Comparison of Multiparametric MRI-targeted and Systematic Biopsies for Detection of Cribriform and Intraductal Carcinoma Prostate Cancer.

Background Intraductal carcinoma (IDC) and invasive cribriform (Cr) subtypes of prostate cancer (PCa) are an indication of aggressiveness, but the evidence regarding whether MRI can be used to detect Cr/IDC-pattern PCa is contradictory. Purpose To compare the detection of Cr/IDC-pattern PCa at multiparametric MRI (mpMRI)-targeted biopsy versus systematic biopsy in biopsy-naive men at risk for PCa. Materials and Methods This study was a secondary analysis of a prospective randomized controlled trial that recruited participants with a clinical suspicion of PCa between April 2017 and November 2019 at five centers. Participants were randomized 1:1 to either the MRI arm or the systematic biopsy arm. Targeted biopsy was performed in participants with a Prostate Imaging Reporting and Data System score of at least 3. MRI features were recorded, and biopsy slides and prostatectomy specimens were reviewed for the presence or absence of Cr/IDC histologic patterns. Comparison of Cr/IDC patterns was performed using generalized linear mixed modeling. Results A total of 453 participants were enrolled, with 226 in the systematic biopsy arm (median age, 65 years [IQR, 59-70 years]; 196 biopsies available for assessment) and 227 in the mpMRI-targeted biopsy arm (median age, 67 years [IQR, 60-72 years]; 132 biopsies available for assessment). Identification of Cr/IDC PCa was lower in the systematic biopsy arm compared with the mpMRI arm (31 of 196 biopsies [16%] vs 33 of 132 biopsies [25%]; P = .01). No evidence of a difference in mean cancer core length (CCL) (11.3 mm ± 4.4 vs 9.7 mm ± 4.5; P = .09), apparent diffusion coefficient (685 µm2/sec ± 178 vs 746 µm2/sec ± 245; P = .52), or dynamic contrast-enhanced positivity (27 [82%] vs 37 [90%]; P = .33) for clinically significant PCa (csPCa) was observed between participants with or without Cr/IDC disease in the MRI arm. Cr/IDC-positive histologic patterns overall had a higher mean CCL compared with Cr/IDC-negative csPCa (11.1 mm ± 4.4 vs 9.2 mm ± 4.1; P = .009). Conclusion MRI-targeted biopsy showed increased detection of Cr/IDC histologic patterns compared with systematic biopsy. Clinical trial registration no. NCT02936258 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Scialpi and Martorana in this issue.

Stimulated Raman histology as a method to determine the adequacy of renal mass biopsy and identify malignant subtypes of renal cell carcinoma.

INTRODUCTION: Renal tumor biopsy requires adequate tissue sampling to aid in the investigation of small renal masses. In some centers the contemporary nondiagnostic renal mass biopsy rate may be as high as 22% and may be as high as 42% in challenging cases. Stimulated Raman Histology (SRH) is a novel microscopic technique which has created the possibility for rapid, label-free, high-resolution images of unprocessed tissue which may be viewed on standard radiology viewing platforms. The application of SRH to renal biopsy may provide the benefits of routine pathologic evaluation during the procedure, thereby reducing nondiagnostic results. We conducted a pilot feasibility study, to assess if renal cell carcinoma (RCC) subtypes may be imaged and to see if high-quality hematoxylin and eosin (H&E) could subsequently be generated. METHODS/MATERIALS: An 18-gauge core needle biopsy was taken from a series of 25 ex vivo radical or partial nephrectomy specimens. Histologic images of the fresh, unstained biopsy samples were obtained using a SRH microscope using 2 Raman shifts: 2,845 cm-1 and 2,930 cm-1. The cores were then processed as per routine pathologic protocols. The SRH images and hematoxylin and eosin (H&E) slides were then viewed by a genitourinary pathologist. RESULTS: The SRH microscope took 8 to 11 minutes to produce high-quality images of the renal biopsies. Total of 25 renal tumors including 1 oncocytoma, 3 chromophobe RCC, 16 clear cells RCC, 4 papillary RCC, and 1 medullary RCC were included. All renal tumor subtypes were captured, and the SRH images were easily differentiated from adjacent normal renal parenchyma. High quality H&E slides were produced from each of the renal biopsies after SRH was completed. Immunostains were performed on selected cases and the staining was not affected by the SRH image process. CONCLUSION: SRH produces high quality images of all renal cell subtypes that can be rapidly produced and easily interpreted to determine renal mass biopsy adequacy, and on occasion, may allow renal tumor subtype identification. Renal biopsies remained available to produce high quality H&E slides and immunostains for confirmation of diagnosis. Procedural application has promise to decrease the known rate of renal mass nondiagnostic biopsies, and application of convolutional neural network methodology may further improve diagnostic capability and increase utilization of renal mass biopsy among urologists.

