Cancer Antigen 15-3 Serum Level as a Biomarker for Advanced Micropapillary Urothelial Carcinoma of the Bladder: A Case Report.

A 73-year-old woman with no history of disease was referred to our hospital with fatigue and joint pain. Screening blood test showed that her cancer antigen 15-3 (CA 15-3) serum level was elevated to 36.6 U/mL, and a contrast-enhanced computed tomography scan revealed a bladder tumor without metastasis. Cystoscopy showed a papillary and a small kissing tumor, and the histopathological analysis of the bladder tumor obtained by transurethral resection (TUR) showed invasive urothelial carcinoma (UC) with micropapillary variant (pT1). At 4 weeks after TUR, the CA 15-3 serum level was markedly increased to 180.6 U/mL, and radiographic examinations revealed multiple regional and nonregional lymph node metastases. The patient received systemic therapy with gemcitabine and cisplatin. After 3 cycles of chemotherapy, the size of all lymph node metastases reduced by 80% in diameter, and the CA 15-3 serum level decreased from 238.2 to 11.4 U/mL. Immunohistological analysis showed that the bladder tumor was positive for mucin 1, of which CA 15-3 is an epitope. In our patient, changes in the CA 15-3 serum levels were in congruence with the clinical course of advanced micropapillary UC (MPUC). Therefore, the CA 15-3 serum level may be a potentially valuable biomarker for MPUC.

Cyto-histo correlations of plasmacytoid and micropapillary variants of high-grade urothelial carcinoma: do they fit well in The Paris System for reporting urinary cytology?

INTRODUCTION: Plasmacytoid and micropapillary variants of high-grade urothelial carcinoma (HGUC) exhibit unique histologic morphology and very aggressive clinical behavior. However, the morphology of these 2 variants in urinary cytology is not well studied and evaluated using The Paris System for reporting urinary cytology. MATERIALS AND METHODS: A database search was performed in all patients with the diagnosis of plasmacytoid or micropapillary HGUC. A total of 5 patients with positive urinary cytology cases were identified. The cytomorphology of every urinary cytology case was correlated with the histologic features in the surgical specimens from the same patient. RESULTS: One urine and 4 bladder washings were evaluated. Cytologically, plasmacytoid HGUCs are characterized by single, large tumor cells with hyperchromasia, irregular nuclear membranes, and vacuolated cytoplasm. The nuclear-to-cytoplasmic (N:C) ratio was less than 0.5 in many of the malignant cells due to the abundant cytoplasm. The cytology features of micropapillary HGUC include the presence of micropapillae of tumor cells with no fibrovascular core. Individual high-grade urothelial cells were also identified in all 4 cases, but 1 (25%) of these had only rare cells meeting The Paris System criteria for HGUC due to abundant cytoplasm and lack of hyperchromasia in most malignant cells. CONCLUSIONS: Plasmacytoid and micropapillary variants of HGUC have unique cytomorphologic features in urinary cytology specimens, which are reflective of the corresponding histological findings. These 2 clinically aggressive variants of HGUC may not be as readily interpreted as malignant using The Paris System for reporting urinary cytology, creating potential diagnostic pitfalls.

A Rare Case of Pulmonary Tumor Thrombotic Microangiopathy Associated with Micropapillary Urothelial Carcinoma of the Urinary Bladder: An Autopsy Case.

A 70-year-old woman was hospitalized with dyspnea. A transthoracic echocardiogram indicated an elevated systolic pulmonary artery pressure, and the cytology specimens obtained using a pulmonary artery catheter confirmed adenocarcinoma metastasis. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected high-signal-intensity lesions in the urinary bladder. The patient died of respiratory failure and a postmortem examination was performed. Tumor cells in the bladder were immunohistochemically positive for GATA3, indicating micropapillary urothelial carcinoma, which is a rare variant of urothelial carcinoma and considered an adenocarcinoma subtype. This case is the first autopsy case of pulmonary tumor thrombotic microangiopathy (PTTM) associated with micropapillary urothelial carcinoma of the urinary bladder.

Cytological features of micropapillary and plasmacytoid variants of urothelial carcinoma.

