Gleason score of 8–10 on biopsy. In the CPE, 717 (93.9%) men presented with one high-risk feature (P = 0.004) and 494 (68.9%) men had a Gleason score of 8–10.
At 10 years, biochemical-free survival (BFS) was 44.1% and 36.4% in the EPE and CPE, respectively (P = 0.04); metastases-free survival (MFS) was 77.1% and 85.1% (P = 0.6); and PC-specific survival (CSS) was 83.3% and 96.2% (P = 0.5).
BFS, MFS and CSS were worse for men with more than one high-risk feature in both eras.
Over the PSA era, an increasing percentage of men with high-risk PC were categorized by a biopsy Gleason score of 8–10.
The accumulation of multiple high-risk features increases the risk of biochemical recurrence, the development of metastases and death from PC.
BFS, MFS and CSS are stable over the PSA era for these men. The balance between a greater proportion of men having high Gleason disease and a greater proportion with small, less advanced tumours may explain the stability in MFS and CSS over time.
high-risk; outcomes; prostate cancer
Renal medullary carcinoma is an aggressive renal neoplasm without currently available effective therapy to our knowledge. Topoisomerase II α is a gyrase involved in cell proliferation, and DNA maintenance and repair. Topoisomerase II α is a target of inhibiting agents such as anthracyclines. Triggered by a recent response to topoisomerase II α inhibitors in a patient with renal medullary carcinoma, we evaluated topoisomerase II α expression in relation to the proliferation index and topoisomerase II α gene copy number status in a larger series of patients with renal medullary carcinoma.
Materials and Methods
Archival tissues from 14 renal medullary carcinomas were retrieved from our 3 institutions. Immunohistochemistry was performed using monoclonal antibodies for topoisomerase II α and Ki67. The percent of cells with positive nuclear staining was assessed in the highest area of expression for each marker. A previously suggested greater than 5% cutoff was used for topoisomerase II α over expression. The topoisomerase II α gene copy number was evaluated using fluorescence in situ hybridization. Locus specific topoisomerase II α gene and chromosome 17 centromere probes were used. The total number of topoisomerase II α and chromosome 17 centromere signals was counted in 150 cells per tumor and a topoisomerase II α-to-chromosome 17 centromere signal ratio was calculated in each tumor. A topoisomerase II α-to-chromosome 17 centromere ratio of 2.0 or greater and less than 0.8 was used as a cutoff for amplification and deletion, respectively. The percent of tumor cells with polysomic, eusomic or monosomic chromosome 17 status was also determined.
On immuno-expression analysis topoisomerase II α immunohistochemistry was technically inconclusive in 1 renal medullary carcinoma. Topoisomerase II α was over expressed in 11 of 13 renal medullary carcinomas (85%) (median 50%, range 1% to 80%). As expected, a high Ki67 proliferation index was noted in 13 of 14 tumors (median 87.5%, range 2% to 100%). Ki67 expression was greater than topoisomerase II α expression in all 13 informative tumors. A strong, statistically significant correlation was found for topoisomerase II α and Ki67 expression (pairwise CC 0.9, p = 0.0000). Topoisomerase II α over expression was associated with shorter survival (p = 0.000). On fluorescence in situ hybridization no topoisomerase II α amplification was detected in any of the 14 renal medullary carcinomas, including the 11 with topoisomerase II α over expression. Topoisomerase II α gene deletions were noted in 4 tumors. Two of 4 deletions were associated with chromosome 17 monosomy and 2 were in eusomic chromosome 17 tumors.
Topoisomerase II α is over expressed in 85% of renal medullary carcinomas, potentially supporting the use of topoisomerase II α inhibitor agents to treat this aggressive renal tumor. Our findings suggest that topoisomerase II α over expression in our renal medullary carcinoma cohort was not due to gene amplification, but rather to transcriptional or post-transcriptional modifications. The significance of the incidentally found topoisomerase II α deletions in 28% of renal medullary carcinomas requires further evaluation.
kidney; carcinoma; kidney medulla; DNA topoisomerase II alpha; gene deletion
Collecting duct carcinoma (CDC) is a relatively rare but aggressive type of renal malignancy with variable morphologic features. One of the World Health Organization diagnostic criteria for CDC is the exclusion of urothelial carcinoma of renal pelvis from the differential diagnosis. PAX8 is a novel lineage restricted transcription factor expressed in renal tubules. We investigated the expression pattern of PAX8 in CDC and its utility, in combination with p63, in resolving the differential diagnosis of CDC versus upper tract urothelial carcinoma (UUC).