Unexpected diagnosis of metastatic breast carcinoma in an endomyocardial biopsy done for cardiac allograft rejection evaluation.

We report a case of a 75-year-old female post orthotopic heart transplantation, who presented to the emergency department with a six-week history of shortness of breath, hand tremor and ultimately delirium. She had lobular breast carcinoma more than 5 years prior to her heart transplant, treated by lumpectomy followed by anthracycline based chemotherapy. The reason for her heart transplant was heart failure that was suspected to be from anthracycline cardiomyopathy, however, her explanted heart actually showed cardiac sarcoidosis. She was placed on long-term immunosuppression with tacrolimus, mycophenolate mofetil and prednisone. Two years after her heart transplant, she underwent bilateral mastectomies for recurrent breast cancer. Her neurological workup, including brain imaging (CT, MRI, LP and EEG) did not show any structural abnormalities, ischemia, mass or neurosarcoidosis as cause for delirium. Tacrolimus was held due to renal dysfunction and hemolytic anemia, and then she developed signs of right heart failure so an endomyocardial biopsy was carried out for suspected allograft rejection. The biopsy did not show any evidence of cellular or antibody medicated rejection; however, it demonstrated infiltration by bland appearing cells with signet ring morphology cells many of which showed intracytoplasmic mucin. The cells were strongly positive with cytokeratins AE1/3, CK7 and mammaglobin. The morphology and immunoprofile were consistent with metastatic lobular breast carcinoma and this was thought to be the cause of her clinical presentation with delirium, hemolytic anemia and renal dysfunction as a paraneoplastic syndrome.

Evaluation of individual and cumulative sites of extrarenal tumor invasion in pT3a clear cell renal cell carcinoma.

INTRODUCTION: The Tumor-Node-Metastasis classification of renal cell carcinoma (RCC) for pT3a tumors includes sinus fat invasion (SFI), perinephric fat invasion (PFI), renal vein invasion (RVI), and/or pelvicaliceal system invasion (PSI). The purpose of this study was to determine the association between these patterns of invasion (assessed individually and cumulatively) with the development of metastases and cancer-specific mortality (CSM). MATERIALS AND METHODS: We identified 160 patients who underwent radical nephrectomy for pT3a clear cell RCC between 2011 and 2017. The association between individual patterns of invasion and metastases and cancer-specific survival were evaluated with multivariate logistic regression. Cox Hazard proportion ratios and Kaplan-Meier survival curves were generated for patterns of invasion (assessed individually and cumulatively). RESULTS: The number of individual invasive patterns was as follows: 97/160 (61%) presented with RVI, 91/160 with SFI (57%), 62/160 with PFI (39%), and 24/160 (15%) with PSI. At multivariate analysis, both PFI and RVI were associated with metastases (P < 0.001 and 0.028, respectively). PFI (hazard ratio [HR] 4.12, 95% confidence interval [CI] 2.14-7.92; P < 0.001), RVI (HR 2.44, 95% CI 1.18-5.01; P = 0.015), SFI (HR 2.13, 95% CI 1.05-4.34; P = 0.036) had higher CSM, while PSI (HR 1.43, 95% CI 0.65-3.16; p = 0.38) did not show increased CSM. Furthermore, cumulative analysis showed that multiple invasive patterns resulted in worse CSM (p < 0.001). CONCLUSIONS: In our study, PFI was associated with the most aggressive behavior while PSI was the most indolent. Furthermore, the presence of more than one pattern of invasion was associated with worse CSM. These results indicate that reporting of the individual location and cumulative amount of pT3a patterns of invasion in clear cell RCC is clinically relevant.

Characteristics and outcomes in a prospective cohort of patients with histologically diagnosed aortitis.

