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

doi:10.1016/j.urolonc.2012.04.020

Urologic Oncology: Seminars and Original Investigations

Volume 32, Issue 2, February 2014, Pages 110-116

https://doi.org/10.1016/j.urolonc.2012.04.020 Get rights and content

Abstract

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.

Introduction

Bladder cancer is a major public health problem in the USA [1]. In 2011, an estimated 69,250 Americans will be diagnosed with bladder cancer and 14,990 Americans will die of bladder cancer [1]. Bladder cancer can be categorized based on histologic type as pure urothelial carcinoma (UC), urothelial carcinoma with aberrant differentiation, and pure nonurothelial carcinoma [2]. The most common aberrant differentiation patterns are squamous and/or glandular, small-cell carcinoma, sarcomatoid, and micropapillary carcinoma [2], [3], [4]. Pure forms of nonurothelial carcinomas include squamous cell carcinoma, adenocarcinoma, and small-cell carcinoma [2], [3], [4].

Micropapillary urothelial carcinoma (MUC) is a rare histologic variant that closely resembles papillary serous carcinoma of the ovary [5]. It is estimated to account for approximately 0.7%–2.2% of all urothelial tumors and less than 200 cases of bladder MUC have been reported in the medical literature [6], [7], [8], [9], [10], [11], [12]. Current evidence from case series suggests that MUC is an aggressive histologic variant associated with poorer prognosis [10], [12]. However, the role of MUC variant histology as an independent prognostic factor for survival outcomes after radical cystectomy has not been studied [13]. Here we examined the impact of MUC on survival after radical cystectomy. We hypothesized that MUC would be independently associated with poorer prognosis.

Section snippets

Study cohort

Fig. 1 presents the study cohort selection process. We identified 1,681 patients who underwent open radical cystectomy and extended pelvic lymph node dissection for primary urothelial carcinoma of the urinary bladder at the University of Southern California (USC) in a prospectively maintained Institutional Review Board-approved database. Three hundred one patients were excluded, and the final study cohort included 1,347 patients with pure UC and 33 patients with MUC treated between January 1,

Results

A total of 1,347 patients with pure UC and 33 patients with MUC were included in the current analyses; 27 out of 33 patients (82%) with MUC had an incidental diagnosis based on pathologic analysis of the radical cystectomy specimen. The median follow-up duration for the overall cohort was 10 years (range, 0–25 years). The median follow-up duration for patients with UC and MUC was 10 and 4 years, respectively (P = 0.28).

Discussion

Numerous variants of UC of the urinary bladder have been described [13]. Micropapillary urothelial carcinoma is a rare histologic variant of UC with an aggressive biological phenotype [16], [17]. Although the prognostic implications of tumors with MUC variant histology are poorly defined, current thinking is that this type of aberrant differentiation portends poorer prognosis [13]. In this study from the University of Southern California, we evaluated the impact of MUC variant histology on

Conclusions

In summary, outcomes of radical cystectomy for patients with MUC are similar to those with UC when controlling for other clinical and pathologic factors. Further prospective, multi-institutional evaluation of MUC variant histology is needed.

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Cited by (52)