Archival tissues from 21 CDC and 34 UUC were retrieved from our institutional files. Immunohistochemistry for PAX8 and p63 were performed on routine and tissue microarray sections using standard immunohistochemistry protocol. Intensity of nuclear staining was evaluated for each marker and assigned an incremental 0, 1+, 2+, and 3+ score. Extent of staining was categorized as focal (<25%), nonfocal (25% to 75%), or diffuse (>75%).
CDC: All 21 (100%) CDC were positive for PAX8. Intensity of expression was moderate to strong (2+/3+) in 19 cases (90%). Extent of staining was diffuse in 13 of 21 tumors. The p63 was positive in 3 of 21 (14%) CDC cases (PAX8+/p63+). UUC: The 34 UUC included 5 pT1, 4 pT2, and 25 pT3/pT4 tumors. Thirty-one of 34 (91.2%) UUC were negative for PAX8, whereas 33 of 34 (97%) were p63 positive. Staining intensity was moderate in 15 cases (44%), of which 12 were nonfocal or diffuse. The unique p63-negative UUC was a pT1 tumor that was also negative for PAX8 (PAX8−/p63−).
We propose the use of the combination of PAX8 and p63 in the diagnosis of poorly differentiated renal sinus epithelial neoplasms where the differential diagnosis includes CDC versus UUC. The immunoprofile of PAX8+/p63− supports the diagnosis of CDC with a sensitivity of 85.7% and a specificity of 100%. In contrast, a (PAX8−/p63+) profile supports the diagnosis of UUC with a sensitivity of 88.2% and a specificity of 100%. The inverse PAX8/p63 expression seen in CDC and UUC supports a renal tubular rather than an urothelial differentiation in CDC given the nephric lineage restriction of PAX8.
collecting duct carcinoma; urothelial carcinoma; PAX8; p63
Small cell carcinoma of the prostate is a rare subtype with an aggressive clinical course. Despite the frequent occurrence of ERG gene rearrangements in acinar carcinoma, the incidence of these rearrangements in prostatic small cell carcinoma is unclear. In addition, molecular markers to distinguish prostatic small cell carcinomas from lung and bladder small cell carcinomas may be clinically useful. We examined the occurrence of ERG gene rearrangements by fluorescence in situ hybridization in prostatic, bladder and lung small cell carcinomas. We also examined the expression of ERG, androgen receptor (AR) and NKX3-1 by immunohistochemistry in prostatic cases. Overall, 45% (10/22) of prostatic small cell carcinoma cases harbored ERG rearrangements, whereas no cases of bladder or lung small cell carcinomas showed ERG rearrangement (0/12 and 0/13, respectively). Of prostatic small cell carcinoma cases, 80% (8/10) showed ERG deletion and 20% (2/10) showed ERG translocation. In 83% (5/6) of prostatic small cell carcinoma cases in which a concurrent conventional prostatic acinar carcinoma component was available for analysis, there was concordance for the presence/absence of ERG gene rearrangement between the different subtypes. ERG, AR and NKX3-1 protein expression was detected in a minority of prostatic small cell carcinoma cases (23, 27 and 18%, respectively), while these markers were positive in the majority of concurrent acinar carcinoma cases (66, 83 and 83%, respectively). The presence of ERG rearrangements in nearly half of the prostatic small cell carcinomas is a similar rate of rearrangement to that found in prostatic acinar carcinomas. Furthermore, the high concordance rate of ERG rearrangement between the small cell and acinar components in a given patient supports a common origin for these two subtypes of prostate cancer. Finally, the absence of ERG rearrangement in bladder or lung small cell carcinomas highlights the utility of detecting ERG rearrangement in small cell carcinomas of unknown primary for establishing prostatic origin.