OBJECTIVES: Our aim was to evaluate characteristics and prospective adverse aortic outcomes in a cohort of patients with non-infectious histological aortitis. METHODS: Patients with histological aortitis, diagnosed at the Ottawa Hospital after surgical repair of thoracic aortic aneurysms or dissections, consented to enrolment in a prospective observational cohort. Patients were assessed for an underlying inflammatory condition and followed prospectively with periodic clinical, laboratory and radiographic assessments. Aortic outcomes during follow-up included significant events, defined as new thoracic or abdominal aortic aneurysms, dissections, ruptures or other complications requiring aortic intervention, in addition to aortic branch ectasias, aneurysms and stenosis. RESULTS: Sixteen patients with histological aortitis from surgical procedures performed between 2010 and 2017 were included; nine had idiopathic and seven had secondary aortitis. Idiopathic patients were more likely to have smoked (100 vs 43%, P = 0.02) and had more associated arch or descending aortic aneurysms on pre-operative baseline imaging compared with secondary aortitis (6 vs 0, P = 0.01). At the median 3.6 years of follow-up, eight patients (50%) had 10 significant aortic events. The incidence of aortic dissection was higher in the first year post-surgery, compared with subsequent years, whereas incident aneurysms occurred throughout follow-up. Elevated inflammatory markers during follow-up trended towards association with accumulation of severe aortic damage. CONCLUSION: This is the first reported prospective study in patients with histological aortitis. Within the limitations of a small cohort, we report a high incidence of aortic complications. Studies with a larger sample size and longer follow-up are needed to corroborate these findings.

Lysosomal storage disorders affecting the heart: a review.

Lysosomal storage disorders (LSD) comprise a group of diseases caused by a deficiency of lysosomal enzymes, membrane transporters or other proteins involved in lysosomal biology. Lysosomal storage disorders result from an accumulation of specific substrates, due to the inability to break them down. The diseases are classified according to the type of material that is accumulated; for example, lipid storage disorders, mucopolysaccharidoses and glycoproteinoses. Cardiac disease is particularly important in lysosomal glycogen storage diseases (Pompe and Danon disease), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease). Various disease manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular diseases. Endomyocardial biopsies can play an important role in the diagnosis of these diseases. Microscopic features along with ancillary tests like special stains and ultrastructural studies help in the diagnosis of these disorders. Diagnosis is further confirmed based upon enzymatic and molecular genetic analysis. Emerging evidence suggests that Enzyme replacement therapy (ERT) substantially improves many of the features of the disease, including some aspects of cardiac involvement. The identification of these disorders is important due to the availability of ERT, the need for family screening, as well as appropriate patient management and counseling.

Transforming the prostatic tumor microenvironment with oncolytic virotherapy.

Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo. An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance. Treatment of mice with bulky TRAMP-C2 tumors using oncolytic STEAP immunotherapy induced an overt delay in tumor progression, marked intratumoral lymphocytic infiltration with an active transcriptional profile and up-regulation of MHC class I. The preclinical data generated here offers clear rationale for clinically evaluating this approach for men with advanced PCa.

Acute Management of Infected Chronic Thromboembolic Disease.

A 29-year-old man with chronic pulmonary emboli presented to the hospital with progressive pleuritic chest pain. He was in acute right ventricular failure and received intrapulmonary arterial tissue plasminogen activator. Massive hemoptysis developed, requiring emergent thromboendarterectomy. A clot was visualized in the main left pulmonary artery that had formed a bronchovascular fistula into the left upper lobe bronchus. Pathology of the clot revealed fibrinopurulent exudate and Gram-positive cocci. The left pulmonary artery was repaired with a pericardial patch, and the left upper lobe was oversewn with subsequent left upper lobectomy. The patient was discharged home on postoperative day 23.

Evaluation of tumor morphologies and association with biochemical recurrence after radical prostatectomy in grade group 5 prostate cancer.

