Surgical management of bladder urothelial carcinoma with squamous differentiation

Surgical management of bladder urothelial carcinoma with squamous differentiation

Urologic Oncology: Seminars and Original Investigations ] (2015) ∎∎∎–∎∎∎ Seminar article Surgical management of bladder urothelial carcinoma with sq...

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Urologic Oncology: Seminars and Original Investigations ] (2015) ∎∎∎–∎∎∎

Seminar article

Surgical management of bladder urothelial carcinoma with squamous differentiation Jay D. Raman, M.D.*, Syed M. Jafri, M.D. Division of Urology, Penn State Milton S. Hershey Medical Center, Hershey, PA Received 28 April 2015; received in revised form 16 June 2015; accepted 17 June 2015

Abstract Background: Urothelial carcinoma (UC) with squamous differentiation (UC w/SD) is the most common variant bladder cancer histology. Main Findings: Accurate identification at the time of transurethral resection is critical although current barriers exist, which include tumor heterogeneity, sampling limitation during resection, and pathologic interpretation of specimens. Although many cases of UC w/SD present with muscle-invasive bladder cancer, those cancers that are confirmed to be truly nonmuscle invasive can be managed with endoscopic resection, adjuvant intravesical therapies (i.e., Bacillus Calmitte Guerin), and close surveillance. Radical cystectomy series suggest that UC w/SD tends to present at a more advanced stage than pure UC does although survival outcomes are similar when controlling for standard clinicopathologic factors. Principal Conclusions: Future basic science and clinical studies are requisite to better investigate the biology of urothelial carcinoma with squamous differentiation and response to multimodal therapies. r 2015 Elsevier Inc. All rights reserved.

Keywords: Bladder cancer; Transurethral resection; Variant histology; Survival outcomes

Introduction Bladder cancer is the seventh most prevalent cancer worldwide, accounting for 3.2% of all malignancies [1]. At present, it is the fifth leading new cancer diagnosis in the United States with most patients (475%) presenting with nonmuscle-invasive (NMI) disease [2]. In the United States, 90% to 95% of bladder cancers are histologically pure urothelial carcinoma (UC) with the remaining tumors consisting of UC with aberrant differentiation or nonurothelial histologies [3]. The most common aberrant differentiation patterns include squamous differentiation (SD) or glandular differentiation (GD) or both in 10% to 60% of patients [4,5], small cell carcinoma in 0.5% to 1.2% [6,7], micropapillary carcinoma in 0.7% [8], and sarcomatoid carcinoma in 0.2% [9]. All of these variant histologies are believed to be derived from common urothelial

progenitor cells that give rise to either pure tumor cell populations or mixed urothelial and variant patterns [10,11]. Among the histologic variants described earlier, UC with squamous differentiation (UC w/SD) remains the most common pathologic entity. Nonetheless, the literature to date remains conflicting regarding the biology of this variant particularly when compared with pure UC or squamous cell carcinoma (SCC). Specific considerations include appropriate recognition of this entity at the time of transurethral resection, management of NMI bladder UC w/SD, as well as outcomes of muscle-invasive bladder disease treated by radical surgery. We focus on these aforementioned issues with a specific focus on the surgical management of UC w/SD. Moreover, these presented observations dovetail with the subsequent article discussing integration of multimodal therapies for the advanced disease. Methods

Corresponding author. Tel.: þ1-717-531-6979; fax: þ1-717-531-4475. E-mail address: [email protected] (J.D. Raman). * 1078-1439/r 2015 Elsevier Inc. All rights reserved.

The Pubmed and Medline databases were queried for all relevant articles published between 2000 and 2015 that


