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We describe 33 cases of myxoid pseudotumor involving the renal sinus from 31 patients. Patients included 21 men and 10 women, ages 30 to 95 years. Twenty-seven cases (82%) had an associated malignancy, including urothelial carcinoma of the renal pelvis (22 cases), clear cell renal cell carcinoma (3 cases), urothelial carcinoma of the bladder (1 case), and poorly differentiated carcinoma of uncertain lineage (1 case). The remaining 6 (18%) had no associated malignancy and included 3 nephrectomies for ureteral stricture, 2 ureteropelvic junction repairs, and 1 resection of a "periureteral mass" (subsequently shown to be myxoid pseudotumor). Myxoid pseudotumor was identified by preoperative computed tomography imaging in 2 patients (6%) and identified by the gross dissector in 9 cases (27%). The mean size was 14 mm (range: 5 to 38 mm). All cases had an admixture of adipocytes, myxoid stromal matrix, variable collagenization, and a hypocellular population of bland spindled and stellate stromal cells. No multilobated atypical stromal cells were present. Clinical follow-up was available for 28 patients (90%), ranging from 1 to 132 months (mean: 24.6 mo). No patients had adverse events related to the myxoid pseudotumor. Myxoid pseudotumor of the renal sinus is often associated with a variety of adjacent neoplastic and non-neoplastic conditions and may present as a mass lesion detectable by imaging and/or gross inspection. Awareness of this benign process is important to avoid confusion with a neoplasm, especially liposarcoma., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Based on the current WHO 2016 classification, the spectrum of flat urothelial lesions with atypia includes reactive urothelial atypia, urothelial atypia of unknown significance, urothelial dysplasia, and urothelial carcinoma in situ (CIS). Classification along this continuous spectrum of atypia can be one of the most challenging areas in all genitourinary pathology. This review will focus on the diagnosis of urothelial CIS in routine clinical practice, emphasising histological criteria, histological spectrum (i.e., 'variant' types), adjunctive immunohistochemistry, intraoperative evaluation, and distinction from its morphological mimics., (Copyright © 2020 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Aims: Invasive micropapillary carcinoma is a recognised aggressive urothelial carcinoma variant. One prior study focusing on non-invasive (pTa) high-grade papillary urothelial carcinoma with micropapillary architecture has been reported., Methods and Results: We collected bladder transurethral resection specimens showing non-invasive high-grade papillary urothelial carcinoma with non-hierarchical secondary papillae lacking fibrovascular cores (i.e. micropapillary architecture). Cases with any invasive component or any prior history of invasive urothelial carcinoma were excluded. Twenty cases were identified from 16 male and two female patients (aged 55-86 years). Micropapillary architecture comprised from 10 to 95% (mean = 31%), but non-invasive cribriform (15 cases, comprising 5-60%, mean = 19%) and villoglandular patterns (nine cases, comprising 5-60%, mean = 24%) were commonly admixed. Treatment data were available for 16 patients: surveillance (n = 13), cystoprostatectomy (n = 1), BCG plus mitomycin (n = 1) and BCG (n = 1). Follow-up data were available from 16 patients (range = 1-128 months, mean = 50 months): 13 patients had no new occurrences to date (81%), two had stage progression to pT1 papillary urothelial carcinoma (13%) with one dying of other causes, and one died of other causes with no evidence of disease (6%)., Conclusion: Non-invasive urothelial carcinomas with micropapillary architecture are often admixed with non-invasive cribriform and villoglandular patterns. Stage progression to lamina propria invasion in only two of 16 patients (13%) is not higher than expected for otherwise typical pTa high-grade urothelial carcinomas and no progression to invasive micropapillary carcinoma was identified, adding further support to the current World Health Organisation recommendation excluding use of the term 'micropapillary' for pTa urothelial carcinoma., (© 2020 John Wiley & Sons Ltd.)