We assessed Gleason pattern 5 (GP5) and other prostatic adenocarcinoma (PCa) morphologies to determine their association with biochemical recurrence (BCR). A search for grade group 5 PCa with radical prostatectomy (RP) yielded 49 patients. RPs were reviewed for %GP5 and morphologies (sheets, single cells, cords, small solid cylinders, solid medium to large nests with rosette-like spaces [SMLNRS], comedonecrosis, cribriform glands, glomerulations, intraductal carcinoma of the prostate [IDC-P], and prostatic ductal adenocarcinoma [PDCa]). Prevalence of morphologies was as follows: single cells 100%, cribriform glands 98.7%, cords 85.7%, IDC-P 77.6%, comedonecrosis 53.1%, sheets 49.0%, small solid cylinders 49.0%, PDCa 44.9%, glomerulations 34.7%, and SMLNRS 14.3%. From 28 patients who were treated with RP as monotherapy, 64.3% (18/28) had BCR. Comedonecrosis, sheets, small solid cylinders, IDC-P, and PDCa were significantly associated with BCR. Number of morphologies on RP and %GP5 were higher in patients with BCR (6.8 ± 2.1 versus 3.7 ± 2.9%; P < 0.001 and 26.9 ± 16.8 versus 11.4 ± 14.1%; P = 0.02) with area under ROC curve of 0.89 (confidence intervals [CI] 0.77-1.00). Sensitivity/specificity was 77.8/80.0% for predicting BCR when ≥ 5 morphologies were present and 0.79 (CI 0.60-0.99) with sensitivity/specificity of 66.7/80.0% for predicting BCR when ≥ 15% GP5 was present. Hazard ratio for BCR was higher with increasing number of morphologies (1.23, CI 1.02-1.49; P = 0.034) but not %GP5 (0.99, CI 0.97-1.02, P = 0.622). Our results indicate that GP5 morphologies may represent a biologically heterogeneous group and that an increasing number of PCa morphologies on RP is strongly associated with an increased risk of BCR.

A case series of surgically diagnosed idiopathic aortitis in a Canadian centre: a retrospective study.

BACKGROUND: Idiopathic aortitis became recognized relatively recently, and the body of knowledge concerning this condition is scarce. We aimed to determine the frequency of idiopathic aortitis in aortic specimens, the clinical, laboratory and radiologic characteristics at diagnosis and during follow-up, and the approach to investigation, treatment and monitoring taken by the treating physicians. METHODS: We identified cases of aortitis diagnosed on pathological specimens of the aorta between Jan. 1, 2003, and July 31, 2013, at The Ottawa Hospital by reviewing the hospital's pathology database. Charts of identified patients were reviewed, and data on patient demographic characteristics, clinical features, laboratory and imaging tests, treatment and outcomes were analyzed. RESULTS: A total of 684 aortic specimens were analyzed during the study period; 47 cases of aortitis were identified, 32 of which were idiopathic. Twenty-one patients (66%) had complete imaging of branch vessels at baseline, 16 (76%) of whom had additional aortic or branch vessel lesions. Twelve patients (38%) received corticosteroids postoperatively. Over a mean follow-up period of 47.5 months, among the 12 patients (38%) who had complete imaging of branch vessels at least once, new aortic or branch lesions were diagnosed in 5 (42%); 3/32 patients (9%) required additional vascular surgery; and a new systemic condition was diagnosed in 2/32 (6%). INTERPRETATION: Idiopathic aortitis is commonly discovered incidentally on examination of the pathological specimen following ascending aortic aneurysm repair. No guidelines exist for the investigation, treatment and follow-up of this condition, resulting in great variability of practice. Good-quality prospective studies are needed to address the many unanswered clinical questions regarding idiopathic aortitis and to allow formulation of more definitive recommendations.

Primary amyloidosis of the bladder; a mimicker of bladder cancer.

Amyloidosis is a protein folding disorder characterized by the deposition of fibrillar proteins into solid organs or tissues. Primary localized amyloidosis of the bladder is very rare and can mimic bladder cancer in its presentation with hematuria, lower urinary tract symptoms or a mass on imaging. A case of localized amyloidosis of the bladder in a 48-year-old man with painless gross hematuria and evidence of bladder mass on ultrasound is presented. Amyloidosis is a rare but important non-malignant process of the bladder. We present a review of the literature and suggestions for management of this rare bladder disease.

Flat Intraurothelial Neoplasia Exhibiting Diffuse Immunoreactivity for CD44 and Cytokeratin 5 (Urothelial Stem Cell/Basal Cell Markers): A Variant of Intraurothelial Neoplasia Commonly Associated With Muscle-invasive Urothelial Carcinoma.

