Samson W. Fine

A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score.

BACKGROUND Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8-10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3+4=7 and 4+3=7 are often considered the same prognostic group. OBJECTIVE To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. DESIGN, SETTING, AND PARTICIPANTS Between 2005 and 2014, 20,845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. RESULTS AND LIMITATIONS In the surgery cohort, we found large differences in recurrence rates between both Gleason 3+4 versus 4+3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3+4, 4+3, 8, and 9-10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five-grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. CONCLUSIONS The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. PATIENT SUMMARY We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.

The role of SPINK1 in ETS rearrangement-negative prostate cancers

ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

TMPRSS2-ERG Gene Fusion Is Not Associated with Outcome in Patients Treated by Prostatectomy

A significant number of prostate cancers have been shown to have recurrent chromosomal rearrangements resulting in the fusion of the androgen-regulated TMPRSS2 promoter to a member of the ETS transcription factor family, most commonly ERG. This results in ERG overexpression, which may have a direct causal role in prostate tumorigenesis or progression. However, the clinical significance of the rearrangement is unclear, and in particular, relationship to outcome has been inconsistent in recent reports. We analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization in 521 cases of clinically localized surgically treated prostate cancer with 95 months of median follow-up and also in 40 unmatched metastases. Forty-two percent of primary tumors and 40% of metastases had rearrangements. Eleven percent had copy number increase (CNI) of the TMPRRS2-ERG region. Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases, or death. CNI with and without rearrangement was associated with high grade and advanced stage. Further, a subgroup of cancers with CNI and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive. DNA index assessment revealed that the majority of tumors with CNI of TMPRSS2-ERG had generalized aneuploidy/tetraploidy in contrast to tumors without TMPRSS2-ERG CNI, which were predominantly diploid. We therefore conclude that translocation of TMPRSS2-ERG is not associated with outcome, and the aggressive clinical features associated with CNI of chromosome 21 reflect generalized aneuploidy and are not due to CNI specifically of rearranged TMPRSS2-ERG.

Prostate Cancer: Identification with Combined Diffusion-weighted MR Imaging and 3D 1H MR Spectroscopic Imaging—Correlation with Pathologic Findings1

PURPOSE To retrospectively measure the mean apparent diffusion coefficient (ADC) with diffusion-weighted magnetic resonance (MR) imaging and the mean metabolic ratio (MET) with three-dimensional (3D) hydrogen 1 ((1)H) MR spectroscopic imaging in regions of interest (ROIs) drawn over benign and malignant peripheral zone (PZ) prostatic tissue and to assess ADC, MET, and combined ADC and MET for identifying malignant ROIs, with whole-mount histopathologic examination as the reference standard. MATERIALS AND METHODS The institutional review board approved this HIPAA-compliant retrospective study and issued a waiver of informed consent. From among 61 consecutive patients with prostate cancer, 38 men (median age, 61 years; range, 42-72 years) who underwent 1.5-T endorectal MR imaging before radical prostatectomy and who fulfilled all inclusion criteria of no prior hormonal or radiation treatment and at least one PZ lesion (volume, >0.1 cm(3)) at whole-mount pathologic examination were included. ADC maps were generated from diffusion-weighted MR imaging data, and MET maps of (choline plus polyamine plus creatine)/citrate were calculated from 3D (1)H MR spectroscopic imaging data. ROIs in the PZ identified by matching pathologic slides with T2-weighted images were overlaid on MET and ADC maps. Areas under the receiver operating characteristic curves (AUCs) were used to evaluate accuracy. RESULTS The mean ADC +/- standard deviation, (1.39 +/- 0.23) x 10(-3) mm(2)/sec, and mean MET (0.92 +/- 0.32) for malignant ROIs differed significantly from the mean ADC, (1.69 +/- 0.24) x 10(-3) mm(2)/sec, and mean MET (0.73 +/- 0.18) for benign ROIs (P < .001 for both). In distinguishing malignant ROIs, combined ADC and MET (AUC = 0.85) performed significantly better than MET alone (AUC = 0.74; P = .005) and was also better than ADC alone (AUC = 0.81), although the difference was not statistically significant (P = .09). CONCLUSION The combination of ADC and MET performs significantly better than MET for differentiating between benign and malignant ROIs in the PZ.