Flat urothelial lesions with atypia may pose significant diagnostic challenges. Given frequent increased proliferation rates in florid reactive urothelial atypia and limited studies on the interpretation of p53 stains in the urothelium (following current standard guidelines for correlation with P53 mutation status), we sought to further study the discriminatory value of Ki-67 and p53 for florid reactive urothelial atypia versus urothelial carcinoma in situ (CIS). Bladder specimens diagnosed as reactive urothelial atypia (n = 40) and CIS (n = 40) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, CD44, and CK20. Immunoreactivity was scored based on percent cells positive for Ki-67 and pattern of reactivity with p53 (aberrant: diffuse strong positive or negative; normal: patchy/wild type). CD44 and CK20 reactivity patterns served as adjunctive internal validation controls for reactive urothelial atypia and CIS, as previously described. In reactive urothelial atypia, Ki-67 ranged from 0% to 90% (mean, 34% ± 26) with 30 cases (75%) having >10%. In CIS, Ki-67 ranged from 5% to 95% (mean, 50% ± 25) with 17 cases (43%) having >50%. In all 40 cases (100%) of reactive urothelial atypia, p53 expression had a wild-type pattern. In CIS, aberrant p53 expression was identified in 15 cases (37%): 3 cases (7%) were p53 negative (i.e. null phenotype) and 12 cases (30%) showed strong and diffuse nuclear reactivity (in >85% of cells). The remaining 25 cases (63%) of CIS had a p53 wild-type pattern of expression. Cytoplasmic CK20 immunoreactivity in umbrella cells was seen in 34 cases (85%) of reactive urothelial atypia, and 6 cases (15%) were negative. In addition, 35 cases (88%) of reactive urothelial atypia demonstrated full-thickness CD44 expression, while 5 cases (12%) had expression confined to the basal/parabasal layers of the urothelium. Strong and diffuse CK20 positivity was present in 39 cases (98%) of CIS, and patchy positivity was detected in 1 case (2%). None of the CIS cases overexpressed CD44: 16 cases (40%) showed focal expression in the nonneoplastic basal cell layer; 24 cases (60%) demonstrated no staining. In summary, Ki-67 has poor discriminatory value for reactive urothelial atypia versus CIS and adds little to the classic CK20/CD44 immunophenotype. While p53 sensitivity for CIS is relatively low (30%) and interpretation as either wild type or negative may be challenging in a small subset of cases, strong and diffuse nuclear reactivity was 100% specific in the distinction from florid reactive urothelial atypia in this cohort., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although there are 5 well-described morphologic patterns of (nonglandular) urothelial carcinoma in situ (CIS), we have encountered a novel pattern of flat urothelial carcinoma with plasmacytoid features characterized by a triad of morphologic findings including abnormal architecture with cellular rounding, enlarged nuclei with eccentric nuclear localization, and dense globular eosinophilic cytoplasm. A total of 23 cases of plasmacytoid CIS (mean age: 74.1 y, range: 58 to 91 y) were collected and reviewed. We excluded cases in which the diagnostic biopsy had any of the following findings admixed in the same tissue biopsy sample as the plasmacytoid CIS: traditional patterns of CIS, noninvasive glandular CIS, papillary urothelial carcinoma, or invasive carcinoma. Immunostains for CK20, CD44, p53, and e-cadherin were performed on available blocks. History of prior urothelial neoplasia, prior treatment, and clinical follow-up were obtained from medical records and pathology re-review. Immunohistochemical analysis of plasmacytoid CIS showed diffuse/strong CK20 reactivity in 96% of cases (23/24), an abnormal p53 reactivity pattern (either overexpression or "null phenotype") in 37% of cases (7/19), absence of CD44 reactivity in the neoplastic cells in 63% of cases (15/24), and retained membranous e-cadherin expression in 100% of cases (18/18). Clinical follow-up (average follow-up time: 37.7 mo, range: 7 to 115 mo) showed recurrence/new occurrence in 52% of cases (12/23), including all 4 of the 23 patients who initially presented with de novo plasmacytoid CIS (ie, no prior or concomitant urothelial neoplasia). The histologic features, the immunophenotype, the association with other forms of urothelial neoplasia, and the risk of recurrence and progression in de novo lesions support that plasmacytoid CIS represents a novel pattern of flat urothelial carcinoma. These histologic features may be more subtle than in other more typical patterns of CIS and should be carefully distinguished from therapy-related/reactive changes.

Context.—: Since the publication of the previous World Health Organization (WHO) Classification of Tumours on the Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs in 2004, significant new knowledge has been generated regarding the pathology and genetics of bladder neoplasia. Publication of the 2016 WHO "Blue Book" has codified that new data into updated recommendations for classification and prognostication. Similarly, the recent release of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, which was implemented in January 2018, has also addressed staging criteria for bladder cancer in several unique settings to clarify their application., Objective.—: To highlight subtle changes within the recent WHO and AJCC publications that may affect daily surgical pathology practice., Data Sources.—: Peer-reviewed published literature, the 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs , and the 8th edition of the AJCC Cancer Staging Manual were reviewed., Conclusions.—: Selected changes and/or clarifications are discussed and include classification of flat and papillary urothelial neoplasia, select variant patterns of invasive urothelial carcinoma, staging of invasive carcinoma in bladder diverticula, and staging of carcinomas involving the prostate gland.

Purpose: Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets., Experimental Design: Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody-drug conjugate (ADC)., Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most "normal-like" pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most "metastasis-like" pattern had the shortest OS ( P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS ( P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model., Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC., (©2018 American Association for Cancer Research.)

The classification of neoplastic precursor lesions in the urinary tract has evolved slowly with the gradual accumulation of clinicopathological data. Current nomenclature was codified most recently by the 2016 WHO classification, which is based on primary data with clinical outcome, consensus group statements and considerations of practical utility in routine diagnosis. This review discusses precursor lesions of urothelial, squamous and glandular lineage. For urothelial neoplasia, both flat lesions with atypia and early 'difficult-to-classify' proliferations are considered. Subtypes of squamous metaplasia, florid non-invasive squamous proliferations and frank squamous dysplasia are also addressed. Finally, rare glandular precursors of adenocarcinoma are reviewed, to include intestinal metaplasia, glandular dysplasia and villous adenoma. For each category, morphology (including differential diagnostic considerations), immunohistochemistry and any known molecular correlates are detailed. The goal is to provide a concise, practical up-to-date overview of this complex topic., (© 2018 John Wiley & Sons Ltd.)

Immunohistochemistry may be a very useful adjunct to morphologic diagnosis in many areas of surgical pathology, including genitourinary pathology. In this review, we address common diagnostic dilemmas where immunophenotypic analysis may be utilized and we highlight pitfalls specific to each scenario. For prostate, we review the diagnosis of limited prostatic adenocarcinoma and the distinction of high-grade prostatic adenocarcinoma from urothelial carcinoma. We also cover markers of urothelial lineage in the diagnosis of metastatic carcinoma of unknown primary site. In the kidney, distinction of poorly differentiated renal cell carcinoma from urothelial carcinoma and epithelioid angiomyolipoma, adjuncts to the recognition of hereditary renal neoplasia, and the diagnosis of metastatic renal cell carcinoma are discussed. Finally, for testis we address distinction of germ cell tumors from sex cord-stromal tumors, as well as the diagnosis of metastatic germ cell tumors.