androgen receptor; ERG; gene fusion; NKX3-1; prostatic adenocarcinoma; small cell carcinoma; TMPRSS2-ERG
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.
micropapillary carcinoma; urothelial; bladder; breast; lung; ovary; immunohistochemistry
Ductal adenocarcinoma of the prostate is an unusual subtype that may be associated with a more aggressive clinical course, and is less responsive to conventional therapies than the more common prostatic acinar adenocarcinoma. However, given its frequent association with an acinar component at prostatectomy, some have challenged the concept of prostatic ductal adenocarcinoma as a distinct clinicopathologic entity. We studied the occurrence of the TMPRSS2-ERG gene fusion, in 40 surgically resected ductal adenocarcinoma cases, and in their associated acinar component using fluorescence in situ hybridization. A group of 38 ‘pure’ acinar adenocarcinoma cases matched with the ductal adenocarcinoma group for pathological grade and stage was studied as a control. Compared with the matched acinar adenocarcinoma cases, the TMPRSS2-ERG gene fusion was significantly less frequently observed in ductal adenocarcinoma (45 vs 11% of cases, P=0.002, Fisher’s exact test). Here, of the ductal adenocarcinoma cases with the gene fusion, 75% were fused through deletion, and the remaining case was fused through translocation. The TMPRSS2-ERG gene fusion was also rare in the acinar component of mixed ductal–acinar tumors when compared with the pure acinar adenocarcinoma controls (5 vs 45%, P = 0.001, Fisher’s exact test). In 95% of the ductal adenocarcinoma cases in which a concurrent acinar component was analyzed, there was concordance for presence/absence of the TMPRSS2-ERG gene fusion between the different histologic subtypes. In the control group of pure acinar adenocarcinoma cases, 59% were fused through deletion and 41% were fused through translocation. The presence of the TMPRSS2-ERG gene fusion in some cases of prostatic ductal adenocarcinoma supports the concept that ductal adenocarcinoma and acinar adenocarcinoma may be related genetically. However, the significantly lower rate of the gene fusion in pure ductal adenocarcinoma cases underscores the fact that genetic and biologic differences exist between these two tumors that may be important for future therapeutic strategies.
Prostatic adenocarcinoma; ductal adenocarcinoma; endometrioid; TMPRSS2-ERG; gene fusion
Glomerulations in prostatic adenocarcinoma are characterized by dilated glands containing intraluminal cribriform structures with a single point of attachment, resembling a renal glomerulus. On prostate biopsy, glomerulations are exclusively associated with carcinoma and not associated with benign mimickers. However, the Gleason grading of carcinoma with glomerulations on needle biopsy remains controversial. We prospectively collected 45 prostate needle biopsies containing carcinoma with glomeruloid features from our consult files for a 9-month period and examined the association between glomerulations and the presence of concurrent high-grade carcinoma. Glomerulations were overwhelmingly associated with high-grade cancer on the same core, composed of either Gleason pattern 4 (n = 36, 80% of cases) or Gleason pattern 5 (n = 2, 4% of cases). Only a minority of glomerulations were surrounded exclusively by pattern 3 cancer (n = 7, 16% of cases) on the same core. Most of the cases with surrounding pattern 4 cancer were scored as 3 + 4 = 7 (n = 24, 66%), whereas a smaller fraction were scored as 4 + 3 = 7 (n = 9, 26%), and only a minority were 4 + 4 = 8 (n = 3, 9%). In most cases, glomeruloid change was present on the same core as the highest Gleason score carcinoma of the case. None of the pattern 3 cases and only a minority of the pattern 4 cancers had higher Gleason score carcinoma on additional cores (n = 5, 14%). Glomeruloid structures are a rare but diagnostic feature of prostatic carcinoma on needle biopsy. Our data indicate that glomerulations are overwhelmingly associated with concurrent Gleason pattern 4 or higher-grade carcinoma. In several cases, transition could be seen among small glomerulations, large glomeruloid structures, and cribriform pattern 4 cancer. These data suggest that glomerulations represent an early stage of cribriform pattern 4 cancer and, until follow-up data are available, are best graded as Gleason pattern 4.