BACKGROUND: Immunoreactivity for CD44 and cytokeratin (CK)5 (urothelial stem/basal cell markers) are decreased/negative in the common type of intraurothelial neoplasia including urothelial carcinomas (UC) in situ. Recent studies also reveal that a majority of muscle-invasive UC are basal-like UC with large areas of positive CD44/CK5 immunoreactivity. In addition, approximately 80% of muscle-invasive UC develop de novo as nonpapillary invasive UC. In this study, we investigate the CD44/CK5 immunoreactivity of the flat intraurothelial neoplasia (FIUN) associated with nonpapillary invasive UC. MATERIALS AND METHODS: Consecutive cases of nonpapillary UC were submitted for immunostaining. Immunostaining for CK5/CD44 was scored as high for staining of >25% thickness of urothelium and low for lesser immunoreactivity. RESULTS: In total, 109 consecutive cases were grouped into: in situ UC [carcinoma in situ (CIS)] (n=11), pT1 (n=14), and pT2-4 (n=84) with surface urothelium available for study. Forty-four cases including CIS (n=9), pT1 (n=12), and pT2-4 (n=23) showed FIUN with low/negative CD44/CK5 reactivity; 40 cases showed strong CK20 reactivity. Sixty-two cases including CIS (n=2), pT1 (n=2), and pT2-4 (n=58) showed extensive FIUN exhibiting high CD44/CK5 reactivity; 30 cases showed reactive CK20. FIUN lesions with high CD44/CK5 reactivity scores were associated with mild (urothelial dysplasia) to moderate atypia (CIS) and were rarely preceded by papillary UC. Most invasive UC associated with FIUN with high CD44/CK5 reactivity also exhibited extensive CD44/CK5 reactivity. The remaining 3 cases showed only reactive urothelium. Of interest, 4 cases with FIUN showed negative CD44/CK5/CK20 reactivity. CONCLUSIONS: Existence of CD44/CK5-immunoreactive (or basal-like) FIUN is consistent with the recent distinction of basal and luminal subtypes of UC. This type of FIUN is often associated with UC with progression to high-stage disease not preceded by recurrent papillary UC.

Clear Cell Urothelial Carcinoma.

Clear cell urothelial carcinoma (CCUC) is a rare variant of urothelial carcinoma (UC) and its clinical significance has not been well elucidated. Consecutive cases of UC over a period of 5 years were reviewed. Histopathological tumor parameters, including the proportion of tumor cells with clear cell change, and patient outcomes were recorded. Expression of the following immunohistochemical markers was investigated: CK7, CK20, CK5, CD44, and PAX8. We also conducted a review of the literature for case reports/series of CCUC. Ten CCUCs were identified out of a total of 872 cases of UC. The clear cell component was characterized by prominent cytoplasmic membranes and voluminous clear cytoplasm, and accounted for 30% to 90% of the invasive tumor component. Of all the non-CCUC cases reviewed, at least 50% (noninvasive or invasive UC) showed focal areas of clear cell change that accounted for less than 5% of the neoplastic cells. Immunohistochemically, CCUC exhibited positive reactivity for CK5/CD44 (n = 9); CK20 (n = 5), PAX8 (very focal to extensive) (n = 6), and GATA3/CK7 (n = 10). Eight of 10 CCUC were of advanced clinical stage (pT3/pT4) and 6 of 10 experienced tumor recurrence and/or death due to disease. In conclusion, CCUC can be distinguished from non-CCUC by the extensive clear cell change in more than 30% of cells. This variant is associated with rapid progression to muscle invasion and metastasis, with an aggressive clinical course. Expression of CK5/CD44 may represent basal cell features in most CCUC cases, while PAX8 expression is suggestive of mesonephric derivation.

Perineural invasion on biopsy is associated with upstaging at radical prostatectomy in Gleason score 3 + 4 = 7 prostate cancer.

