- [Show abstract] [Hide abstract] ABSTRACT: Objectives: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC). Materials and methods: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test. Results: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had<pT2 disease. Analysis of pre- and posttreatment tumors demonstrated significantly decreased pSFK (P = 0.003) but no overall significant changes in Ki-67 or Cas3. In total, 4 cases demonstrated a nonsignificant decrease in Ki-67, of which 3 cases also demonstrated a decrease in pSFK and 2 cases had marginal increase in Cas3. Conclusions: Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.
- [Show abstract] [Hide abstract] ABSTRACT: Intraoperative pathologic consultation provides critical information that determines immediate diagnostic decision making for optimal patient care. Frequent indications for intraoperative consultation during urinary bladder surgery include assessment of surgical margin status during partial or radical cystectomy and diagnosis of extravesical masses or pelvic lymph nodes. Distal ureters and, less frequently, distal urethra are often submitted for frozen section assessment of surgical margins of radical cystectomy specimen. Frozen section diagnosis of urothelial dysplasia or carcinoma in situ is often challenging due to reactive atypia frequently seen in patients with bladder cancer. For assessment of partial cystectomy specimens, effective communication between surgeon and pathologist is particularly important. When intraoperative consultation is requested on bladder lesions in which conclusive diagnosis has never been made, a “good enough” diagnosis such as “high-grade carcinoma with invasion into muscularis propria” is usually sufficient for immediate management. To determine the presence of lymph node metastasis, a cytoscrape preparation is useful. Common pitfalls in the frozen section diagnosis include various types of artifacts such as thermal injury, crush artifact, and freeze artifact. Recognizing these artifacts as well as reviewing previous biopsy materials prior to the intraoperative consultation is always helpful for adequate interpretation of the specimens.
- [Show abstract] [Hide abstract] ABSTRACT: Intraoperative pathologic consultation provides critical information that determines immediate diagnostic decision making for optimal patient care. Frequent indications for intraoperative consultation during kidney surgery include assessment of renal masses, surgical margin status during partial or radical nephrectomy, and extrarenal masses/lymph nodes. Only gross examination of renal masses during radical nephrectomy may suffice unless the macroscopic findings are equivocal. Nonetheless, it is particularly important to distinguish between benign versus malignant conditions and renal cell carcinoma versus urothelial carcinoma. The intraoperative diagnosis may result in changes in the surgical procedure, for instance, partial nephrectomy for benign conditions, radical nephrectomy for renal cell carcinomas, and nephroureterectomy for urothelial carcinoma. For the assessment of surgical margins of partial nephrectomy specimens, the pathologist should be aware that normal proximal renal tubules may mimic an oncocytoma with a tubular growth pattern and that distorted renal tubules at the periphery of the tumor can be mistaken as a low-grade renal cell carcinoma. Other common pitfalls in the frozen section diagnosis include various types of artifacts such as thermal injury, crush artifact, and freeze artifact. Recognizing these artifacts, reviewing clinical and imaging finding as well as previous biopsy material if available prior to the intraoperative consultation is always helpful for adequate interpretation of the specimens.
- [Show abstract] [Hide abstract] ABSTRACT: Intraoperative frozen section (FS) evaluation of ureteral and urethral margins is frequently requested during radical cystoprostatectomy in patients with bladder urothelial carcinoma. However, it is still controversial whether intraoperative FSs of ureteral and urethral margins are necessary in all patients with cystoprostatectomy or a risk-based assessment with limited to the high risk patients is the best approach. A total of 203 radical cystoprostatectomy specimens with FS evaluation on margin status from men treated for bladder urothelial carcinoma from 2003 to 2010 in our institution were reviewed. Clinicopathologic features studied include: patients' age, pathologic tumor stage, presence of carcinoma in- situ (CIS), and intraoperative FS diagnosis. All 203 patients had intraoperative FS evaluation of ureter, and of these, 37 patients had additional urethra FS evaluation. Of the 203 ureteral FS cases, 17 (8.4%) had positive margin for CIS (16 cases) or CIS with invasive urothelial carcinoma (1 case). All 17 patients with positive ureteral margin on FS had concomitant CIS in the bladder (15.5%; 17 of 110 patients). In contrast, none of the patients without concomitant CIS (n=93) had positive ureteral margins on FS. Among 37 patients who also had FS evaluation on urethral resection margin, 3 patients (8.1%) had positive margins for CIS and all three of them had concomitant CIS in the bladder. Positive ureteral/urethral margin was not associated with patients' age or tumor stage, but was significantly associated with the presence of CIS in the bladder (p<0.001). Our study demonstrates that presence of concomitant CIS in bladder cancer was often associated with positive ureteral or urethral margin for CIS or invasive carcinoma; therefore, intraoperative FS evaluation may be indicated to these patients with concomitant bladder CIS. In contrast, in patients with no associated concomitant CIS in the bladder, FS of ureteral/urethral margins may not be necessary unless other clinical justification is present.