Aims: The large nested variant of urothelial carcinoma (LNUC) has been added to the World Health Organization (WHO) 2016 classification. Scant data exist, and little is known about its clinical behaviour., Material and Results: Cases fulfilling the morphological criteria of LNUC were collected. Pure and mixed cases (i.e. with other patterns of invasive UC) were studied. Immunohistochemical staining with cytokeratin (CK)7, p63, GATA-3, CK20, p53 and Ki-67 was performed. Included were 26 cystectomies (RC) and 10 resections (TURB) belonging to 36 patients with an average age of 66.7 years. Fourteen (39%) were pure LNUCs, and 22 (61%) displayed mixed features. Seventy per cent of the TURBs had pT2 tumours, while 58% of RCs had extravesical disease (≥pT3 and/or ≥pN1), with the rate of advanced disease being higher in mixed (69%) in comparison to pure cases (40%). Similarly, 38% of mixed cases had nodal metastases in comparison to 20% of pure cases. Overall, eight patients (24%) died of disease at a mean interval time of 21.7 months and seven patients (21%) showed recurrence or metastases. Disease progression was significantly higher in mixed cases (55 and 31% in mixed and pure cases, respectively). Positive staining was: CK7 = 87.5%, CK20 = 72%, GATA-3 = 91%, P63 = 100%, p53 = 56% and Ki-67 = mean of 16%., Conclusion: Despite the bland cytological appearance and deceptive pattern of invasion of the LNUC, our study validates its fully malignant potential with metastatic spread and tumour-related deaths. Distinguishing mixed from pure LNUCs seems to be of value. LNUCs show comparable immunophenotype to both conventional urothelial carcinoma and the nested variant of urothelial carcinoma., (© 2017 John Wiley & Sons Ltd.)

Context: -Sarcomatoid urothelial carcinoma (UCa) is a rare but aggressive variant of bladder cancer that can show diagnostic challenges even using ancillary techniques., Objective: -To examine immunohistochemical markers in the context of sarcomatoid UCa, including those associated with epithelial-to-mesenchymal transition., Design: -Twenty-eight cases of sarcomatoid UCa were rereviewed. Clinical outcomes were obtained through database search. Immunohistochemistry for clinical and epithelial-to-mesenchymal transition markers was performed., Results: -All patients had biopsy-proven invasive UCa; 61% (17 of 28) had sarcomatoid UCa at initial diagnosis. A recognizable epithelial component(s) was present in 17 lesions. The sarcomatoid component accounted for 65% of the lesion (average), with heterologous elements present in 3 of 28 cases (11%). The morphologic spectrum of the sarcomatoid element included spindled not otherwise specified, myxoid, pseudoangiosarcomatous, and malignant fibrous histiocytoma-like undifferentiated features. The sarcomatoid component was immunoreactive for pancytokeratin (22 of 26; 85%), p63 (20 of 26; 77%), cytokeratin 903 (17 of 26; 65%), cytokeratin 7 (16 of 26; 62%), GATA3 (16 of 26; 62%), and cytokeratin 5/6 (16 of 26; 62%). STAT-6, CD31, CD34, and HMB45 were all nonreactive, whereas smooth muscle actin often showed at least focal immunoreactivity (22 of 26; 85%). Epithelial-to-mesenchymal transition markers were frequently expressed, including vimentin (26 of 26; 100%), FoxC2 (26 of 26; 100%), SNAIL (23 of 26; 88.5%), and ZEB1 (18 of 26; 69.2%). Follow-up was available for 24 patients (median, 7 months). Sixteen of 28 patients (57%) died of disease (overall mean survival, 9.1 months). The presence of myxoid or chordoid features was associated with reduced survival (P < .05)., Conclusions: -Sarcomatoid UCa is an aggressive form of UCa that frequently expresses epithelial-to-mesenchymal transition markers, suggesting a possible mechanism associated with aggressive tumor behavior.

The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a 'Pathology of Bladder Cancer Work Group,' have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting., Competing Interests: Disclosure/conflict of interest The authors declare no conflict of interest.

Purpose: Androgen receptor (AR) is a recognized immunohistochemical marker of prostate cancer. However, the sensitivity and specificity of AR for prostate cancer in the setting of other genitourinary neoplasms has not been rigorously studied., Methods: We employed tissue microarrays containing prostate carcinomas, urothelial carcinomas, renal cell carcinomas, and testicular neoplasms. Slides were stained immunohistochemically for AR., Results: Androgen receptor was positive in 95% of prostate carcinomas (n=230), but 19% of invasive urothelial carcinomas of the bladder (n=190) and 33% of non-invasive bladder urothelial carcinomas were also AR positive (N=107). Furthermore, 16% of renal pelvis urothelial carcinomas (n=43) were positive. Of primary renal cell carcinomas, 19% were AR positive (n=307). From a metastatic renal cell carcinoma cohort, 28% of metastases were AR positive (N=126). Six percent of non-teratomatous testicular germ cell tumors stained for AR (n=103)., Conclusions: Our data show that the sensitivity of AR immunohistochemistry for prostate cancer is 94.8%. However, the specificity of AR is only 81.4%, among our cohort of invasive genitourinary tumors. Thus, we find the specificity of AR suboptimal, yet AR may remain useful as a component of an immunostain panel.

The pseudoangiosarcomatous pattern has been described mostly in cutaneous and some visceral squamous cell carcinomas and is unique for its striking morphologic resemblance to angiosarcoma. Herein, we describe the clinicopathologic features of 7 pseudoangiosarcomatous urothelial carcinomas that occurred in the urinary bladder. The patients included 6 men and 1 woman ranging in age from 47 to 87 years (median 70 y). The pseudoangiosarcomatous morphology was observed in 7 urothelial carcinomas including 3 with squamous differentiation and comprised 35% to 85% of the invasive tumor. Histologically, the pseudoangiosarcomatous carcinomas were characterized by tumor cell discohesion and lysis that created pseudolumina formations surrounded by attached residual tumor cells. Detached degenerating tumor cells variably admixed with inflammatory cells were common in the false lumina. Partly intact urothelial carcinoma nests contained irregular or cleft-like spaces and disintegrating tumor cells with stretched intercellular bridges. The tumor was commonly associated with a dense collagenous matrix, often surrounding the lytic nests. Similar tumor cell discohesion and breakdown were observed in 3 tumors with foci of squamous cell differentiation, distinguished by the presence of dyskeratosis and keratin formation. All 7 tumors contained other nonpseudoangiosarcomatous carcinoma components such as conventional urothelial carcinoma (5), squamous differentiation (4), sarcomatoid spindle cell carcinoma (2), small cell carcinoma (1), micropapillary carcinoma (1), and glandular differentiation (1). The pseudoangiosarcomatous urothelial carcinomas were all (7/7) diffusely CK7 positive, most (6/7) were GATA3 positive, and none (0/7) expressed vascular-associated markers. There was no evidence to suggest that apoptosis (by TUNEL assay and cleaved caspase-3 immunostaining) or loss of the adhesion molecules CD138 and e-cadherin were possible causes for the tumor cell discohesion and breakdown. All 7 tumors were high stage at cystectomy and included 1 pT3a, 2 pT3b, and 4 pT4a tumors, and 3 had pelvic lymph node involvement. Follow-up data available in 6 cases revealed a poor outcome with an overall median survival of 8.5 months. In conclusion, we present an unusual morphology of bladder carcinoma that has a striking resemblance to a malignant vasoformative tumor. Our series showed that bladder pseudoangiosarcomatous carcinoma morphology is associated with a higher tumor stage at cystectomy, commonly admixed with other aggressive carcinoma variant morphologies, and portend a poorer outcome. Knowledge of this pattern is also important to avoid misdiagnosis, particularly in limited tissue samples.