J.D. Raman, S.M. Jafri / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–5

focused on the surgical management of UC w/SD. Original articles, editorial comments, as well as review articles were all used as source documents for creation of this review. Given the focus of this article, search terms of interest included “UC w/SD,” “variant histology,” “radical cystectomy” (RC), “transurethral resection,” and “outcomes.” Other topic areas including pathologic evaluation and multimodal treatments (chemotherapy and radiation treatment) are addressed in accompanying articles of this seminars series. Challenges associated with transurethral resection Transurethral resection of bladder tumors (TURBT) is the referent standard for establishing a histologic diagnosis of bladder cancer. Beyond diagnosis, however, TURBT provides detailed pathologic information regarding clinical grade and stage. Both of these latter 2 variables are critical in the management algorithm for bladder cancer and dictate the need for adjuvant therapies with or without more radical surgery. Identification of bladder cancervariant histologies (when present) at TURBT is also a critical component of diagnostic information necessary in the patient with bladder cancer. Indeed studies have suggested therapeutic implications when variant histologies are present, which in turn serve as predictors of treatment response and patient outcomes [12–14]. However, accurate recognition and diagnosis of variant histologies including UC w/SD has proven to be challenging with barriers related both to transurethral technique as well as pathologic interpretation. In 2013, el-Latif et al. [12] investigated the sensitivity of initial TUR or transurethral biopsy for detecting bladder cancer variants recognized at the time of RC. In this retrospective study of 302 patients, 159 (53%) had variant histology either at endoscopic bladder biopsy, TURBT, or RC. Among the variant histologies, UC w/SD was the most common, accounting for 45% of cases. Overall, initial bladder biopsy/TURBT sensitivity was only 39% for predicting variant morphology at RC. Furthermore, subset analysis revealed that the sensitivity for UC w/SD was 47%. The authors concluded that sensitivity of endoscopic bladder sampling for variant histologies is relatively low and suggested that such observations were likely owing to sampling and tumor heterogeneity rather than to an inaccurate pathological diagnosis. Clearly, however, experienced pathologic review is associated with increased likelihood of identifying variant histologies when present. In 2013, Shah et al. [13] presented data on 589 TUR specimens, which were re-reviewed at a tertiary care medical center before instituting definitive therapy. Of the 589 TUR specimens, 115 (19.5%) were UC demonstrating variant histologic differentiation with UC w/SD being the most common type (32% of variant cases). Most specimens demonstrated only a single variant pattern (90%) with more than half having an extensive amount of variant pathology in the specimen. Overall,

variant histologic differentiation was not reported by the referring institution in 44% of cases, among which 47% were extensive in nature. The authors emphasized the importance of central pathologic review of TUR specimens to ensure adequate identification of variant patterns. The implications for appropriate recognition of variant histologies are highlighted by the series demonstrating pathologic outcomes of these entities at the time of RC. One such study by Wasco et al. [14] reviewed pathologic specimens from 448 consecutive TURBT specimens and 295 subsequent RC specimens. This group found that 25% of TURBT specimens contained variant histologies, with UC w/SD (40%) and UC with GD (18%) being the most common. Tumors with mixed histologies were of almost uniformly high grade and invasive. Additionally, when compared with pure UC, mixed histology tumors were more likely to have muscle-invasive disease at TUR (P o 0.0001) and extravesical disease at RC (P ¼ 0.0001). In summary, although TURBT specimens currently present the optimal means to identify UC with variant differentiation, significant challenges both from surgical sampling and pathologic interpretation exist when attempting to characterize this entity. Given the implications of aggressive disease, additional molecular markers may be crucial to aid characterization at TUR before proceeding with more definitive therapy.

NMI bladder cancer and variant histologies Data regarding management of NMI bladder cancer (NMIBC) and variant histologies are limited owing to the aggressive biology of disease. Indeed, as highlighted earlier, many cases of UC with differentiation present at a higher grade and stage compared with pure urothelial tumors. Therefore, meticulous TURBT with appropriate restaging is critical to accurately characterize such a tumor as being NMI. Furthermore, axial imaging with either computed tomography or magnetic resonance imaging is needed for accurate staging to confirm that disease is indeed confined to the bladder. For UC with variant histologies, the incidence of NMI tumors is approximately 20% to 30% with many of these lesions being of high grade and cT1 stage [15,16]. Analysis of the Netherlands Cancer Registry between 1995 and 2006 by Ploeg et al. [15] identified more than 28,000 cases of T1 or greater bladder cancer. Of these cases, 7.7% had nonpure urothelial histologies and 23% were T1 with the remainder being of higher stage. Shapur et al. [16] explored this similar concept albeit in a single-institution series with treatment considerations. In this series of 760 patients treated by initial TUR, 79 (10.4%) had evidence of variant histologic tumors of which 57 (72%) had muscle-invasive bladder cancer (MIBC) or extensive NMIBC whereas 22 (28%) had NMIBC managed by TUR and adjuvant intravesical Bacillus Calmitte Guerin

J.D. Raman, S.M. Jafri / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–5

(BCG) therapy. Of these 22 cases, 7 patients had UC w/SD, 6 with nested, 4 with GD, 4 with micropapillary, and 1 patient with sarcomatoid variant. Clinical outcomes of these 22 patients were compared to a similar cohort of 144 patients with pure high-grade NMI urothelial cancer. At a median follow-up of 46 months, the authors found no difference in recurrence-free survival (P ¼ 0.68) or disease-specific survival (P ¼ 0.34) between the 2 cohorts. Nonetheless, the 2- and 5-year progression rates to muscle invasion were greater in those with variant disease (P ¼ 0.02). Collectively, this group emphasized that NMI variants can be managed with TUR and intravesical immunotherapy, citing similar survival outcomes, despite a greater progression to muscle-invasive disease. In 2014, Porten et al. [17] highlighted some of the dilemmas associated with NMIBC management when considering variant histologies. Appropriately, they advocate for RC (with or without neoadjuvant chemotherapy) in patients with pure squamous or adenocarcinoma, those with small cell carcinoma, as well as those patients with sarcomatoid, plasmacytoid, and micropapillary patterns. They underscore that UC w/SD or GD, however, may be amenable to TUR with intravesical BCG therapy. Key elements of this approach require restaging TUR, cross-sectional imaging, BCG induction with maintenance, vigilant follow-up, and adequate counseling regarding early cystectomy if the disease response is suboptimal [17].