Prostate Tumor Volume Measurement with Combined T2-weighted Imaging and Diffusion-weighted MR: Correlation with Pathologic Tumor Volume

PURPOSE To retrospectively determine the accuracy of diffusion-weighted (DW) magnetic resonance (MR) imaging for identifying cancer in the prostate peripheral zone (PZ) and to assess the accuracy of tumor volume measurements made with T2-weighted imaging and combined T2-weighted and DW MR imaging by using surgical pathologic examination as the reference standard. MATERIALS AND METHODS The institutional review board issued a waiver of informed consent for this HIPAA-compliant study. Forty-two patients underwent endorectal MR at 1.5 T before undergoing radical prostatectomy for prostate cancer and had at least one PZ tumor larger than 0.1 cm(3) at surgical pathologic examination. On T2-weighted images, an experienced radiologist outlined suspected PZ tumors. Two apparent diffusion coefficient (ADC) cutoff values were identified by using the Youden index and published literature. Image cluster analysis was performed on voxels within the suspected tumor regions. Associations between volume measurements from imaging and from pathologic examination were assessed by using concordance correlation coefficients (CCCs). The sensitivity and specificity of ADCs for identifying malignant PZ voxels were calculated. RESULTS In identifying malignant voxels, respective ADC cutoff values of 0.0014 and 0.0016 mm(2)/sec yielded sensitivity of 82% and 95% and specificity of 85% and 65%, respectively. Sixty PZ cancer lesions larger than 0.1 cm(3) were found at pathologic examination; 43 were detected by the radiologist. CCCs between imaging and pathologic tumor volume measurements were 0.36 for T2-weighted imaging, and 0.46 and 0.60 for combined T2-weighted and DW MR imaging with ADC cutoffs of 0.0014 and 0.0016 mm(2)/sec, respectively; the CCC of combined T2-weighted and DW MR imaging (ADC cutoff, 0.0016 mm(2)/sec) was significantly higher (P = .006) than that of T2-weighted imaging alone. CONCLUSION Adding DW MR to T2-weighted imaging can significantly improve the accuracy of prostate PZ tumor volume measurement. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/252/2/449/DC1.

Germline BRCA Mutations Denote a Clinicopathologic Subset of Prostate Cancer

Purpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer. Clin Cancer Res; 16(7); 2115–21. ©2010 AACR.

Urachal carcinoma: a clinicopathologic analysis of 24 cases with outcome correlation.

Background Urachal carcinomas occur mostly in the bladder dome, comprising 22% to 35% of vesical adenocarcinomas, and are generally treated by partial cystectomy with en bloc resection of the median umbilical ligament and umbilicus. Detailed pathologic studies with clinical outcome correlation are few. Design We reviewed histologic material and clinical data from 24 cases selected from a database of 67 dome-based tumors diagnosed and treated at our institution from 1984 to 2005. Follow-up information was available for all 24 patients. Result The mean age at diagnosis was 52 years (range: 26 to 68 y). Fifteen patients were male and 9 were female. Location was the dome in 23 and dome and anterior wall in 1. Thirteen cases were pure adenocarcinoma, not otherwise specified, 9 were enteric type adenocarcinoma, and 2 were adenocarcinoma with focal components of lymphoepithelioma-like carcinoma and urothelial carcinoma with cytoplasmic clearing. Signet ring cell features were focally seen in 2 cases. Cystitis cystica and cystitis glandularis were seen in 4 and 2 cases, respectively. In all instances but 1, cystitis cystica/glandularis was focal and predominantly in the bladder overlying the urachal neoplasm. Urachal remnants were identified in 15 cases: the urachal epithelium was benign urothelial-type in 6 cases and showed adenomatous changes in 9. The overlying bladder urothelium was colonized by adenocarcinoma in 3 cases. In all 3, urachal remnants were identified and showed transition from benign to adenomatous epithelium. On immunohistochemistry, these tumors were positive for CK20 and variably positive for CK7 and 34BE12. The majority showed a cytoplasmic membranous staining pattern for β-catenin, although in 1 case, focal nuclear immunoreactivity was identified. The Sheldon pathologic stage was pT1 in 0, pT2 in 2, pT3a in 8, pT3b in 11, pT3c in 1, pT4a in 1, and pT4b in 1 patient. One patient had a positive soft tissue margin. The mean follow-up period was 40 months (range: 0.3 to 157.6 mo). Seven of 24 (29%) cases recurred locally. The incidence of local recurrence was higher in patients who underwent a partial cystectomy alone (37.5%) versus those who had a more radical surgery (27%). Distant metastases occurred in 9 (37.5%) patients, 4 of whom had no prior local recurrence. Seven patients (29%) died of the disease. All cases with locally recurrent and metastatic disease belonged to stage pT3 or higher. Conclusions Pathologic stage is an important prognostic factor in urachal carcinoma. Surface urothelial involvement by carcinoma and presence of cystitis cystica/glandularis do not necessarily exclude the diagnosis of urachal carcinoma. Immunostains do not unequivocally discriminate a urachal from a colorectal carcinoma, but diffuse positivity for 34BE12 would support, and diffuse nuclear immunoreactivity for β-catenin would militate against, a diagnosis of urachal carcinoma. Local recurrence may be owing to seeding within the distal urothelial tract, particularly in tumors with a configuration that is polypoid and which open into the bladder cavity. The type of surgery performed may have an effect on local recurrence despite negative margins of resection.

Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins.

Over the past few years several investigators have independently described unique low-grade renal epithelial neoplasms with clear cytoplasm, focal to diffuse papillary architecture, and occasional leiomyomatous stromal metaplasia that are not currently recognized in the World Health Organization classification of renal tumors. These tumors have been referred to by a variety of names including clear-cell papillary renal cell carcinoma and recently “clear-cell tubulopapillary renal cell carcinoma”. On the basis of the available data, such tumors are positive for cytokeratin 7 (CK7) and carbonic anhydrase IX (CA9), while being negative for CD10, α-methylacyl-CoA racemase (AMACR), and TFE3. These tumors reportedly lack trisomies of chromosomes 7 and 17, deletions of 3p25, von Hippel–Lindau (VHL) gene mutations, and VHL promoter hypermethylation. Herein, we report on nine cases of this tumor emphasizing detailed studies of the VHL gene and hypoxia-inducible factor (HIF) pathway. Molecular studies performed included VHL mutational analysis, copy number changes assessed using single-nucleotide polymorphism arrays, and qRT-PCR for VHL mRNA expression. Immunohistochemical stains for markers of HIF pathway activation (HIF-1α, CA9, and glucose transporter-1 (GLUT-1)) as well as other relevant markers (CK7, CD10, AMACR, and TFE3) were performed. None of our tumors harbored VHL gene mutations, losses of chromosomal region 3p25, or trisomies of chromosomes 7 or 17. VHL mRNA was overexpressed in our tumors relative to normal renal tissue and clear-cell renal cell carcinoma. All cases showed strong co-expression of CK7, HIF-1α, GLUT-1, and CA9. No expression of TFE3, CD10, or AMACR was seen. The morphological, immunophenotypic, and molecular features of these unique low-grade tumors are sufficiently distinct to allow separation from other renal cell carcinoma subtypes. The co-expression of CA9, HIF-1α, and GLUT-1 in the absence of VHL gene alterations in clear-cell papillary renal cell carcinoma suggests activation of the HIF pathway by non-VHL-dependent mechanisms.