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.

Urothelial carcinoma in situ (CIS) is a prognostically and therapeutically significant lesion with considerable morphologic overlap with reactive conditions especially in the setting of prior therapy. Various markers including CK20, CD44s, and p53 have been used as an adjunct in making this distinction; however, the utility of these markers in the posttreatment scenario is not fully established. α-Methylacyl-CoA racemase (AMACR) is a tumor-associated marker that is expressed in a subset of high-grade urothelial carcinomas but has not been studied in CIS. This study was undertaken to evaluate the immunoreactivity of CK20, CD44s, and p53 as a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3) in distinguishing CIS from its mimics and to compare its utility with AMACR in the diagnosis of CIS. A total of 135 specimens (7 benign ureters and 128 bladder biopsies-28 reactive, 33 posttherapy reactive, 43 CIS, 24 CIS posttherapy) were included in this study. Immunostaining for p53 (brown, nuclear), CD44s (brown, membranous), and CK20 (red, cytoplasmic and membranous) was performed as a cocktail, and the staining pattern was further classified as: malignant (full-thickness CK20 and/or full-thickness p53 with CD44s negativity), reactive/benign (CK20 limited to the umbrella cell layer, p53 negative, and CD44s positivity ranging from basal to full thickness), and indeterminate (CK20 and p53 positive but not full thickness and/or CD44s positive). AMACR staining was performed in 50 cases. Cytoplasmic staining for AMACR was graded as negative (absent to weak focal staining [<5% cells]) and positive (≥5%). The "IUN-3 malignant" pattern was observed in 84% of cases of CIS without a history of prior therapy and in 71% of the cases of CIS with a history of prior therapy. Cases with posttherapy reactive atypia showed an "IUN-3 reactive" pattern in 84% cases and "IUN-3 indeterminate" pattern in 16% of the cases; the IUN-3 malignant pattern was not identified in any of the cases. Benign and reactive urothelium (with and without a history of therapy) showed an IUN-3 reactive pattern and negative AMACR staining in all the cases (100%). AMACR positivity was observed in 78% of nontreated CIS cases and 50% of CIS posttherapy cases. In these cases, the IUN-3 cocktail showed an IUN-3 malignant pattern in 83% of untreated CIS cases and 88% of CIS posttherapy cases. AMACR positivity is a potentially useful marker of CIS. However, the IUN-3 malignant pattern is a more reliable indicator of CIS compared with AMACR, especially in the posttreatment setting. The simultaneous evaluation of all 3 markers (p53, CD44s, and CK20) in a single slide in the form of a cocktail is advantageous, especially in small biopsy specimens.

Background and Purpose: Emerging optical imaging technologies such as confocal laser endomicroscopy (CLE) hold promise in improving bladder cancer diagnosis. The purpose of this study was to determine the interobserver agreement of image interpretation using CLE for bladder cancer., Methods: Experienced CLE urologists (n=2), novice CLE urologists (n=6), pathologists (n=4), and nonclinical researchers (n=5) were recruited to participate in a 2-hour computer-based training consisting of a teaching and validation set of intraoperative white light cystoscopy (WLC) and CLE video sequences from patients undergoing transurethral resection of bladder tumor. Interobserver agreement was determined using the κ statistic., Results: Of the 31 bladder regions analyzed, 19 were cancer and 12 were benign. For cancer diagnosis, experienced CLE urologists had substantial agreement for both CLE and WLC+CLE (90%, κ 0.80) compared with moderate agreement for WLC alone (74%, κ 0.46), while novice CLE urologists had moderate agreement for CLE (77%, κ 0.55), WLC (78%, κ 0.54), and WLC+CLE (80%, κ 0.59). Pathologists had substantial agreement for CLE (81%, κ 0.61), and nonclinical researchers had moderate agreement (77%, κ 0.49) in cancer diagnosis. For cancer grading, experienced CLE urologists had fair to moderate agreement for CLE (68%, κ 0.64), WLC (74%, κ 0.67), and WLC+CLE (53%, κ 0.33), as did novice CLE urologists for CLE (53%, κ 0.39), WLC (66%, κ 0.50), and WLC+CLE (61%, κ 0.49). Pathologists (65%, κ 0.55) and nonclinical researchers (61%, κ 0.56) both had moderate agreement for CLE in cancer grading., Conclusions: CLE is an adoptable technology for cancer diagnosis in novice CLE observers after a short training with moderate interobserver agreement and diagnostic accuracy similar to WLC alone. Experienced CLE observers may be capable of achieving substantial levels of agreement for cancer diagnosis that is higher than with WLC alone.

Context: To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the pathology of bladder cancer using an evidence-based strategy., Objective: To standardize descriptions of the diagnosis and reporting of urothelial carcinoma of the bladder and help optimize uniformity between individual pathology practices and institutions., Evidence Acquisition: A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to pathology. Proceedings from the last 5 yr of major conferences were also searched., Evidence Synthesis: The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed., Conclusions: Providing the best management for patients with bladder neoplasia relies on close cooperation and teamwork among urologists, oncologists, radiologists, and pathologists., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Distinction between primary lung carcinomas and metastases from other sites, especially the urinary tract, is a common diagnostic dilemma. As urothelial carcinomas can demonstrate a broad range of morphology and frequently demonstrate squamous differentiation, discerning metastatic urothelial carcinoma to the lung from primary pulmonary squamous cell carcinoma can be challenging., Objective: To investigate immunostains that may aid in the distinction of urothelial carcinoma metastatic to the lung., Design: Staining patterns of 14 markers in primary urothelial carcinoma of the bladder and primary squamous cell carcinoma of the lung were examined to establish a diagnostic panel. These antibodies were subsequently tested on tumors taken from 30 patients with a paired urinary tract and metastatic lung lesion., Results: The best markers to distinguish poorly differentiated metastatic urothelial carcinoma from primary pulmonary squamous cell carcinoma were CK7, CK20, GATA-3, CK14, desmoglein-3, and uroplakin III, with the utility of the latter dependent upon the quantity of tissue available for analysis. The observed percentage positive staining in nonmetastatic urothelial carcinoma versus primary pulmonary squamous cell carcinoma with these antibodies was as follows: CK7 (100% versus 33%), CK20 (54% versus 7%), GATA-3 (78% versus 23%), CK14 (32% versus 77%), desmoglein-3 (11% versus 87%), and uroplakin III (14% versus 0%). Similar expression patterns were observed among the paired cases., Conclusion: When interpreted in correlation with clinical history and histomorphology, a panel of immunostains including CK7, CK20, GATA-3, CK14, desmoglein-3, and uroplakin III may be a useful adjunct in the distinction of metastatic urothelial carcinoma to the lung.

Purpose: Bladder plasmacytoid carcinoma is an invasive urothelial carcinoma subtype that is emphasized for its morphological overlap with plasma cells and metastatic carcinoma. Our experience suggests frequent intraperitoneal spread that is not typical of conventional urothelial carcinoma., Materials and Methods: We identified cases of plasmacytoid urothelial carcinoma diagnosed on radical cystectomy. Patient age, gender, American Joint Committee on Cancer (7th edition) stage, metastatic spread/recurrence sites and clinical disease status at last followup were recorded., Results: A total of 10 male and 5 female patients 42 to 81 years old were identified. One tumor was pT2, 11 pT3 and 3 pT4. Six of 15 patients (40%) presented with lymph node metastasis and 5 (33%) had intraperitoneal metastasis at cystectomy. These initial sites of metastatic spread included the prerectal space, ovary and vagina, ovary and fallopian tube, bowel serosa, and omentum and bowel serosa in 1 case each. Three patients had subsequent metastasis involving the prerectal space, pleural fluid and small bowel serosa, and bowel serosa in 1 each. Eight patients had followup information available, including 3 who died of disease, 3 with disease and 2 with no evidence of disease., Conclusions: Of the patients 33% with the plasmacytoid variant of urothelial carcinoma presented with intraperitoneal disease spread and 20% had subsequent metastasis involving serosal surfaces. The possibility of noncontiguous intraperitoneal spread involving serosal surfaces should be recognized to ensure proper intraoperative staging and clinical followup for patients with plasmacytoid carcinoma., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The vast majority of urachal epithelial neoplasms are adenocarcinomas with several described morphologic subtypes that include both enteric and nonenteric histologies. Adenocarcinoma from several other primaries may mimic any of these urachal adenocarcinoma subtypes in the bladder or at distant sites. However, data regarding the immunohistochemical profile of urachal carcinoma are limited, let alone its correlation with the different histologic subtypes that may have implications in the differential diagnostic workup with their morphologic mimics. Herein, we performed an immunohistochemical analysis in a broad spectrum of 39 urachal epithelial neoplasms (34 adenocarcinomas, 1 urothelial carcinoma, and 4 noninvasive mucinous cystic tumors), 13 urachal remnants, and 6 secondary colonic adenocarcinomas of the bladder, using an antibody panel that included novel and traditional gastrointestinal tract-associated markers. Expression levels of p63, CK7, CK20, CDX2, nuclear β-catenin, claudin-18, and Reg IV in urachal adenocarcinoma were as follows: 3%, 50%, 100%, 85%, 6%, 53%, and 85%. In urachal adenocarcinoma subtypes, expression levels of CDX2, nuclear β-catenin, claudin-18, and Reg IV were as follows: mucinous (8/8, 0/8, 6/8, 8/8), enteric (10/11, 1/11, 3/11, 8/11), not otherwise specified (5/7, 0/7, 3/7, 5/7), and signet ring cell (4/6, 0/6, 4/6, 6/6) type. All urachal adenocarcinomas had membrano-cytoplasmic β-catenin staining and only 2 tumors had nuclear localization that were focal to moderate, in contrast to secondary colonic adenocarcinoma of the bladder, which mostly had both membrano-cytoplasmic and nuclear positivity. Claudin-18 positivity was observed only in frankly malignant tumors and not in noninvasive urachal tumors and urachal remnants. Reg IV expression seemed to be related to mucin production, which was often diffuse in mucinous and signet ring cell subtypes and focal in enteric subtype, with goblet cell-like reactivity similar to secondary colonic adenocarcinoma. p63 expression was present in urothelial urachal remnants (3/3) and contrasted with CDX2 expression seen in glandular (5/6) and mixed urothelial/glandular remnants (2/4). Thus, this study showed that CDX2 is expressed by urachal remnants of glandular type, noninvasive urachal mucinous cystic tumors and urachal adenocarcinomas, and can be diffuse in urachal adenocarcinomas, even without the classic enteric morphology. Nuclear localization of β-catenin can rarely occur in urachal adenocarcinoma; however, diffuse nuclear reactivity argues against its diagnosis. The novel gastrointestinal tract markers claudin-18 and Reg IV are both expressed in urachal adenocarcinoma, including in signet ring cell carcinoma, and thus refutes the suggested specificity for gastrointestinal tract signet ring cell carcinomas. An immunohistochemical panel that includes β-catenin and CK7 may have value in differentiating urachal adenocarcinoma of enteric morphology from colonic adenocarcinoma. Overall, this study suggests that the different morphologic presentations of urachal adenocarcinomas have a relatively similar or overlapping immunophenotype. Knowledge of the similarity in immunostaining to its different morphologic mimics may help avoid misdiagnosis in urachal adenocarcinoma.