- [Show abstract] [Hide abstract] ABSTRACT: The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.
- [Show abstract] [Hide abstract] ABSTRACT: We have recently shown seminal vesicle intraepithelial involvement of prostate cancer in cases with seminal vesicle invasion (pT3b). Based on the manner of seminal vesicle invasion, there could be two possible mechanisms of seminal vesicle intraepithelial involvement: direct intraepithelial invasion from prostate carcinoma in the muscular wall of seminal vesicles, or intraepithelial involvement of cancer from the invaginated extraprostatic space (IES)/ejaculatory duct system to extraprostatic seminal vesicle. We aimed to clarify the manner and clinicopathological significance of seminal vesicle intraepithelial involvement. Of 1,629 consecutive radical prostatectomies, 109 cases (6.7%) showed seminal vesicle invasion in whole-mounted radical prostatectomy specimens. In these pT3b cases, 18 (17%) showed seminal vesicle intraepithelial involvement by prostate cancer. Stromal invasion of the IES/ejaculatory duct system and ejaculatory duct intraepithelial invasion by prostate cancer were identified in 62 and 5 of 109 pT3b cases, respectively. However, the presence/absence of IES/ejaculatory duct system involvement by prostate cancer does not predict seminal vesicle intraepithelial involvement. No statistically significant correlation was observed between all pathological parameters/biochemical recurrence and the presence/absence of seminal vesicle intraepithelial involvement in the pT3b cases. These findings suggest that seminal vesicle intraepithelial involvement is more likely due to direct invasion of carcinoma from the muscular wall of seminal vesicles rather than intraepithelial extension from the ejaculatory duct system in the IES. Further studies with a substantially greater case number are needed to clarify the clinicopathologic significance of seminal vesicle intraepithelial involvement in a better manner.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose: We determined the likelihood that transurethral resection biopsy of the prostatic urethra adjacent to the verumontanum would detect prostatic involvement of urothelial carcinoma in patients with bladder carcinoma. Materials and methods: We compared precystectomy transurethral resection biopsy specimens of the prostatic urethra with those of the matched radical cystoprostatectomy in 272 patients with urothelial carcinoma of the bladder. All prostates were evaluated by whole mount step sections. Results: Prostatic involvement by urothelial carcinoma was detected by transurethral resection biopsy or radical cystoprostatectomy in 101 patients (37.1%). Transurethral resection biopsy detected urothelial carcinoma in 72 cases with 71.3% sensitivity and 100% specificity. The overall accuracy of transurethral resection biopsy to detect urothelial carcinoma of the prostate was 89% (positive and negative predictive values 100% and 86%, respectively). Invasive prostatic urothelial carcinoma arising from the prostatic urethra was detected by transurethral resection biopsy in 21 of 26 patients (81%) while prostatic carcinoma in situ was detected in 39 of 52 (75%). Transurethral resection biopsy detected prostatic invasive urothelial carcinoma resulting from transmural invasion of a bladder tumor in 4 of 15 patients. Conclusions: Prostatic involvement by urothelial carcinoma of the bladder was found in 37.1% of patients. Transurethral resection biopsy missed most tumors resulting from transmural invasion of the bladder primary lesion. Carcinoma in situ and invasive urothelial carcinoma arising from the prostatic urethra were detected in most cases. Transurethral resection biopsy of the prostatic urethra can complement staging and support clinical decision making with respect to neoadjuvant chemotherapy and planning for an orthotopic neobladder.