A Contemporary Study Correlating Prostate Needle Biopsy and Radical Prostatectomy Gleason Score

PURPOSE We determined whether contemporary practice patterns of Gleason grading for prostate needle biopsy and radical prostatectomy have evolved. MATERIALS AND METHODS We correlated needle biopsy (assigned at Johns Hopkins Hospital and other institutions) and radical prostatectomy Gleason score for 1,455 men who underwent radical prostatectomy at Johns Hopkins Hospital from 2002 to 2003, and compared the results with those of a 1994 study of similar design. RESULTS Outside institutions diagnosed Gleason score 2-4 in 1.6% (23 of 1,455) of needle biopsies vs 22.3% (87 of 390) in 1994. Of needle biopsies labeled Gleason score 2-4, 30.4% revealed radical prostatectomy Gleason score 7-10. In 2002 to 2003 no Johns Hopkins Hospital needle biopsy was assigned Gleason score 2-4. Needle biopsies designated Gleason score 6 or less had 80.0% accuracy with regard to radical prostatectomy Gleason score vs 63% accuracy in older data. For needle biopsy Gleason score 7 or greater, 35.5% (outside institution) and 24.8% (Johns Hopkins Hospital) of radical prostatectomies displayed Gleason score less than 7. Overall, outside and Johns Hopkins Hospital needle biopsy diagnoses showed 69.7% and 75.9% agreement with radical prostatectomy Gleason score, respectively. Direct comparison of Johns Hopkins Hospital and needle biopsy Gleason scores elsewhere revealed 81.8% agreement, with 87.1% for Gleason score 5-6, 68.1% for Gleason score 7 and 35.1% for Gleason score 8-10. For 59.4% of outside needle biopsies with Gleason score 8-10, Johns Hopkins Hospital Gleason score was 7 or less. Conversely, for 64.9% of Johns Hopkins Hospital needle biopsies with Gleason score 8-10, outside Gleason score was 7 or less. For needle biopsies with Gleason score 5-6, 7 and 8-10, the incidence of nonorgan confined disease at radical prostatectomy was 17.7%, 47.8% and 50.0%, respectively, for Johns Hopkins Hospital vs 18.2%, 44.6% and 37.5% for outside institutions. CONCLUSIONS The last decade has seen the near elimination of once prevalent under grading of needle biopsy. All cases still assigned Gleason score 2-4 show Gleason score 5 or greater at radical prostatectomy and nearly a third reveal Gleason score 7-10, reaffirming that Gleason score 2-4 is a needle biopsy diagnosis that should not be made. As evidenced by variable over grading and under grading, as well as poor correlation with pathological stage, difficulties in the assignment of Gleason pattern 4 and overall Gleason score of 8-10 on needle biopsy remain an important issue.

Expanding the histologic spectrum of mucinous tubular and spindle cell carcinoma of the kidney

Mucinous tubular and spindle cell carcinomas (MTSCs) are polymorphic neoplasms characterized by small, elongated tubules lined by cuboidal cells and/or cords of spindled cells separated by pale mucinous stroma. Nonclassic morphologic variants and features of MTSC have not been well studied. We identified 17 previously unreported MTSCs from Surgical Pathology and consultative files of the authors and their respective institutions and studied their morphologic features. A total of 10/17 cases were considered “classic,” as described above, with 5/10 showing at least focal (20% to 50%) tubular predominance without apparent mucinous matrix. Alcian blue staining revealed abundant (>50%) mucin in all classic cases. Seven of 17 MTSCs were classified as “mucin-poor,” with little to no extracellular mucin appreciable by hematoxylin and eosin. Four of these cases showed equal tubular and spindled morphology, 2 cases showed spindle cell predominance (70%; 95%), and 1 case showed tubular predominance (90%). In 5/7 mucin-poor cases, staining for Alcian blue revealed scant (<10%) mucin in cellular areas with the other 2 cases having 30% mucin. Unusual histologic features identified in the 17 cases were: foamy macrophages (n=8), papillations/well formed papillae (n=6/n=1), focal clear cells in tubules (n=3), necrosis (n=3), oncocytic tubules (n=2; 40%, 5%), numerous small vacuoles (n=2), heterotopic bone (n=1), psammomatous calcification (n=1), and nodular growth with lymphocytic cuffing (n=1). An exceptional case contained a well-circumscribed, HMB45-positive angiomyolipoma within the MTSC. MTSCs may be “mucin-poor” and show a marked predominance of either of its principal morphologic components, which coupled with the presence of other unusual features such as clear cells, papillations, foamy macrophages, and necrosis, may mimic other forms of renal cell carcinoma. Pathologists must be aware of the spectrum of histologic findings within MTSCs to ensure their accurate diagnosis.