Invasive micropapillary carcinoma (IMPC) of the urinary tract is a well-described variant of the urothelial carcinoma with aggressive clinical behavior. Recent studies have proposed that patients with IMPC on transurethral resection should be treated with radical cystectomy regardless of the pathologic stage. Despite the potentially important therapeutic implications of this diagnosis, interobserver variation in the diagnosis of IMPC has not been studied. Sixty digital images, each from hematoxylin and eosin-stained slides, representing 30 invasive urothelial carcinomas (2 images per case), were distributed to 14 genitourinary subspecialists and each pathologist was requested to classify cases as IMPC or not. These cases included "classic" IMPC (n=10) and urothelial carcinoma with retraction and variably sized nests that might potentially be regarded as IMPC (n=20). The following 13 morphologic features were recorded as positive/negative for all cases independent of the reviewers' diagnoses: columnar cells, elongate nests or processes, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial ring forms, intracytoplasmic vacuolization, multiple nests within the same lacunar space, back-to-back lacunar spaces, epithelial nest anastomosis/confluence, marked nuclear pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, and tumor nest size. In addition, a mean tumor nest size was calculated for each image based on the number of nuclei spanning the width of the nests. Interobserver reproducibility was assessed and the morphologic features were correlated with the classic IMPC and nonclassic/potential IMPC groups. In addition, the relationships between morphologic features, pathologists' interpretations, and case type (classic IMPC vs. nonclassic/potential IMPC) were evaluated using unsupervised hierarchical clustering analysis. Interobserver reproducibility for a diagnosis of IMPC in the 30 study cases was moderate (kappa: 0.54). Although classification as IMPC among the 10 "classic" IMPC cases was relatively uniform (93% agreement), the classification in the subset of 20 invasive urothelial carcinomas with extensive retraction and varying sized tumor nests was more variable. Multiple nests within the same lacunar space had the highest association with a diagnosis of classic IMPC. These findings suggest that more study of IMPC is needed to identify the individual pathologic features that might potentially correlate with an aggressive outcome and response to intravesical therapy.

In this report, we present the clinicopathologic features of 27 cases of the lipid cell variant of urothelial bladder carcinoma. This is a rare variant of bladder cancer recognized by the current WHO classification of urologic tumors. The lipid cell component varied from 10% to 50% of the tumor specimen; in 11 cases the lipid cell component composed greater than 30% of the tumor. The architectural pattern of the tumor varied from solid expansile to infiltrative nests. The large epithelial tumor cells had an eccentrically placed nucleus and abundant vacuolated cytoplasm resembling signetring lipoblasts. Mucin stains were negative in all the cases. Typical features of high grade conventional urothelial carcinoma were present in all the cases with micropapillary or plasmacytoid carcinoma in 2 and 1 cases, respectively; extensive squamous or glandular differentiation was present in 2 additional cases. Most neoplastic cells had nuclei of intermediate nuclear grade with occasional nuclear pleomorphism. Immunohistochemical staining showed that the lipid cell component was positive for cytokeratins 7, 20, CAM 5.2, high molecular weight (34ssE12) and AE1/AE3, epithelial membrane antigen, and thrombomodulin; vimentin and S100 protein were negative. The loss of heterozygosity (LOH) analysis was done on 8 cases using 4 polymorphic microsatellite markers (D9S171, D9S177, IFNA, and TP 53); LOH at least in 1 marker was present in 6 cases. The LOH results were the same for lipid variant and conventional urothelial carcinoma. Pathologic stage was Ta (n=1), T1 (=2), T2, at least (n=7), T3a (n=4), T3b (n=8), and T4a (n=5). Electron microcopy analysis based on 2 cases supported lipid content in tumor cells. Follow-up information was available in all the cases, ranging from 6 to 58 months (mean, 28 mo). Sixteen of the patients died of disease at 16 to 58 months (mean, 33 mo) and 8 patients were alive with disease at 8 to 25 months (mean, 22 mo). Another 3 patients died of other causes at 6 to 15 months (mean, 10 mo). In summary, lipid cell urothelial bladder carcinoma is typically associated with advanced stage high-grade urothelial carcinoma, in which the prognosis is poor and clonally related to the concurrent conventional urothelial carcinoma. In limited samples, it may be misdiagnosed as liposarcoma, sarcomatoid carcinoma (carcinosarcoma), or signetring cell carcinoma. Morphologic distinction from other malignant neoplasms with lipid cell phenotype is critical for its clinical management.