This study assesses if perineural invasion (PNI) detected on biopsy with Gleason score (GS) 3 + 4 = 7 prostate cancer (PCa) is associated with upstaging/upgrading of disease after radical prostatectomy (RP). 154 patients with GS 3 + 4 = 7 PCa diagnosed from biopsy who underwent RP were assessed for PNI. The percentage of biopsy sites with PNI (%PNI) was also calculated. Pattern 4 morphologies (ill-defined glands [IDG], fused, cribriform, and glomerulations) were also assessed. Clinical information, GS and stage after RP were retrieved from the medical records. 45 % (69/154) of patients were upstaged (≥pT3) and 29 % (44/154) were upgraded to GS >3 + 4 = 7 after RP. 37 % (57/154) of patients had PNI which was associated with upstaging (RR 1.4; P = 0.04) but not upgrading (RR 0.9; P = 0.7). There was higher %PNI in upstaged patients (12.1 % ± 1.8 vs. 7.1 % ± 1.5, P = 0.03) with a significant correlation between %PNI and ≥pT3 (r = 0.178, P = 0.027). After multivariate analysis, only cribriform formations were significantly associated with upstaging (P = 0.009). The presence of PNI in biopsies with GS 3 + 4 = 7 PCa is associated with upstaging at RP but is a weaker predictor of ≥pT3 disease than cribriform morphology.

Utility of Gleason pattern 4 morphologies detected on transrectal ultrasound (TRUS)-guided biopsies for prediction of upgrading or upstaging in Gleason score 3 + 4 = 7 prostate cancer.

Selected patients with Gleason score (GS) 3 + 4 = 7 prostate cancer (PCa) detected on transrectal ultrasound (TRUS)-guided biopsies may be considered for active surveillance (AS); however, a proportion of these will harbor more aggressive disease. The purpose of this study was to determine if morphologies of Gleason pattern 4 PCa may predict upgrading and/or upstaging after radical prostatectomy (RP). A database search for men with GS 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy that underwent RP between January 2010 and October 2015 identified 152 patients. Two blinded genitourinary pathologists independently reviewed the biopsies and assessed ill-defined glands (IDG), fused glands, small or large cribriform patterns, and glomerulations. Patient age, serum prostate-specific antigen (PSA), percentage (%) of biopsy sites involved by 3 + 4 = 7 PCa, and overall extent of pattern 4 were also recorded. GS and stage (presence or absence of extraprostatic extension [EPE]) were retrieved from RP reports. Data were compared using independent t tests and chi-square. Inter-observer agreement was calculated using Cohen's Kappa statistic. Percent of biopsy sites and extent of pattern 4 were compared to statistically significant morphologies using the Spearman correlation. 28.3 % (43/152) of patients were upgraded to GS >3 + 4 = 7 at RP (GS 4 + 3 = 7 [N = 17], GS 4 + 3 = 7 with tertiary pattern 5 [N = 25], and GS 4 + 5 = 9 [N = 1]) and 44.1 % (67/152) showed EPE after RP. PSA was associated with both upgrading (8.5 ± 5.4 vs. 6.9 ± 3.2 ng/mL, [p = 0.04]) and EPE (8.2 ± 4.6 vs. 6.7 ± 3.2 ng/mL, [p = 0.03]). IDG, fused glands, and glomerulations were not associated with upgrading or EPE (p > 0.05) with moderate to strong inter-observer agreement (K = 0.76-0.88). There was strong inter-observer agreement for small and large cribriform formations (K = 0.93 and 0.94, respectively) and both patterns were strongly associated with upgrading (p < 0.001) and EPE (p = 0.02) on RP. Strong associations were observed between increasing number of morphologies and both upgrading (p = 0.0.25) and EPE (p < 0.001). Overall extent of pattern 4 was associated with upgrading (p = 0.009) and EPE (p = 0.019) while percent of sites involved by GS 3 + 4 = 7 was only associated with EPE (p = 0.023). Cribriform morphology correlated to percentage of sites with 3 + 4 and overall extent of pattern 4 (rho = 0.25, p = 0.002, rho = 0.20, p = 0.015, respectively). Presence of cribriform morphology on TRUS-guided biopsy is strongly associated with upgrading and upstaging at RP and shows near-perfect inter-observer agreement whereas IDG, fused glands, and glomerulations were not useful. Cribriform morphology may be of importance when considering treatment plans for patients with intermediate risk PCa.

Noninvasive Papillary Basal-like Urothelial Carcinoma: A Subgroup of Urothelial Carcinomas With Immunohistochemical Features of Basal Urothelial Cells Associated With a High Rate of Recurrence and Progression.