Prostatic adenocarcinoma; Glomeruloid; Glomerulations; Gleason grading
For prostate cancer patients with small, lower-grade tumors, expectant management with delayed surgical intervention (active surveillance) is a rarely used therapeutic option because the opportunity for cure may be lost. We compared outcomes of 38 patients with small, lower-grade prostate cancer in an expectant management program who underwent delayed surgical intervention at a median of 26.5 months (95% confidence interval [CI] = 17 to 32 months; range = 12.0–73.0 months) after diagnosis with 150 similar patients who underwent immediate surgical intervention at a median of 3.0 months (95% CI = 2 to 4 months; range = 1.0–9.0 months) after diagnosis. Noncurable cancer was defined as adverse pathology associated with a less than 75% chance of remaining disease-free for 10 years after surgery. Noncurable cancer was diagnosed in nine (23%) of the 38 patients in the delayed intervention cohort and in 24 (16%) of the 150 men in the immediate intervention group. After adjusting for age and prostate-specific antigen (PSA) density (i.e., PSA value divided by prostate volume) in a Mantel–Haenszel analysis, the risks of noncurable cancer associated with delayed and immediate intervention did not differ statistically significantly (relative risk = 1.08, 95% CI = 0.55 to 2.12; P = .819, two-sided Cochran–Mantel–Haenszel statistic). Age, PSA, and PSA density were all statistically significantly associated with the risk of noncurable cancer (P = .030, .013, and .008, respectively; two-sided chi-square test). Thus, delayed prostate cancer surgery for patients with small, lower-grade prostate cancers does not appear to compromise curability.
We sought to predict biopsy progression in men on prostate cancer surveillance.
Materials and Methods
A total of 376 men with a median age of 65.5 years (range 45.8 to 79.5) with low risk prostate cancer on surveillance underwent at least 1 followup biopsy after diagnosis. Progression was defined at surveillance biopsy as Gleason pattern 4 or 5, greater than 2 biopsy cores with cancer or greater than 50% involvement of any core with cancer. Proportional hazards analysis was used to evaluate the association between covariates and progression at surveillance biopsy. The Kaplan-Meier method was used to estimate the probability of disease progression.
Of the 376 men 123 (32.7%) had progression a median of 5.6 years (range 0.3 to 8.5) after diagnosis. Percent free PSA and maximum percent core involvement at diagnosis were associated with progression, allowing stratification of the progression risk at initial surveillance biopsy. Cancer presence and PSA density at initial surveillance biopsy were associated with subsequent progression, allowing stratification of the cumulative incidence of progression 3 years after initial surveillance biopsy (cumulative incidence 11.1%, 95% CI 4.7 to 25.2 for negative biopsy and PSAD less than 0.08 ng/ml/cm3 vs 53.6%, 95% CI 38.6 to 70.0 for positive biopsy and PSAD 0.08 ng/ml/cm3 or greater, log rank test p < 0.0001).
Clinical variables at diagnosis and at first surveillance biopsy during followup in an active surveillance program can be used to inform men about the likelihood of an unfavorable prostate biopsy. This information could improve patient and physician acceptance of active surveillance in carefully selected men.
prostate; prostatic neoplasms; biopsy; prostate specific antigen; disease progression
The pathological characteristics of stage Tlc cancers in the era of widespread prostate specific antigen (PSA) testing were determined, and the ability of pretreatment parameters to predict tumor significance in men with stage Tlc disease was evaluated.