- [Show abstract] [Hide abstract] ABSTRACT: Intraductal carcinoma of the prostate (IDC-P) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two distinct intraductal lesions; the former is usually associated to invasive carcinoma and has an aggressive course while the latter is considered a precancerous lesion. In addition, there are morphologically not well characterized lesions that fall between IDC-P and HGPIN, consequently termed “atypical cribriform lesions (ACLs).” Using whole mounted radical prostatectomy specimens, we evaluated the relationship between these intraductal proliferative lesions and clinicopathological parameters. In this study, ACLs were characterized as a loose cribriform intraductal proliferation with greater architectural complexity when compared to HGPIN, but lacking significant nuclear pleomorphism and/or comedonecrosis. Of 901 radical prostatectomies (2006-2012), IDC-P, ACL, and HGPIN were recorded in 155, 22, 436 cases, respectively. Patients with IDC-P showed more aggressive pathologic features when compared to HGPIN. Invasive cancers in patients with ACL had higher Gleason score (P = 0.00016), larger tumor volume (P = 0.025), and more advanced pT stage (P = 0.023) than those with HGPIN. Cases with ACL showed a higher risk of biochemical recurrence than those with HGPIN and a lower risk than those with IDC-P based on log-rank tests. (P = 0.0045 and P = 0.0069, respectively). In multivariate analysis, the presence of HGPIN was identified as an independent predictor for infrequent biochemical recurrence (P = 0.0058). We confirmed IDC-P as a marker of adverse pathologic features and clinical aggressiveness. Our results suggest that ACL should be distinguished from HGPIN and these lesions mandate active clinical surveillance.
- [Show abstract] [Hide abstract] ABSTRACT: Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants has so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S100P (86%), uroplakin III (20%), thrombomodulin (40%), CK7 (80%), CK20 (55%), p63 (87%) and HMCK (89%); b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell and microcystic): GATA3 (88%), S100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%) and HMCK (96%); and c) undifferentiated carcinomas (LELC, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%) and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared to the other urothelial carcinoma variants. This study provides a comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S100P, CK7, CK20, HMCK and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies.
- [Show abstract] [Hide abstract] ABSTRACT: Intraductal carcinoma of the prostate (IDC-P) has been described as a lesion associated with intraductal spread of invasive carcinoma and consequently aggressive disease. However, there are a few reported cases of pure IDC-P without an associated invasive component, strongly suggesting that this subset of IDC-P may represent a precursor lesion. We compared the clinicopathological features between the morphologically "regular type" IDC-P and "precursor-like" IDC-P. IDC-P was defined as follows; 1) solid/dense cribriform lesions or 2) loose cribriform/micropapillary lesions with prominent nuclear pleomorphism and/or non-focal comedonecrosis. We defined precursor-like IDC-P as follows; 1) IDC-P without adjoining invasive adenocarcinoma but carcinoma present distant from the IDC-P or 2) IDC-P having adjoining invasive microcarcinoma (less than 0.05 ml) and showing a morphologic transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to the IDC-P. IDC-P lacking the features of precursor-like IDC-P was categorized as regular type IDC-P. Of 901 radical prostatectomies performed at our hospital, 141 and 14 showed regular type IDC-P and precursor-like IDC-P in whole-mounted specimens, respectively. Regular type IDC-P cases had significantly higher Gleason score, more frequent extraprostatic extension and seminal vesicle invasion, more advanced pathological T stage, and lower 5-year biochemical recurrence-free rate than precursor-like IDC-P cases. Multivariate analysis revealed nodal metastasis and the presence of regular type IDC-P as independent predictors for biochemical recurrence. Our data suggest that IDC-P may be heterogeneous with variable clinicopathological features. We also suggest that not all IDC-P cases represent intraductal spread of pre-existing invasive cancer, and a subset of IDC-P may be a precursor lesion.
- [Show abstract] [Hide abstract] ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with characteristic tumors involving multiple organ systems. Whereas renal angiomyolipoma (AML) is common in TSC, renal cell carcinoma (RCC) is rarely reported. Fifty-seven RCCs from 13 female and 5 male TSC patients were reviewed. Age at surgery ranged from 7 to 65 years (mean: 42 y). Nine patients (50%) had multiple synchronous and/or metachronous RCCs (range of 2 to 20 RCCs) and 5 had bilateral RCCs (28%). Seventeen patients (94%) had histologically confirmed concurrent renal AMLs, including 15 with multiple AMLs (88%) and 9 (50%) with AMLs with epithelial cysts. None of the 15 patients with available clinical follow-up information had evidence of distant metastatic disease from 6 to 198 months after their initial surgery (mean: 52 mo). The 57 RCCs exhibited 3 major distinct morphologies: (1) 17 RCCs (30%) had features similar to tumors previously described as "renal angiomyoadenomatous tumor" or "RCC with smooth muscle stroma"; (2) 34 RCCs (59%) showed features similar to chromophobe RCC; and (3) 6 RCCs (11%) showed a granular eosinophilic-macrocystic morphology. Distinct histologic changes were also commonly present in the background kidney parenchyma and included cysts or renal tubules lined by epithelial cells with prominent eosinophilic cytoplasm, nucleomegaly, and nucleoli. Immunohistochemically, all RCCs tested showed strong nuclear reactivity for PAX8 and HMB45 negativity. Compared with sporadic RCCs, TSC-associated RCCs have unique clinicopathologic features including female predominance, younger age at diagnosis, multiplicity, association with AMLs, 3 recurring histologic patterns, and an indolent clinical course. Awareness of the morphologic and clinicopathologic spectrum of RCC in this setting will allow surgical pathologists to better recognize clinically unsuspected TSC patients.