BACKGROUND: Micropapillary and plasmacytoid variants of urothelial carcinoma (UC) exhibit very aggressive clinical behavior. To date, only a small number of cytology cases have been reported in either of these variants. Herein, we report 15 cases of UC with combined micropapillary and plasmacytoid features based on urine cytology. METHODS: We performed a retrospective analysis of all patients with carcinoma of bladder with predominant plasmacytoid and micropapillary histology who had been seen from 2005 to 2017. A total of 15 cases (six cases of plasmacytoid variant and nine cases of micropapillary variant of bladder cancer) with urine specimen were evaluated. The cytomorphological features were compared between two histological variants. RESULTS: Fifteen urine cytology cases with the diagnosis of high-grade UC were investigated. The ratio man to women was 5:1 with a median age of 79 years (range: 72-90 years). Single-cell pattern, flat sheets, three-dimensional clusters, micropapillae, nuclear grade, cytoplasmic vacuoles, and necrosis, were evaluated in urine samples of micropapillary variant. The cytological features of plasmacytoid are characterized by large, discohesive, isolated tumor cells that have abundant, thick cytoplasm, and eccentrically located, hyperchromatic nuclei with coarse chromatin and inconspicuous nucleoli. CONCLUSION: It is important to recognize the cytological characteristics of these uncommon but aggressive entities to determine a precise diagnosis. Attention to morphological features, together with clinical history and appropriate immunohistochemical studies may be useful to urologist in pre-operative planning and may lead to a more aggressive surgical approach.

Prognostic values of the clinicopathological characteristics and survival outcomes in micropapillary urothelial carcinoma of the bladder: A SEER database analysis.

PURPOSE: To study prognostic values of the clinicopathological characteristics and survival outcomes in micropapillary urothelial carcinoma (MPUC) of the urinary bladder. METHOD: We used the national Surveillance, Epidemiology, and End Results database (2004-2016) to compare MPUC with transitional cell carcinoma (TCC) and to investigate prognostic values of clinicopathological characteristics, as well as survival outcomes, in MPUC of the urinary bladder. A multivariable Cox proportional hazard model, subgroup analyses, and propensity score matching were used. RESULTS: In all, 519 patients with MPUC and 154 453 patients with TCC were enrolled. Compared with TCC, patients with MPUC had a higher rate of muscle invasive disease (P < .001), lymph node metastasis (P < .001), and distal metastasis (P < .001), as well as higher tumor grade (P < .001). According to the survival analyses, the MPUC group also had lower survival probability in both cancer-specific mortality (CSM) (P < .0001) and overall mortality (OM) analyses (P < .0001). Cox proportional hazard regression showed that the MPUC group had a higher risk of OM (hazard ratios [HR] = 1.39, 95% confidence intervals [CI] = 1.22-1.57, P < .0001), although the CSM (HR = 1.18, 95% CI = 1.00-1.40, P = .0505) in that group was fair. In the subgroup analysis, only MPUC patients without distal metastasis faced a higher risk of CSM (HR = 1.33, 95% CI = 1.101.61, P < .0001). CONCLUSIONS: Micropapillary urothelial carcinoma prognosis is poorer than that of TCC. Micropapillary urothelial carcinoma is an independent prognostic factor for OM in patients with urinary bladder cancer.

What Is the Significance of Variant Histology in Urothelial Carcinoma?

CONTEXT: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. OBJECTIVE: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. EVIDENCE ACQUISITION: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". EVIDENCE SYNTHESIS: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. CONCLUSIONS: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. PATIENT SUMMARY: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: A multi-institutional investigation.

PURPOSE: To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy. MATERIALS AND METHODS: Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival. RESULTS: Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P ≥ 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P < 0.01) and lymphovascular invasion (29% vs. 58%; P < 0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P < 0.01) and OS (61% vs. 38%; P < 0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12). CONCLUSIONS: This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors.

Intratumoral heterogeneity of ERBB2 amplification and HER2 expression in micropapillary urothelial carcinoma.

Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. MPUC has been shown to commonly exhibit ERBB2 amplification and HER2 protein overexpression, but the frequency and distribution of these findings within micropapillary (MP) and not otherwise specified (NOS) components of tumors with mixed histology have not been addressed. Therefore, we evaluated ERBB2 amplification and HER2 expression in 43 MPUC cases by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Of the 35 tumors containing both MP and NOS components, ERBB2 amplification was present in both the MP and NOS components of 12 tumors (34.3%), in only the MP component of 11 tumors (31.4%), and exclusively in the NOS component of 4 tumors (11.4%). HER2 protein overexpression was significantly more commonly present in the MP component compared to the NOS component within the same tumor (68.6% versus 34.3%, P = .012). Overall, there was a moderately positive correlation between HER2 protein expression and ERBB2 amplification in both MP (ρ = 0.59, P < .001) and NOS (ρ = 0.70, P < .001) components. All MP/NOS areas with IHC score 3+ and none of MP/NOS areas with IHC score 0 were associated with ERBB2 amplification. We conclude that ERBB2 amplification and HER2 overexpression are preferentially but not exclusively identified in the MP component compared to the NOS component within the same tumor. Our findings identify the presence of intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC and provide grounds for further investigation into the mechanisms underlying the development of MPUC.