Materials and Methods
Of 336 men with stage Tlc prostate cancer seen between 1994 and 1996, 240 (71.4%) were treated with radical prostatectomy, 20 (6%) with radiation therapy and 76 (22.6%) expectantly. Recommendations for treatment were based on previously determined criteria predictive of a significant stage Tlc cancer (more than 0.2 cm.3: 1) PSA density 0.15 ng./ml./gm. or more, 2) Gleason score 7 or greater, 3) 3 or more cores involved with cancer, or 4) 50% or more involvement of any core with cancer. Pathological evaluation of prostatectomy specimens allowed classification of tumors as insignificant (confined tumor smaller than 0.2 cm.3 with a Gleason score of less than 7), minimal (confined tumor 0.2 to less than 0.5 cm.3 with a Gleason score of less than 7), moderate (0.5 cm.3 or larger disease, or capsular penetration with a Gleason score of less than 7) and advanced (capsular penetration with a Gleason score of 7 or more, or positive margins, seminal vesicles or lymph nodes). Pathological characteristics of tumors in this series were compared to a previous series of 157 men with stage Tlc cancers who underwent radical prostatectomy between 1988 and 1992.
Of 240 men who underwent radical prostatectomy tumors were insignificant in 40 (17%), minimal in 29 (12%), moderate in 124 (52%) and advanced in 47 (19%). An increase in organ confined cancers (51 to 72%) and a decrease in positive margins (17 to 8%) were noted when comparing stage Tlc series (1988 to 1992 versus 1994 to 1996) but the percentage of insignificant tumors remained stable (16 versus 17%) between series. Ultrasound and sextant biopsies were available for review in 72 cases (current series). If the pretreatment criteria used to recommend therapy suggested significant tumor (64 cases) then insignificant tumor was present in only 10 (16%). If pretreatment criteria suggested insignificant tumor (8 cases), insignificant or minimal tumor was present in 6 (75%) and moderate organ confined disease was present in 2 (25%). The absence of a lesion on ultrasound and measurement of total length of cancer within the biopsy specimen were not predictive of an insignificant tumor.
In a nonscreened population stage Tlc cancers are being discovered earlier with widespread PSA testing. Even with the detection of earlier cancers we demonstrated that it is possible to minimize the number of patients with small tumors who will undergo radical prostatectomy using pretreatment criteria to counsel men regarding appropriate management options.
adenocarcinoma; prostatic neoplasms; pathology
The role of TMPRSS2–ERG gene fusion in prostate cancer prognostication remains controversial. We evaluated the prognostic role of TMPRSS2–ERG fusion using fluorescence in situ hybridization analysis in a case–control study nested in The Johns Hopkins retropubic radical prostatectomy cohort. In all, 10 tissue microarrays containing paired tumors and normal tissues obtained from 172 cases (recurrence) and 172 controls (non-recurrence) matched on pathological grade, stage, race/ethnicity, and age at the time of surgery were analyzed. All radical prostatectomies were performed at our institution between 1993 and 2004. Recurrence was defined as biochemical recurrence, development of clinical evidence of metastasis, or death from prostate carcinoma. Each tissue microarray spot was scored for the presence of TMPRSS2–ERG gene fusion and for ERG gene copy number gains. The odds ratio of recurrence and 95% confidence intervals were estimated from conditional logistic regression. Although the percentage of cases with fusion was slightly lower in cases than in controls (50 vs 57%), the difference was not statistically significant (P=0.20). The presence of fusion due to either deletion or split event was not associated with recurrence. Similarly, the presence of duplicated ERG deletion, duplicated ERG split, or ERG gene copy number gain with a single ERG fusion was not associated with recurrence. ERG gene polysomy without fusion was significantly associated with recurrence (odds ratio 2.0, 95% confidence interval 1.17–3.42). In summary, TMPRSS2–ERG fusion was not prognostic for recurrence after retropubic radical prostatectomy for clinically localized prostate cancer, although men with ERG gene copy number gain without fusion were twice more likely to recur.