- [Show abstract] [Hide abstract] ABSTRACT: Context.- Laboratories must validate all assays before they can be used to test patient specimens, but currently there are no evidence-based guidelines regarding validation of immunohistochemical assays. Objective.- To develop recommendations for initial analytic validation and revalidation of immunohistochemical assays. Design.- The College of American Pathologists Pathology and Laboratory Quality Center convened a panel of pathologists and histotechnologists with expertise in immunohistochemistry to develop validation recommendations. A systematic evidence review was conducted to address key questions. Electronic searches identified 1463 publications, of which 126 met inclusion criteria and were extracted. Individual publications were graded for quality, and the key question findings for strength of evidence. Recommendations were derived from strength of evidence, open comment feedback, and expert panel consensus. Results.- Fourteen guideline statements were established to help pathology laboratories comply with validation and revalidation requirements for immunohistochemical assays. Conclusions.- Laboratories must document successful analytic validation of all immunohistochemical tests before applying to patient specimens. The parameters for cases included in validation sets, including number, expression levels, fixative and processing methods, should take into account intended use and should be sufficient to ensure that the test accurately measures the analyte of interest in specimens tested in that laboratory. Recommendations are also provided for confirming assay performance when there are changes in test methods, reagents, or equipment.
- [Show abstract] [Hide abstract] ABSTRACT: Study hemangiomas in end-stage renal disease (ESRD). Twenty ESRD nephrectomies from 16 patients (9 months to 68 years old) were due to hypertension (4), focal segmental glomerulosclerosis (4), lupus nephritis (3), diabetes (1), IgA nephropathy (1), hereditary nephritis (1), congenital nephrotic syndrome (1), and unknown cause (1). Tumors measured 0.2 to 3.5 cm. Hemangiomas appeared as a single mass (15), 2 masses (1), 3 masses (1), 4 masses (2), and 8 masses (1) per kidney. Four patients had bilateral hemangiomas. All tumors were in the medulla and often abutted renal sinus fat. All except one of the tumors were anastomosing hemangioma showing isolated or interconnected sinusoidal capillary-sized vascular channels lined by a single layer of benign cuboidal CD34+, CD31+, D2-40- endothelial cells, separated by loose stroma with spindle cells. One tumor was cellular capillary hemangioma. Intravascular growth was seen in 9 specimens. All hemangiomas had extramedullary hematopoiesis. Acquired cystic kidney disease (ACKD) was seen in 11 kidneys (9 patients), renal cell carcinoma (RCC) in 5, ACKD-associated RCC precursors in 3, Wilms' tumor in 1, and papillary adenomas in 6. Anastomosing hemangioma appears as a distinctive clinicopathologic entity which develops in kidneys with ESRD, with or without ACKD. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Clear cell papillary renal cell carcinoma (CCP-RCC) has recently been recognized as a distinct subtype of renal cell carcinoma (RCC) due to its unique morphologic, immunohistochemical, and genetic features and indolent clinical behavior. However, the incidence of this tumor in a nephrectomy series for renal mass has not been fully investigated. Twelve cases of CCP-RCC were identified from a total of 290 consecutive partial (n = 137) or radical nephrectomies (n = 153) for RCC from 2010 to 2012 in our hospital. In this series, CCP-RCC was the fourth most common (4.1%) kidney tumor following clear cell (conventional) (70%), papillary (16.6%), and chromophobe (5.9%) RCCs. The average age of the CCP-RCC patients was 58.2 years (range, 18-81 years), with an equal sex distribution. Four cases (33.3%) were associated with end-stage renal disease. Of the 12 CCP-RCCs, 9 presented as solitary tumors; 2 coexisted with clear cell RCC; and 1 with papillary RCC. The average size of tumors was 2.5 cm (range, 0.8-6.0 cm). All tumors were pT1 (10 pT1a and 2 pT1b). Two cases were initially misclassified as clear cell RCC. Strong positive cytokeratin 7 stain and negative stains with α-methylacyl-CoA racemase and RCC marker differentiate CCP-RCC from low-grade clear cell RCC with similar histologic features. We conclude that CCP-RCC is a common renal neoplastic entity, representing the fourth most common (4.1%) RCC. It can be easily misclassified due to its overlapping features with low-grade clear cell RCC. In equivocal cases, immunohistochemical stains with a small panel of markers (cytokeratin 7, α-methylacyl-CoA racemase, RCC marker, or CD10) are warranted in making the correct histologic classification.
- [Show abstract] [Hide abstract] ABSTRACT: Current oncology guidelines and clinical trials consider giving adjuvant chemotherapy to bladder cancer patients with at least microscopic perivesical tissue invasion (MPVTI) (≥pT3a) on cystectomy. The boundary of muscularis propria (MP) and perivesical tissue is commonly ill defined, and hence, when the tumor involves the interface, interpretation of MPVTI is likely to be subjective. In this study, 20 sets of static images that included 1 nontumoral bladder wall for defining MP-perivesical tissue boundary and 19 bladder cancer cases equivocal for MPVTI with confounding factors were sent to 17 expert genitourinary pathologists for review. The confounding factors were "histoanatomic," as defined by the irregular MP-perivesical tissue boundary, and "tumor related," such as fibrosis, dense inflammation, tumor cells at the edge of the outermost MP muscle bundle, and lymphovascular invasion. These equivocal cases were divided into 3 categories according to the following factors: (1) histoanatomic only (7/19), (2) histoanatomic+tumor related (7/19), and (3) tumor related only (5/19). Participating genitourinary pathologists used different criteria to assess MPVTI: (A) drawing a straight horizontal line using the outermost MP muscle bundle edge as the MP-perivesical tissue boundary reference (3/17); (B) drawing multiple straight lines interconnecting the outermost MP muscle bundle edges (9/17); (C) following the curves of every outermost MP muscle bundle edge (4/17). In category 1 cases, most pathologists who used the A criterion called for absence (6/7), whereas those who used the C criterion called for presence (5/7) of MPVTI, which resulted in disparity in 4/7 cases. There was no circumstance in which criteria A and C agreed on the presence or absence of MPVTI but was opposed by the B criterion in category 1 cases. Median pairwise agreement among all pathologists (regardless of criteria) for all cases (regardless of category) was only "fair" (κ=0.281). However, when only the B criterion was assessed for category 1 cases, median agreement was "substantial" (κ=0.696), and pairwise rater comparisons included 6/36 (17%) "near perfect," 13/36 (36%) "substantial," and 11/36 (31%) "moderate" agreements. When all cases with histoanatomic factors (categories 1 and 2) were combined, median pairwise agreements were: (A) κ=0.588, (B) κ=0.423, and (C) κ=0.512, and the B criterion rater comparisons included 0/36 (0%) "near perfect," 6/36 (17%) "substantial," and 16/36 (44%) "moderate" agreements, which showed the confounding effect of tumor-related factors. For category 3 cases, median pairwise agreement for all pathologists was "fair" (κ=0.286), with consensus agreement in only 2/5 of these equivocal cases. Lymphovascular invasion only at the MP-perivesical tissue boundary was not staged as MPVTI by 87.5% of pathologists. In conclusion, this study showed that interpretation of equivocal cases for MPVTI can be made difficult by factors intrinsic to bladder histoanatomy, defined by an irregular MP-perivesical tissue boundary, and factors related to tumor spread. There are at least 3 different approaches to demarcating an irregular outer MP boundary, and agreement is improved on equivocal cases when a common histoanatomic criterion is used. However, inconsistent agreement of anatomic criteria may cause systematic discrepancy in assessing MPVTI. Tumor-related factors such as dense fibrosis or desmoplasia, obscuring inflammation, tumor cells at the edge of the outermost MP muscle bundle, and admixed lymphovascular invasion can also negatively influence the agreement on interpretation of MPVTI. This study highlights the need to adopt common criteria in defining the outer MP boundary. Future studies may identify the most clinically relevant histoanatomic criteria for MPVTI.
Article: Renal Tumors[Show abstract] [Hide abstract] ABSTRACT: The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants’ responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.
- [Show abstract] [Hide abstract] ABSTRACT: The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of bio-markers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cyto-genetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prog-nostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Al-though no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell car-cinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/ or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.
- [Show abstract] [Hide abstract] ABSTRACT: Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8–20 weeks) or concurrent and subsequent (8–32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non–muscle-invasive disease was present in animals treated with tamoxifen before (5–8 weeks) or after (20–32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.
Cornell UniversityИтак, New York, United States
Weill Cornell Medical College
New York City, New York, United States
- Department of Surgery
Houston Methodist HospitalHouston, Texas, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
- Department of Pathology