Urothelial carcinoma is morphologically heterogeneous and many variant forms have been described. We have encountered several invasive urothelial carcinomas with a unique chordoid morphology characterized by prominent cellular cording and associated myxoid stromal matrix, a pattern closely resembling extraskeletal myxoid chondrosarcoma. This morphologic appearance, to our knowledge, has not been formally described in urothelial carcinoma. A series of 166 consecutive invasive urothelial carcinomas were reviewed to identify cases with cellular cording and myxoid stroma. The patient age, sex, tumor stage, morphologic features, association with typical urothelial carcinoma, and clinical outcome were recorded. Immunostains for p63, cytokeratin (CK) 34BE12, CK20, calponin, glial fibrillary acidic protein, S-100 protein, oncofetal protein glypican-3, and brachyury were performed on 7 cases. Mucin histochemistry was performed on 8 cases to evaluate the extracellular myxoid material. Eleven of the 166 (7%) consecutive invasive urothelial carcinomas had areas with a chordoid appearance. A total of 12 cases were analyzed including the addition of a consult case. The patients' ages ranged from 50 to 85 years (mean: 68 y); there were 8 males and 4 females. The specimens consisted of 5 cystectomies, 6 transurethral resections, and 1 anterior exenteration with right nephroureterectomy. Morphologically, each case had at least focal areas in which acellular myxoid stroma was associated with the carcinoma cells. When well developed, the neoplastic cells had scant eosinophilic cytoplasm and were arranged into cords closely mimicking extraskeletal myxoid chondrosarcoma, chordoma, mixed tumor/myoepithelioma of soft tissue, and yolk sac tumor. The percentage of tumor with a chordoid appearance ranged from 5% to 95% (mean: 39%; median: 25%). No conventional sarcomatous differentiation, no intracytoplasmic mucin, and no glandular formation were present in any case. All 12 cases had foci of typical urothelial carcinoma present at least focally and a gradual transition to the chordoid pattern was commonly seen. Immunophenotypically, all 7 cases evaluated showed strong immunoreactivity for p63 (nuclear) and CK34BE12 (cytoplasmic). Immunostains for CK20, calponin, glial fibrillary acidic protein, oncofetal protein glypican-3, and brachyury and were negative in the 7 cases studied (0 out of 7), whereas S-100 protein had focal staining (<5%) in 1 case. The myxoid stromal component was diffusely colloidal iron and Alcian blue positive in all 8 cases examined; periodic acid Schiff was negative in all 8 cases, whereas mucicarmine was only focally positive in 2 of 8 cases. Most cases were high stage (pT4: 5, pT3: 4, pT2: 2, and pT1: 1), and 6 of 8 cases (75%) with nodal sampling had metastatic disease. In 1 case, the lymph node metastasis had areas with chordoid morphology. Nine of 12 patients had available follow-up: 2 were dead of disease (1 and 10 mo), 4 were alive with disease (5 to 8 mo) with distant metastasis in 3, and 3 had no evidence of disease at last follow-up (2 to 120 mo). In summary, we describe a morphologic pattern of urothelial carcinoma with a distinct chordoid appearance that may potentially mimic a spectrum of primary vesical and nonvesical neoplasms with myxoid or mucinous components. These carcinomas maintain an immunophenotype characteristic of urothelial carcinoma and usually present with high stage disease.

On the basis of recent clinical studies, some urologic oncologists do not offer bladder-sparing therapy for patients diagnosed with micropapillary carcinoma of the urinary bladder, even in the setting superficially invasive disease. Unfortunately, the distinction of invasive micropapillary carcinoma from typical invasive urothelial carcinoma with prominent retraction artifact may be difficult in some cases. In this study, we compared the immunophenotype of invasive micropapillary carcinoma to invasive urothelial carcinoma with retraction artifact using antibodies previously reported as specific for micropapillary carcinoma. Immunohistochemical staining was performed on 24 invasive micropapillary carcinomas of the urinary tract and 24 case controls of invasive urothelial carcinoma with retraction artifact using monoclonal antibodies MUC1, CA125, and Her2Neu. The staining extent and intensity for MUC1 and CA125 were scored on one representative section per case. Immunostaining for Her2Neu was scored based on the 2007 CAP/ASCO guidelines for breast carcinoma. Basal ('reverse-apical') MUC1 staining was identified in 23 of the 24 (96%) invasive micropapillary carcinomas and in 15 of the 24 (63%) invasive urothelial carcinomas with retraction artifact (P=0.0102). Membranous reactivity with CA125 was seen in 8 of the 24 (33%) invasive micropapillary carcinomas and in 3 of the 24 (13%) invasive urothelial carcinomas with retraction artifact (P=0.1681). Positive (3+) membranous Her2Neu staining was present in 6 of 24 (25%) invasive micropapillary carcinomas and in 2 of the 24 (8%) invasive urothelial carcinomas with retraction artifact (P=0.2448). The specificity for invasive micropapillary carcinoma vs invasive urothelial carcinoma with retraction artifact using antibodies MUC1, CA125, and Her2Neu was 37, 87, and 92%, respectively. Invasive micropapillary carcinoma more commonly showed immunoreactivity for MUC1, CA125, and Her2Neu compared to invasive urothelial carcinoma with retraction artifact, but only MUC1 reached statistical significance. The lack of specificity of these evaluated markers for invasive micropapillary carcinoma limits their utility in the distinction from invasive urothelial carcinoma with retraction artifact, especially given the potentially significant therapeutic implications.

Rhabdomyosarcoma (RMS) represents the most common malignant soft tissue tumor in children and adolescents with the urinary bladder representing a frequent site. Most of these urinary bladder tumors are embryonal RMS, predominantly the botryoid subtype. RMSs of the urinary bladder in adults are distinctively rare and the subject of only case reports. We report the clinicopathologic features of 5 bladder neoplasms with rhabdomyosarcomatous differentiation in adults and emphasize the differential diagnosis in the adult setting. The patients, 4 men and 1 woman, ranged in age from 23 to 85 years (mean 65.4 y). Gross hematuria was the most common initial symptom, although 2 patients had metastatic disease at presentation. Four cases were pure primary RMSs of the bladder and 1 case was a sarcomatoid urothelial carcinoma with RMS representing the extensive heterologous component. All 5 cases demonstrated a diffuse growth pattern (ie, non-nested), of which 4 cases had nuclear anaplasia (Wilms criteria without the atypical mitotic figure requirement); only 1 case (the sarcomatoid carcinoma) showed obvious rhabdomyoblastic differentiation (ie, strap cells). Three cases were of the alveolar subtype (1 admixed with embryonal histology) and 2 were RMS, not further classified. Microscopically, all tumors had a primitive undifferentiated morphology with cells containing scant cytoplasm, varying round to fusiform nuclei with even chromatin distribution, and frequent mitoses. The degree of morphologic overlap with small cell carcinoma of the bladder, a relatively more common round cell tumor in adults, was striking. The epithelial component of the sarcomatoid carcinoma was high-grade invasive urothelial carcinoma with glandular differentiation. No other case had previous history of bladder cancer or concurrent carcinoma in situ or invasive urothelial carcinoma. All tumors showed immunohistochemical expression for desmin, myogenin, and/or MyoD1. Synaptophysin was performed in 4 cases, and 3 showed weak cytoplasmic immunoreactivity. Two patients received chemotherapy, 2 underwent cystectomy, and 1 had transurethral resection alone. Outcome data were available in 4 cases, and all 4 died of disease (1, 4, 8, and 8 mo). In conclusion, (1) RMS of the urinary bladder in adults more commonly presents as a primitive round blue cell neoplasm that has significant morphologic and immunohistochemical overlap with small cell carcinoma of the bladder. (2) Although RMS in children generally have a botryoid embryonal histology with favorable outcome, bladder RMS in adults frequently demonstrates alveolar or unclassified histology, commonly with anaplasia, and have a uniformly aggressive clinical course.

Spindle cell proliferations of the urinary bladder are uncommon but may cause significant diagnostic difficulty resulting from the degree of morphologic overlap between clinically benign and malignant lesions. These difficulties may be amplified in small biopsies because some of the more specific diagnostic features may not be present for evaluation. In addition, the number of different diagnostic terms applied to the same entity has added confusion to this diagnostic area. This review discusses the nomenclature, morphologic criteria, and immunohistochemical features used to classify spindle cell proliferations occurring in the urinary bladder, including those with myofibroblastic, smooth muscle, skeletal muscle, epithelial (sarcomatoid urothelial carcinoma), fibroblastic, and neural differentiation. A separate discussion of 5 challenging differential diagnostic scenarios is also presented.

The spectrum of neoplasms involving the urinary bladder is diverse, and, at times, different entities with distinct prognostic and managerial implications may have significant morphologic overlap. The presence of a neoplasm with an unusual morphologic appearance, such as an undifferentiated spindled, or plasmacytoid pattern may necessitate immunohistochemistry to establish the diagnosis. In this review, we discuss a series of distinct diagnostic scenarios, including high-grade undifferentiated carcinoma versus prostatic adenocarcinoma, enteric-type adenocarcinoma versus secondary colorectal adenocarcinoma, spindle cell proliferations, neoplasms with plasmacytoid morphology, endophytic tumors with a nested growth pattern, and flat urothelial lesions with atypia. We also discuss markers supporting urothelial differentiation in the context of a metastatic carcinoma from an unknown primary. The importance of using a morphologically derived differential diagnosis to guide the selection and interpretation of immunohistochemical studies is emphasized, and the varying utility (specificity) of the individual immunohistochemical markers within each setting is addressed.

The existence of a papillary lesion of the urinary bladder with a benign clinical course and recognizable morphologic features that merit the benign categorization "papilloma" has been controversial. The clinical aspects and histologic features of these lesions remain to be fully elucidated. We have studied the clinicopathologic features of 26 patients with urothelial papillomas and correlated them with outcome. Papillomas occurred in two distinct clinical settings: (1) de novo neoplasms (23/26) or (2) those occurring in patients with a known clinical history of bladder cancer ("secondary" papillomas; 3/26). Follow-up information was available in 14/23 of the de novo cases (mean = 39 mo) and in 3/3 secondary cases (mean = 24 mo). Patients with de novo papillomas had a mean age of 46 years; 16 were male and 7 were female. Twelve of 14 had a benign clinical course with no recurrences; 1 developed a recurrent papilloma at 3 years, and 1 developed a pT3a high-grade papillary urothelial carcinoma at 4 years. Patients with secondary papillomas had a mean age of 66 years; two were male and one was a female. One of these patients developed two additional recurrences, and two patients had no new recurrences. Morphologically, the papillary architecture ranged from a common simple, nonhierarchical arrangement to, infrequently, more complex anastomosing papillae with budding. The individual papillae ranged from small (most common), with scant stroma and slender fibrovascular cores, to large, with marked stromal edema and/or cystitis cystica-like urothelial invaginations. Common to all was a lining of normal-appearing urothelium without hyperplasia, maintenance of normal polarity, and frequent prominence of the umbrella cell layer. Overall, no patient with a diagnosis of papilloma died of disease; only one patient with a de novo lesion (7.0%) had a recurrent papilloma, and 1/14 (7.0%) progressed to a higher grade and stage of disease, although this patient was on immunosuppressive therapy secondary to a renal transplant. De novo urothelial papillomas occur in younger patients and usually have a benign course. Urothelial papillomas are histologically and probably biologically distinctive tumors and merit distinction from other higher risk papillary neoplasms of the urinary bladder.

The classification of flat urothelial (transitional cell) lesions with atypia has historically varied in its application from institution to institution with no fewer than six major nomenclature systems proposed in the past 25 years. In 1998, the World Health Organization/ International Society of Urological Pathology (WHO/ISUP) published a consensus classification that included the following categories for flat urinary bladder lesions: reactive atypia, atypia of unknown significance, dysplasia (low-grade intraepithelial neoplasia), and carcinoma in situ (high-grade intraepithelial neoplasia). This classification expands the definition traditionally used for urothelial carcinoma in situ, basing its diagnosis primarily on the severity of cytologic changes. In proposing the classification system for flat lesions of the bladder with atypia, it was hoped that consistent use of uniform diagnostic terminology would ultimately aid in a better understanding of the biology of these lesions. In this review, the authors discuss the history of the concept of flat urothelial neoplasia, the rationale and histologic criteria for the WHO/ISUP diagnostic categories, an approach to the diagnosis of flat lesions, and problems and pitfalls associated with their recognition in routine surgical pathology specimens.