MIBC and squamous differentiation Information regarding the clinical behavior of MIBC with variant histologies is more abundant than that previously outlined with NMIBC. Additionally, a number of studies have specifically explored outcomes when focusing on UC w/SD. Interestingly, however, the data are often conflicting with some studies suggesting equivalent clinical outcomes whereas others implicating inferior survival outcomes when SD is present. It is likely that some of these observations are attributable to recognition and quantification of the SD component. Indeed, some studies suggest that 60% of RC specimens have some component of SD although this percentage is rarely quantified and may be critical in the biology of disease. Some of the more salient studies are highlighted later. As discussed earlier, Wasco et al. [14] reported in 2007 that UC with variant differentiation was associated with more advanced pathologic disease at presentation. Nonetheless, the presence of mixed histologic features at TURBT was not associated with disease-specific survival, suggesting a similar behavior when controlling for pathologic stage. Also in 2007, Antunes et al. reported on the prognostic value of UC w/SD in a cohort of 113 patients undergoing RC. In this relatively small series, SD was present in 25 (22.1%) patients and was associated with


higher rates of disease recurrence (64% vs. 34%) and mortality (40% vs. 16%) compared with pure UC. In this study, SD was an independent prognostic factor for cancerspecific survival (CSS) in patients with bladder cancer treated with RC. Larger and more contemporary series appear to better define the biology of UC w/SD. In 2012, Kim et al. [19] from the Mayo Clinic reviewed outcomes of 1,013 patients who underwent RC of which 186 had either SD (n ¼ 132), GD (n ¼ 41), or mixed differentiation (n ¼ 13). In this series, patients with UC with any differentiation pattern were more likely to have pT3/pT4 tumors (70% vs. 38%, P o 0.0001) and lymph node positive disease (20% vs. 15%, P ¼ 0.05) at RC when compared with pure UC neoplasms. Despite this worse pathology at RC, 10-year CSS did not significantly differ between patients with UC and histological differentiation and those with pure UC (52% vs. 51%, P ¼ 0.71). Additionally, after adjusting for standard clinicopathological features, SD or GD or both were not significantly associated with the risk of death from bladder cancer (hazard ratio ¼ 0.79, P ¼ 0.10). Similar observations were reported in 2013 by Xylinas et al. [20], who reviewed a cohort of 1984 RC cases of which 488 (24.6%) had variant histologies. Among these variant patterns, SD (11.4%) and GD (3.8%) were the most common. Histologic variants were associated with advanced tumor stage, lymphovascular invasion, and lymph node metastasis (all P o 0.01) when compared with pure UC. Furthermore, on univariate analysis, patients with nonsquamous UC variants were at higher risk for disease recurrence and cancer-specific mortality than those with pure UC (P ¼ 0.001) and those with UC w/SD (P ¼ 0.04). However, in a multivariate model, variant UC histology was not associated with survival outcomes even when considering the incorporation of adjuvant chemotherapy regimens. Most recently, Mitra et al. [21] from University of Southern California reported very similar observations in a matched pair analysis. In this study encompassing 2,444 patients with RC, 259 patients had either SD (n ¼ 141), GD (n ¼ 97), or mixed differentiation (n ¼ 21). These cases were matched 1:1 with patients with pure UC with respect to demographic, tumor, and treatment characteristics (i.e., delivery of chemotherapy). Following this intensive matching process the authors found no differences in outcomes between cases or controls (P ¼ 0.12). Additionally, on multivariate analysis, only pathologic stage was found to be predictive of outcomes in cases with differentiation (P ¼ 0.004). The Memorial Sloan-Kettering Cancer Center experience with UC w/SD does present some data potentially conflicting with that discussed earlier. Specifically, Ehdaie et al. [22] in 2012 compared clinical outcomes following RC of patients with UC w/SD vs. those with pure SCC. Of the 2,031 patients who underwent RC, 78 had pure SCC whereas 67 had UC w/SD. This study found no difference


J.D. Raman, S.M. Jafri / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–5

Table Summary of surgical series comparing outcomes of radical cystectomy for urothelial carcinoma with squamous (or mixed) differentiation vs. pure histologies Study

Antunes et al. [18]


Total ¼ 113 Pure UC ¼ 88


Total ¼ 1,013




Mean ¼ 31.7 mo; SD ¼ 28.5 mo

Pure UC ¼ 34%

Pure UC ¼ 16%

UC w/SD ¼ 64% (P ¼ 0.0001)

UC w/SD ¼ 40% (P ¼ 0.002)

OR ¼ 5.21 (1.9–14.6) P ¼ 0.002

Median ¼ 11.4 y; IQR: 8.4–15.8

10-Year local recurrence:

5-Year CSS: Pure UC ¼ 57% Variant UC ¼ 56% (P ¼ 0.71)

OR ¼ 0.79 (0.6–1.05) P ¼ 0.10

Pure UC ¼ 827 Variant UC ¼ 186 Xylinas et al. [20]

Total ¼ 1,984 Pure UC ¼ 1,496 UC w/SD ¼ 227

Pure UC ¼ 84% Variant UC ¼ 79% (P ¼ 0.14) Median ¼ 55 mo; IQR: 24–108

5-Year RFS: Pure UC ¼ 61% UC w/SD ¼ 60% Other variant UC ¼ 52% (P ¼ 0.79, Pure UC vs. UC w/SD)

5-Year CSS: Pure UC ¼ 66% UC w/SD ¼ 62% Other variant UC ¼ 54% (P ¼ 0.52, Pure UC vs. UC w/SD)

Median ¼ 15.2 y; (1.2–26.3 y)

5-Year RFS: Pure UC ¼ 64% UC w/SD ¼ 62% (P ¼ 0.79)

5-Year OS: Pure UC ¼ 39% UC w/SD ¼ 43% (P ¼ 0.40)

Median ¼ 44 mo

5-Year CSS:a UC w/SD ¼ 39% Pure SC ¼ 54% (P ¼ 0.17)

Other variant UC ¼ 261 Mitra et al. [21]

Total ¼ 2,444 Pure UC ¼ 141 Other variant UC ¼ 118

Ehdaie et al. [22]

Total ¼ 2,031 Pure UC ¼ 1,886 UC w/SD ¼ 67 Pure SCC ¼ 78



UC w/SD ¼ 25 Kim et al. [19]


Data are provided in this table only when specifically stated in the article. IQR ¼ interquartile range; OR ¼ odds ratio; OS ¼ overall survival; RFS ¼ recurrence-free survival. a The article cites that pure UC had superior CSS although no specific numbers are provided.

in CSS and overall survival between pure SCC and UC w/SD. In this study, the extent of disease was more of a contributing factor to outcome than histology. Nonetheless, these data are somewhat conflicting as the behavior of SCC has generally been considered more ominous than those of pure UC counterparts. Collectively, most of the series highlighted earlier implicate that outcomes of urothelial cancer with SD are similar to those of pure urothelial cancer when controlling for stage at presentation (Table). Clearly, however, these tumors present at a higher stage, contributing to the assertion that it is a more aggressive biologic entity. This characteristic creates a potential role for multimodal therapies and regimens to preserve equivalent oncologic outcomes.

variant UTUC. Analogous to bladder cancer, the most common variant pathology included squamous and GD in 9.9% and 4.4% of cases, respectively. Histologic variants were associated with several adverse pathologic features, including higher stage, multifocality, sessile tumor architecture, tumor necrosis, lymphovascular invasion, and lymph node involvement. Additionally, on univariate analysis, variant histology was associated with disease recurrence (P ¼ 0.002) and cancer-specific mortality (P ¼ 0.003). However, in a multivariable model adjusted for the effects of standard clinicopathological characteristics, variant histology was not associated with either end point. Similar to many of the bladder cancer studies, the authors concluded that variant histology was associated with features of biologically aggressive disease but was not an independent predictor of disease-specific recurrence or mortality.

Upper-tract UC and SD Although the literature is more limited, the behavior of upper-tract UC (UTUC) tumors exhibiting SD appears quite similar to its bladder cancer counterpart. In 2012, Rink et al. [23] published an international multicenter study investigating the effect of variant histologies on UTUC outcomes. This study reviewed 1,648 patients undergoing radical nephroureterectomy, of which 398 (24%) had histologically

Conclusions UC w/SD is the most common variant histology with need for accurate identification at the time of transurethral resection. Although most present with muscle-invasive bladder cancer, those cancers that are confirmed to be truly NMI can be managed with intravesical therapies and close

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surveillance. Most RC series suggest that UC w/SD presents at a more advanced stage but survival outcomes are similar to those of pure UC when controlled for standard clinicopathologic parameters. Future investigation is necessary to better delineate the beneficial role in multimodality regimens to maintain survival outcomes.



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