Clinicopathological implications to micropapillary bladder urothelial carcinoma of the presence of sialyl Lewis X-decorated mucin 1 in stroma-facing membranes.

OBJECTIVES: Bladder urothelial carcinoma (UC) comprises more than 90% of all bladder cancers. Among several UC variants, micropapillary UC (MPUC) is a rare one with high potential for lymphovascular invasion and subsequent lymph node metastasis. Histologically, MPUC is characterized by the presence of small papillary carcinoma cell clusters surrounded by lacunar spaces. Immunohistochemically, the outer circumference of these clusters, that is, the stroma-facing membrane of carcinoma cells, is reportedly almost invariably positive for mucin 1 (MUC1) protein and to a lesser extent for sialyl Lewis X (sLeX) carbohydrates; however, the clinicopathological implications of these expression patterns have not been fully investigated. MATERIALS AND METHODS: We performed immunohistochemical analysis of MPUC (n = 11) and conventional UC (n = 57) for MUC1 and sLeX to determine whether these factors immunolocalized. Dual immunofluorescence staining was also carried out to assess MUC1 and sLeX colocalization. We also performed Western blot analysis of Chinese hamster ovary cells misexpressing both recombinant epitope-tagged MUC1 and glycosyltransferases enabling sLeX biosynthesis. RESULTS: MPUC samples preferentially exhibited both MUC1 protein and sLeX carbohydrate expression on the stroma-facing membrane of carcinoma cells. Based on univariate analysis, MUC1 expression in that pattern was positively correlated with tumor extension, lymphovascular invasion, lymph node metastasis, disease stage, and relatively poor patient prognosis. A comparable sLeX expression pattern also correlated positively with tumor extension and nodal metastasis. Based on multivariate analysis, localization of MUC1 and sLeX on the stroma-facing side of the membrane was positively correlated with lymph node metastasis. CONCLUSIONS: Overall, our immunofluorescence findings as well as immunoprecipitation analyses of Chinese hamster ovary cell transfectants strongly suggest that MUC1 is a potential scaffold protein for sLeX carbohydrates in MPUC. Both MUC1 and sLeX may cooperatively contribute to MPUC histogenesis and clinicopathological characteristics.

Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy.

OBJECTIVES: The role of micropapillary urothelial carcinoma (MUC) variant histology as an independent prognostic factor for survival after radical cystectomy has not been studied. Our aim was to examine the impact of MUC on survival. MATERIALS AND METHODS: A retrospective analysis of prospectively collected data from the University of Southern California (USC) Bladder Cancer Database was performed. Between 1985 and 2008, 1,380 patients underwent radical cystectomy and superextended pelvic lymph node dissection for bladder cancer. All surgical specimens underwent central pathologic review by dedicated genitourinary pathologists. Histologic type was categorized as urothelial carcinoma (UC; n = 1,347) or MUC (n = 33). The outcomes were overall survival (OS) and recurrence-free survival (RFS). The Kaplan-Meier method and Cox proportional regression models were used to analyze survival data. RESULTS: The median follow-up duration was 10 years (range, 0-25 years). Baseline characteristics were similar between histologic types except MUC was associated with advanced clinical (cTanyN1-3: 2% vs. 9%, P = 0.03) and pathologic (pTanyN1-3: 22% vs. 46%, P = 0.01) TNM stage, multifocality (38% vs. 58%, P = 0.02), and high nuclear grade (83% vs. 97%, P = 0.03). The predicted 5-year OS (61% and 67%, Log rank P = 0.96) and RFS (69% and 58%, Log rank P = 0.33) rates did not differ between patients with UC and MUC. Multivariable analysis showed that histologic type was not independently associated with OS (HR 0.91, 95% CI 0.55-1.49, P = 0.70) or RFS (HR 0.97, 95% CI 0.55-1.73, P = 0.92). CONCLUSIONS: Outcomes of radical cystectomy for patients with MUC are similar to those with UC when controlling for other clinical and pathologic factors.