BACKGROUND: We investigated the clinical and pathologic significance of a subgroup of noninvasive papillary urothelial carcinomas (UCs) expressing reactivity to urothelial basal cell markers. DESIGN: In total, 302 consecutive cases of noninvasive papillary UC were evaluated immunohistochemically with cytokeratin 5 (CK5)/CD44. Any UC that was reactive for greater than 25% thickness of the urothelium was designated as basal-like urothelial carcinoma (BUC); remaining UC cases were designated as non-BUC. The follow-up period was up to 3 years. Historical review of UC was extended for up to 3 retrospective years. RESULTS: Among 302 noninvasive UC, BUC was identified in 33 of 256 (12.9%) low-grade UC and 8 of 46 (17%) high-grade UC (P=0.041). Immunoreactivity for CD44 was similar to that of CK5, but displayed weaker and more diffuse staining. CK20 was reactive in 9 cases, primarily high-grade BUC. Other basal cell markers (34bE12, p63, bcl2, and EP4) were found to be neither sensitive nor specific in detecting UC with high CK5 expression. In comparison with non-BUC, BUC was associated with increased multifocality, larger tumor size, higher recurrence rate, and more frequent upgrading and stage progression. In the follow-up period of 3 years, distant metastasis occurred in 6 cases of which 5 were in the BUC subgroup. CONCLUSIONS: Our results showed that noninvasive papillary BUC represents a small subset associated with increased risk of tumor recurrence and progression. The aggressive behavior is likely associated with basal-like features of BUC, as seen in carcinomas with basal cell features in other body sites.

Prostatic ductal adenocarcinoma: An aggressive variant that is underdiagnosed and undersampled on transrectal ultrasound (TRUS)-guided needle biopsy.

INTRODUCTION: We sought to determine if prostatic ductal adenocarcinoma is undersampled and/or underdiagnosed at transrectal ultrasound (TRUS)-guided biopsy. METHODS: With institutional review board approval, we searched our pathology database between 2008 and 2014 for patients with a diagnosis of ≥10% ductal adenocarcinoma on radical prostatectomy and available TRUS-guided needle biopsy specimens. Three blinded genitourinary pathologists independently examined the biopsy slides. The presence or absence of ductal adenocarcinoma was determined. Diagnostic accuracy was calculated using consensus diagnosis as the reference standard. Inter-observer agreement was assessed using Cohen's kappa coefficient. RESULTS: Based on consensus review, 66.7% (12/18) biopsy specimens demonstrated ductal adenocarcinoma and 33.3% (6/18) demonstrated conventional acinar prostatic adenocarcinoma. The sensitivity/specificity for each reader (R) was: 83/100% (R1), 100/83% (R2) and 58/83% (R3) and the inter-observer agreement was only fair (K=0.32). Only two of the original needle-biopsy reports correctly identified ductal adenocarcinoma (sensitivity = 17%). The main limitations of the study are the relatively small sample size and the potential for selection bias since we could only examine patients who underwent radical prostatectomy. CONCLUSIONS: Prostatic ductal adenocarcinoma may be undersampled at TRUS-guided biopsy and in this study was under-reported in routine clinical practice. This highlights the importance of increased awareness of ductal adeoncarcinoma and the need for clear diagnostic criteria. These findings have significant clinical impact especially when determining candidacy for active surveillance protocols.

Cribriform morphology predicts upstaging after radical prostatectomy in patients with Gleason score 3 + 4 = 7 prostate cancer at transrectal ultrasound (TRUS)-guided needle biopsy.

Selected patients with transrectal ultrasound (TRUS)-guided biopsies containing Gleason score 3 + 4 = 7 prostate cancer (PCa) may be considered candidates for active surveillance (AS). The purpose of this study was to determine if there are features that predict PCa upstaging and/or upgrading after radical prostatectomy (RP) in patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsies. We searched our institution's database for patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy who underwent subsequent RP between January 2010 and January 2015. Two blinded genitourinary pathologists independently reviewed and assessed the following on biopsies: (a) nuclear size, nucleolar size and distribution of macronucleoli of PCa, which were subjectively graded using a semi-quantitative scale from 1 to 3, and (b) PCa with cribriform morphology and the size of cribriform disease. Patient age, serum prostate-specific antigen (PSA) and PSA density (PSAD) were also recorded. The Gleason score and stage (presence or absence of organ-confined disease (OCD)) were retrieved from RP reports. Comparisons were performed between groups using the chi-square test and Spearman correlation. One hundred and four patients were identified to have met inclusion criteria. The mean age was 63 (±6.1) years. Mean PSA and PSAD at diagnosis were 7.5 (±4.2) and 0.25 (±0.15) ng/mL, respectively. Gleason scores were upgraded to greater than 3 + 4 = 7 in 26.9 % (28/104) of patients, and 44.2 % (46/104) of patients had no OCD after RP. There was no correlation between age, PSA, PSAD or percent of biopsies with Gleason pattern 4 for either Gleason score upgrading or absence of OCD at the time of RP (p > 0.05). Thirty patients had cribriform morphology on TRUS-guided biopsy of which 60 % (18/30) had no OCD at RP (p = 0.04) while 36.7 % (11/30) were upgraded to Gleason score ≥3 + 4 = 7 after RP (p = 0.15). There was no association between nuclear size, nucleolar size and/or distribution of macronucleoli with upgrading and/or absence of OCD (p > 0.05). The size of cribriform pattern was not associated with the absence of OCD (p = 0.43) or Gleason score upgrade (p = 0.28). A proportion of patients with Gleason score 3 + 4 = 7 PCa at needle biopsy do not have OCD or are upgraded to higher Gleason scores after RP. In our study, patients with Gleason score 3 + 4 = 7 PCa with the presence of cribriform pattern 4 had a significantly increased chance of being found to have no OCD at the time of RP. There were no clinical or pathologic parameters at the time of TRUS-guided biopsy that identified risk factors for Gleason score upgrading at RP in this study. Cribriform morphology detected on biopsy in patients with Gleason score 3 + 4 = 7 PCa is associated with tumour upstaging after RP and may be considered a contraindication to active surveillance.

Invasive urothelial carcinoma exhibiting basal cell immunohistochemical markers: A variant of urothelial carcinoma associated with aggressive features.

We characterize invasive urothelial carcinoma (UC) exhibiting urothelial basal cell immunohistochemical markers. Consecutive invasive UCs were immunostained with CK20 and urothelial basal cell markers, cytokeratin 5 (CK5)/CD44. Immunostaining for CK5 and CD44 was scored as follows: positive for staining of more than 25% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity. Invasive urothelial carcinoma (UC) exhibiting positive CK5/CD44 staining was designated as basal-like UC (BUC). In this study, of 251 invasive UC (pT1 in 57% and pT2-4 in 43%), BUC accounted for 40% of cases (accounting for most pT2-4 UC) and often presented as non-papillary UC without previous history of UC. In addition, BUC exhibited uniform nuclei with lesser degree of atypia than non BUC and decreased or negative cytokeratin 20 reactivity. Nested and microcystic variants of UC immunohistochemically stained as BUCs. Invasive non-BUCs were often papillary with marked cytologic atypia and pleomorphism, and accounted for most pT1 UC. The rates of perivesical invasion, lymph node and distant metastases were higher for BUC than non-BUC. All nine cases with absent/minimal residual in situ UC in 102 radical cystectomy specimens were from invasive non-BUC. BUC is distinguished from non-BUC due to this aggressive behavior, distinct immunohistochemical profile, and predominant non-papillary architecture. Our findings are consistent with recent studies identifying a subtype of muscle-invasive UC with molecular expression of basal cell and luminal cell molecular profiles. Our study further supports categorizing invasive UCs into these subtypes with different biological behaviors, possibly contributing to better therapeutic strategies.

Novel technique of sampling the urinary bladder for urothelial carcinoma specimens.

Sampling of the urinary bladder (UB) in radical cystectomy specimens is usually performed by obtaining sections through the lesions taken in rather random planes. The technique is hindered by the difficulty in identifying the anatomical relationship of the tumor with the remaining urinary bladder. Fifty radical cystectomy specimens were bisected in the horizontal plane at the middle portion of the UB then fixed without tissue stretching in 10% buffered formalin for at least 24 hours. The UBs were serially sectioned in parallel horizontal planes from the UB neck to the dome into rings of 3 to 10 mm thickness. The sections were orderly arranged and photographed. At least one ring of tissue was entirely submitted along with areas of interest or representative areas. Our proposed technique of transverse sections results in a mild increase in the number of sections submitted for microscopic examination. The advantages of our methods are (a) consistency and ease of sampling that help the microscopic-macroscopic correlation, (b) suitability for gross examination and for determining depth of invasion and largest tumor diameter, (c) improved identification of satellite lesions, and (d) suitability for neoplastic mapping and suitability for reexamination. The technique was validated by comparing with results of current technique.