Clinicopathologic Analysis of Micropapillary Urothelial Carcinoma of the Upper Urinary Tract: Implications for HER2-Targeted Therapy
2023, Clinical Genitourinary Cancer
Introduction/Background To determine the clinical significance of micropapillary urothelial carcinoma (MPUC) of the upper urinary tract (UTUC) and a potential therapeutic strategy.
Patients and Methods A retrospective cohort study was conducted to examine the incidence of micropapillary UTUC from 2010 to 2018 and its clinicopathological characteristics. Clinical outcomes and cancer-specific survival (CSS) were compared between MPUC and conventional UTUC matched by stage within a 6-month variation of receiving surgery.
Results A total of 24 MPUC cases were identified out of 901 cases (2.7%) of urothelial carcinoma (UC) of the renal pelvis and ureter. MPUC was significantly smaller (<3 cm) and associated with nodal metastasis compared with conventional UTUC (P = .017 & 0.021, respectively); however, no significant difference was observed for lymphovascular invasion, distant metastasis, or CSS (P > 0.50, respectively) compared with match controls. Six MPUC patients (25%) developed metastasis to the liver, lymph nodes, and lung during follow-up. Patients with HER2-positive MPUC (3 of 4) had a significantly higher risk of metastasis compared with HER2-negative MPUC (3 of 20; P = 0.035).
Conclusions MPUC is an aggressive variant of UTUC and usually presents as a small locally advanced disease. HER2 immunohistochemistry may identify the subset of patients with micropapillary UTUC that are candidates for targeted therapy.
Urothelial Carcinoma: Divergent Differentiation and Morphologic Subtypes
2022, Surgical Pathology Clinics
Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance, Epidemiology, and End Results (SEER) Program
2021, Clinical Genitourinary Cancer
Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare.
We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS.
Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group.
Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.
What Is the Significance of Variant Histology in Urothelial Carcinoma?
2020, European Urology Focus
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.
To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma.
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”.
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.
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.
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.
Micropapillary Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-analysis of Disease Characteristics and Treatment Outcomes
2019, European Urology
The optimal treatment of urothelial bladder cancer (UBC) with micropapillary (MP) variant histology is not clear.
To review the current literature on disease characteristics and treatment outcomes of MP UBC.
A systematic search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. The primary end points were recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS).
We identified 758 reports comprising a total of 3154 patients, of which 28 and 15 articles were selected for qualitative and quantitative analysis, respectively. In patients with T1 MP UBC, the 5-yr CSS rates for early radical cystectomy (RC) ranged from 81% to 100%, while they were between 60% and 85% for transurethral resection of the bladder and Bacillus Calmette-Guérin (BCG). In studies reporting on neoadjuvant chemotherapy (NAC), the rates of complete pathological response (ypT0) ranged from 11% to 55%. Nevertheless, the use of NAC did not improve RFS (hazard ratio [HR] 1.23, 95% confidence interval [CI] 0.52–2.93, p = 0.6), CSS (HR 0.9, 95% CI 0.48–1.7, p = 0.8), or OS (HR 1.35, 95% CI 0.98–1.86, p = 0.1). Fifty-three percent (95% CI 43–63%) of patients who underwent RC alone had locally advanced disease (≥pT3), and 43% (95% CI 33–52%) were harbouring lymph node metastases. MP component at RC was not significantly associated with worse RFS (HR 1.25, 95% CI 0.88–1.78, p = 0.2), CSS (HR 0.96, 95% CI 0.57–1.6, p = 0.9), or OS (HR 1.20, 95% CI 0.88–1.62, p = 0.3) when adjusted for pathological features.
While MP UBC is associated with clinicopathological features of advanced disease, it is not associated with worse survival outcomes in patients undergoing RC. NAC results in pathological downstaging in a significant number of patients. Nevertheless, this does not translate into better survival outcomes. The optimal treatment of patients with cT1 remains controversial.
Our results suggest that micropapillary urothelial bladder cancer does not necessarily mandate different treatment algorithms. Nevertheless, each case should be discussed individually considering other clinicopathological factors.
The impact of variant histological differentiation on extranodal extension and survival in node positive bladder cancer treated with radical cystectomy
2019, Surgical Oncology
Citation Excerpt :
Overall, the impact of variant UCB histology on pathological features and survival metrics remains controversial. While a number of previous reports have found an association of variant UCB histology with adverse pathological features including lymph node status [3,7,18], this association did not indiscriminately translate into inferior survival in adjusted outcome analyses of contemporary series [6,7,19]. Our findings merit several clinical implications.
To investigate the impact of variant urothelial carcinoma of the bladder (UCB) histologies on extra nodal extension (ENE) and survival in lymph node (LN) positive bladder cancer patients undergoing radical cystectomy (RC).
We meticulously reviewed all bladder specimens for presence of variant UCB histologies and LN specimen for presence and extent of ENE in 517 UCB patients treated with RC. Descriptive statistics, the Kaplan Meier method and multivariable Cox regression models evaluated the association between variant UCB histology, ENE and survival metrics including disease recurrence-free, cancer-specific, and overall survival, respectively.
Overall, 138 patients had LN metastasis (27%), with a median number of 15 (IQR 9; 18) LNs removed. Among LN positive patients, 43 (31%) had ENE with a median length of 10 mm. Variant histology was present in 96 patients (18.6%) with squamous cell (12.0%) and sarcomatoid (2.5%) differentiation being the most common. In all patients, the presence of variant histology was neither associated with presence of LN metastasis nor ENE (all p-values = n.s.). In Kaplan-Meier analyses the presence of LN metastases and ENE in LN positive patients was significantly associated with disease recurrence and cancer-specific mortality, respectively (all p < 0.001). The presence of variant histology did not influence these outcomes (p = n.s.). In multivariable analyses, adjusted for standard UCB prognosticators, ENE, but not variant histology, independently predicted disease recurrence-free (hazard ratio (HR) 3.88, 95% confidence intervall (CI) 2.24–6.71, p < 0.001), cancer-specific (HR 4.60; 95% CI, 2.57–8.23, p < 0.001), and overall survival (HR 3.51; 95% CI, 2.10–5.86, p < 0.001).
Variant UCB histologies do not seem to increase the incidence of LN metastasis or ENE. This study confirms ENE being a powerful predictor for outcomes in node positive UCB patients - regardless of variant histological differentiation. Our findings warrant validation in larger cohort setting.

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: The authors declare no conflict of interest.

¹: Presented at the Annual Meeting of the Society of Urologic Oncology, Bethesda, Rockville, MD, November 30–December 2, 2011 and at the Genitourinary Cancer Symposium, San Francisco, CA, 2012, February 2–4, 2012.

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Original articleClinical — bladderImpact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy1

Abstract

Objectives

Materials and methods

Results

Conclusions

Introduction

Section snippets

Study cohort

Results

Discussion

Conclusions

J Urol

Ann Diagn Pathol

Urol Oncol

Eur Urol

Urology

Cancer statistics

CA Cancer J Clin

Pathology and genetic of tumours of the urinary system and male genital organs

The World Health Organization/international society of Urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladderBladder Consensus Conference committee

Am J Surg Pathol

Original article
Clinical — bladder
Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy1