**Abstract**

Bladder cancer (BC) is an increasingly frequent cancer worldwide, being currently the sixth most frequent tumor and the thirteenth leading cause of cancer death. Among all BC cases, pathologists have identified several histomorphologies different from the conventional urothelial carcinoma. Although rare, these histologic variants have a distinct growth pattern, an altered cell differentiation and an unusual clinical behavior, especially concerning clinical presentation at diagnosis, response to the standard treatment and prognosis. Therefore, an updated review of this topic should be useful to aid clinicians in a better evidence-based decision-making. This chapter aims to summarize the current literature on the most common histologic variants regarding their epidemiology, clinical presentation at diagnosis, treatment options and prognosis. This includes both non-muscle invasive BC and muscle invasive BC as well as metastatic disease. A special focus will be placed on the role of neoadjuvant chemotherapy and early cystectomy and its prognostic implications.

**Keywords:** Bladder, Cancer, Histologic, Variants, Prognosis, Treatment

### **1. Introduction**

Bladder cancer is an entity characterized by a wide range of different histomorphologies as well as distinct clinical courses. Approximately 75% of tumors are classified as pure urothelial carcinoma (transitional cell carcinoma), the remaining 25% consist of other histological variants. Several histological variants have been identified throughout the years, based on morphological features [1]. During the past decade, there is a trend of increasing evidence of the clinical relevance of histological variants, some them with data showing adverse pathological features and poor prognosis [2]. The acknowledgment of this information has been changing the clinical reasoning and disease management in patients with BC.

Pure non-urothelial bladder cancer comprises only a small minority (about 5%) of all bladder cancers. They include squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and mixed histology tumors, with squamous and adenocarcinoma comprising the most frequent morphologies. Non-urothelial histologic subtypes were generally thought to have a worse prognosis compared to urothelial

BC [3], however, once corrected for stage and patient-related factors, a significant proportion of them may have a similar prognosis.

On other hand, urothelial tumors with a variant histology component are more frequent than non-urothelial tumours. The classification of histologic variants is mainly based on morphologic features, being each differentiation pattern characterized by a distinct biological behavior, such as propensity for local recurrence and metastasis [4]. Non-muscle invasive BC with variant histology most likely remains underdiagnosed, as it seems challenging to identify its presence on TURB specimens. Current data suggests that variant histologies confer high-risk status to nonmuscle invasive tumors, despite some studies had demonstrated similar progression rates in comparison with pure urothelial carcinomas (UC) associated with high risk factors [5]. Therefore, the question arises, does variant histology justify an aggressive treatment approach with early radical cystectomy?

The treatment of BC has evolved throughout the years such that clinical markers of risk are now used to guide us through algorithms that incorporate transurethral surgery, intravesical chemotherapy and immunotherapy, radical cystectomy, systemic combination chemotherapy, and sometimes radiation therapy. Therefore, the optimal risk stratification may include variant histology as a relevant factor in clinical decision making [6].

This chapter focuses on most common histological variants and discusses different treatment options and their prognostic value.

#### **2. Histologic variants of Urothelial Carcinoma**

Urothelial carcinoma (UC) is remarkable for displaying a wide range of diversity in its morphological appearance, which may reflect its molecular heterogeneity. Urothelial tumors with divergent differentiation are the most common histology variant within urothelial carcinomas [7]. The term refers to tumors that present some degree of typical urothelial carcinoma (invasive or *in situ*) with other histomorphologies such as squamous or glandular differentiation.

Squamous and Glandular differentiation are most common histology variants [8, 9]. UCs with squamous or glandular differentiation are distinct entities and should be distinguished from both pure squamous cell carcinoma (SCC) and or adenocarcinoma (AC) which do not include any urothelial components and subsequently present different clinical behavior. Other subtypes of UC variants include rarer differentiations including trophoblastic and small cell differentiation.

Urothelial carcinomas with divergent differentiation were previously thought to present at a more advanced stage at diagnosis and early reports indicated a poorer survival rate. More recently, studies have shown that, if standardized for stage, patients with either squamous or glandular UCs have survival rates comparable with those with pure UC.

Yet, current guidelines still categorize UC with variant histology in the highest risk category in which early radical cystectomy should be considered [8].

#### **2.1 Urothelial carcinomas with squamous differentiation**

Urothelial carcinomas with squamous differentiation are found in up to 40% of UCs and the inclusion of keratinization and/or intercellular bodies (**Figure 1**) are their main histological hallmarks [7]. The distinction between UC with squamous differentiation and pure squamous cell carcinomas (SCC) of the bladder remains a challenge for pathologists, especially in transurethral resection (TUR) specimens, because both tend to share most of the same immunohistochemical components.

*Bladder Cancer Variant Histologies: Epidemiology, Diagnosis, Treatment and Prognosis DOI: http://dx.doi.org/10.5772/intechopen.98246*

#### **Figure 1.**

*Squamous differentiation is characterized by the presence of both urothelial carcinoma and keratin clusters and intercellular bodies (HE × 100).*

Among NMIBC cases, UCs with squamous differentiation are frequently associated with high-grade and high-stage tumors at diagnosis and tend to have a less favorable response to intravesical chemotherapy or BCG instillations [10]. In the MIBC disease setting, studies have shown that response rate of neoadjuvant chemotherapy may be similar to conventional UC [11], although with a poor prognosis [2].

#### **2.2 Urothelial carcinomas with glandular differentiation**

Glandular differentiation comprises approximately 10% of all UCs and is characterized by true gland formation (**Figure 2**), resembling colonic adenocarcinoma, signet ring carcinoma or mucinous/colloid carcinoma. It may be associated with UC in situ or less frequently with in situ UC with glandular differentiation. Pseudo glandular aspects with mucin expression may be observed in conventional UC and should not be confused with either UC with glandular differentiation or bladder adenocarcinoma, although the lack of immunohistochemical markers makes the distinction challenging [12]. Telomerase reverse transcriptase (TERT) mutations are seen in the majority of UCs with glandular differentiation and not in adenocarcinomas of the bladder [13]; nevertheless, this marker is yet to be implemented in routine clinical use.

In terms of clinical significance of this differentiation, it tends to present at a higher stage, but it is not a predictor of adverse prognosis in stage-matched patients, showing similar rates of recurrence-free and overall survival when compared to conventional UC [5].

It is important to note that data from studies has showed that intravesical BCG treatment might play a key role in patients with UC with glandular differentiation, with this therapy presenting reasonable response rates [14, 15].

#### **2.3 Urothelial Carcinomas with Trophoblastic Differentiation**

UC with trophoblastic differentiation is a rare entity with only a few cases reported, and it is characterized by the expression of the beta subunit of the human chorionic gonadotropin (ßhCG) (**Figure 3**). This subtype must be distinguished from

#### **Figure 2.**

*Glandular differentiation encompasses gland-like lumina or fully developed adenocarcinoma with intestinal morphology (HE × 100).*

#### **Figure 3.**

*The image shows a cluster of syncytiotrophoblastic giant cells enclosed by high-grade urothelial carcinoma (HE × 100).*

pure choriocarcinoma which requires the demonstration of the isochromosome 12p, a hallmark of germ cell tumors. The percentage of ßhCG-immunoreactive cells is associated with higher stage and grade of the disease. Elevated secretion of ßhCG into the serum may be associated with an observable poorer response to chemotherapy and radiation, and it can be used as a marker in the follow-up of these patients [2].