fluorescence in situ hybridization; nested case–control study; prognosis; prostate adenocarcinoma; TMPRSS2–ERG fusion
Minute prostatic adenocarcinomas are considered to be of insufficient virulence. Given recent suggestions of TMPRSS2–ERG gene fusion association with aggressive prostatic adenocarcinoma, we evaluated the incidence of TMPRSS2–ERG fusion in minute prostatic adenocarcinomas. A total of 45 consecutive prostatectomies with minute adenocarcinoma were used for tissue microarray construction. A total of 63 consecutive non-minimal, Gleason Score 6 tumors, from a separate PSA Era prostatectomy tissue microarray, were used for comparison. FISH was carried out using ERG break-apart probes. Tumors were assessed for fusion by deletion (Edel) or split (Esplit), duplicated fusions and low-level copy number gain in normal ERG gene locus. Minute adenocarcinomas: Fusion was evaluable in 32/45 tumors (71%). Fifteen out of 32 (47%) tumors were positive for fusion. Six (19%) were of the Edel class and 7 (22%) were classified as combined Edel+Esplit. Non-minute adenocarcinomas (pT2): Fusion was identified in 20/30 tumors (67%). Four (13%) were of Edel class and 5 (17%) were combined Edel+Esplit. Duplicated fusions were encountered in 5 (16%) tumors. Non-minute adenocarcinomas (pT3): Fusion was identified in 19/33 (58%). Fusion was due to a deletion in 6 (18%) tumors. Seven tumors (21%) were classified as combined Edel+Esplit. One tumor showed Esplit alone. Duplicated fusions were encountered in 3 (9%) cases. The incidence of duplicated fusions was higher in non-minute adenocarcinomas (13 vs 0%; P=0.03). A trend for higher incidence of low-level copy number gain in normal ERG gene locus without fusion was noted in non-minute adenocarcinomas (10 vs 0%; P=0.07). We found a TMPRSS2–ERG fusion rate of 47% in minute adenocarcinomas. The latter is not significantly different from that of grade matched non-minute adenocarcinomas. The incidence of duplicated fusion was higher in non-minute adenocarcinomas. Our finding of comparable rate of TMPRSS2–ERG fusion in minute adenocarcinomas may argue against its value as a marker of aggressive prostate carcinoma phenotype.
minute prostatic adenocarcinoma; TMPRSS2–ERG fusion
We assessed the use of quantitative clinical and pathologic information to predict which patients would eventually require treatment for prostate cancer (CaP) in an expectant management (EM) cohort.
We identified 75 men having prostate cancer with favorable initial biopsy characteristics; 30 developed an unfavorable biopsy (Gleason grade >6, >2 cores with cancer, >50% of a core with cancer, or a palpable nodule) requiring treatment and 45 maintained favorable biopsies throughout a median follow-up of 2.7years. Demographic, clinical data and quantitative tissue histomorphometry determined by digital image analysis were analyzed.
Logistic regression (LR) modeling generated a quantitative nuclear grade (QNG) signature based on the enrollment biopsy for differentiation of Favorable and Unfavorable groups using a variable LR selection criteria of Pz < 0.05. The QNG signature utilized 12 nuclear morphometric descriptors (NMDs) and had an area under the receiver operator characteristic curve (ROC-AUC) of 87% with a sensitivity of 82%, specificity of 70% and accuracy of 75%. A multivariable LR model combining QNG signature with clinical and pathological variables yielded an AUC-ROC of 88% and a sensitivity of 81%, specificity of 78% and accuracy of 79%. A LR model using prostate volume, PSA density, and number of pre-diagnosis biopsies resulted in an AUC-ROC of 68% and a sensitivity of 85%, specificity of 37% and accuracy of 56%.
QNG using EM prostate biopsies improves the predictive accuracy of LR models based on traditional clinicopathologic variables in determining which patients will ultimately develop an unfavorable biopsy. Our QNG-based model must be rigorously, prospectively validated prior to use in the clinical arena.
prostate cancer; expectant management; quantitative nuclear grade; prostate biopsy; low grade and low stage cancer
To determine the relationship between perineural invasion (PNI) on prostate biopsy and radical prostatectomy (RP) outcomes in a contemporary RP series, as there is conflicting evidence on the prognostic significance of PNI in prostate needle biopsy specimens.
PATIENTS AND METHODS
From 2002 to 2007, 1256 men had RP by one surgeon. Multivariable logistic regression and Cox proportional hazards models were used to examine the relationship of PNI with pathological tumour features and biochemical progression, respectively, after adjusting for prostate-specific antigen level, clinical stage and biopsy Gleason score. Additional Cox models were used to examine the relationship between nerve-sparing and biochemical progression among men with PNI.
PNI was found in 188 (15%) patients, and was significantly associated with aggressive pathology and biochemical progression. On multivariate analysis, PNI was significantly associated with extraprostatic extension and seminal vesicle invasion (P < 0.001). Biochemical progression occurred in 10.5% of patients with PNI, vs 3.5% of those without PNI (unadjusted hazard ratio 3.12, 95% confidence interval 1.77–5.52, P < 0.001). However, PNI was not a significant independent predictor of biochemical progression on multivariate analysis. Finally, nerve-sparing did not adversely affect biochemical progression even among men with PNI.
PNI is an independent risk factor for aggressive pathology features and a non-independent risk factor for biochemical progression after RP. However, bilateral nerve-sparing surgery did not compromise the oncological outcomes for patients with PNI on biopsy.
perineural invasion; prostate biopsy; prostate cancer; radical prostatectomy; outcomes
We examined contralateral prostate cancer potentially left behind by focal therapy.
Materials and Methods
We investigated 100 completely embedded radical prostatectomy specimens in which needle biopsy predicted limited disease (less than 3 positive cores, 50% or less involvement of any positive core, Gleason score 6 or less) and all positive needle cores were unilateral. Clinical stage was T1c in 85 and T2a in 15 cases with the palpable lesion on the positive biopsy side.
There was 1 positive core in 66 cases. On average 13.9% of each positive core was involved with tumor. The mean number of separate tumor nodules per radical prostatectomy was 2.9. In 65 radical prostatectomy specimens there was some tumor contralateral to the positive biopsy side. Total tumor volume in the radical prostatectomy contralateral to the positive biopsy side averaged 0.2 cm3 (largest 1.3). In 23 cases contralateral tumor volume was greater than biopsy positive side tumor volume. There were 13 cases in which more than 0.5 cm3 cancer was contralateral to the positive biopsy and 7 with predominantly anterior tumor. Volume contralateral to positive biopsy side could not be predicted by the number of positive cores (1 vs 2) or maximum percent of the core involved. Gleason pattern 4, extraprostatic extension or positive margins were seen contralateral to the positive biopsy side in 13, 1 and 2 cases, respectively.
In a highly selected population with limited unilateral biopsy cancer, tumor contralateral to the positive biopsy side at radical prostatectomy is typically small. However, 20% of radical prostatectomy specimens had some contralateral adverse pathology in terms of size, extraprostatic extension, grade or margins.
prostatic neoplasms; cryosurgery; prostatectomy
Prostate Cancer; High-Risk; Gleason sum
To evaluate long-term outcomes of patients with high Gleason sum (8–10) at radical prostatectomy (RP) and to identify predictors of prostate cancer-specific survival (CSS) in this cohort.
The Institutional RP Database was queried. 9,381 patients with complete follow-up underwent RP from 1982 to 2008; 1,061 patients had pathologic Gleason sum 8–10. Patient and prostate cancer characteristics were evaluated. Survival analyses were performed using Kaplan-Meier method. Univariate and multivariate proportional hazard regression models were created to evaluate pertinent predictors of CSS (death from or attributed to prostate cancer).
Median pre-operative PSA was 7.6 ng/mL; 435 men had clinical stage T1 tumor, 568 had T2, and 36 had T3. Biopsy Gleason sum was <7, =7 and >7 in 244 (22.3%), 406 (37.2%) and 425 (38.9%) patients, respectively. Median follow-up was five years (range 1–23 years). Actuarial 15-year recurrence-free survival, CSS and overall survival rates were 20.7%, 57.4% and 45.4%, respectively. In multivariate analysis, predictors of poor CSS were pathological Gleason sum of 9–10, seminal vesicle and lymph node involvement. Patients with pathological Gleason sum 8 and organ confined disease experienced a CSS of 89.9% at 15 years.
80% of men with Gleason sum 8–10 who undergo RP will experience biochemical recurrence at 15 years. However, CSS approached 90% in men with pathologic organ-confined disease. Higher pathological Gleason sum (9–10), seminal vesicle and lymph node involvement are independent predictors of worse CSS.
Prostate cancer; High-Risk; Gleason sum