**2.4 Urothelial Carcinomas with Small Cell Differentiation**

UC can exhibit neuroendocrine differentiation in the form of small cell carcinoma. These tumors are usually treated similarly to their counterpart in the lungs. *Bladder Cancer Variant Histologies: Epidemiology, Diagnosis, Treatment and Prognosis DOI: http://dx.doi.org/10.5772/intechopen.98246*

## **2.5 Nested Urothelial Carcinoma**

Based on the 2016 WHO classification, the nested variant includes UC with small tubules and microcysts (**Figure 4**). This histologic variant can often resemble benign cytology [16]. It is characterized by disorderly proliferation of confluent nests, with minimal cell atypia [17], which can often delay the definitive diagnosis.

Nested UCs usually present as high stage disease and may be associated with a worse prognosis compared with pure nested variants [14]. It shares similar immunohistochemical features and clinical outcomes with the conventional UC, with little to no difference in recurrence rate or survival when treated with RC in either NMIBC and MIBC [17].

#### **2.6 Microcystic Urothelial Carcinoma**

The microcystic UC variant, like the nested UCs, is characterized by a benign cytologic resemblance features. It is constituted by oval cysts, lined by urothelial, low columnar or flattened epithelium (**Figure 5**) and focal conventional UC may be present in up to 40% of tumors [18]. Foci of high-grade UC are seen in up to 40% of cases, which may help distinguish this variant form benign mimicking tumors [14].

Differential diagnosis includes benign proliferations such as florid polypoid cystitis cystica and glanduraris and adenocarcinoma [19].

There is very limited information about prognostic implications of microcystic histology in BC, only a few case reports and case series have been published. The largest study to date (N = 20) reported 55% of patients died at a mean follow-up of 30 months after radical cystectomy (RC). However, when controlled for stage, there was no statistically significant difference in survival compared with patients with pure UC [20].

#### **Figure 4.**

*The nested variant of urothelial carcinoma consists of small, discrete nests with bland morphology distributed irregularly in the lamina propria. The size of nests is much smaller than von Brunn's nests of normal urothelium (HE × 40).*

#### **Figure 5.**

*Characterized by the formation of microcysts which may mimic cystitis cystica in small specimens. Cytologic atypia is minimal or entirely absent (HE × 100).*

## **2.7 Micropapillary Urothelial Carcinoma**

Micropapillary Urothelial Carcinoma (MPUC) is a variant seen most commonly in males, being characterized by small tumour nests surrounded by lacunar spaces (**Figure 6**). It is a clinically aggressive variant that usually presents at an advanced stage that accounts for 2–5% of UCs [14, 21]. ERBB2 (HER2) amplification by FISH is seen more commonly in patients with MPUC versus conventional UC, such expression has been related to worse cancer-specific survival although it also provides a potential role for HER2 targeted therapy [22]. Single institution case-series

#### **Figure 6.**

*Infiltrating tumors cells with slender filiform processes without fibrovascular cores and multiple small tumor nests within a single lacunar space, mostly not enclosing a true fibrovascular core (HE* **×** *200).*

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

have demonstrated poorer outcomes in patients with MPUC than those with pure UC [23]. However, more recent studies demonstrated that, when controlled for stage, this may not be the case.

Non muscle-invasive MPUC is characterized by high rates of progression to muscle-invasive and metastatic BC. A case series with 44 patients with non-muscle invasive MPUC, amongst those treated with BCG, 67% showed cancer progression with 22% developing metastatic disease, only 19% remained alive at the end of follow-up (10-yeat) without RC. Patients who underwent delayed RC after BCG treatment failure presented a median disease-specific survival (DSS) of 62% at 10 years. On the other hand, patients treated with early RC had a 10-year median DSS of 72% [24].

Patients with UC with a micropapillary component doing upfront RC were not associated with worse recurrence-free, cancer specific or overall survival, when compared to those with pure UC [25].

Therefore, early RC has been considered the standard of care in most centers, however, there have been reports of reasonable outcomes in series in which bladder preservation therapies were applied in highly selected patients with a relatively small micropapillary component [26].

Although there is still scarce evidence regarding muscle-invasive MPUC and the role of Neo-adjuvant chemotherapy (NAC) in opposition to early RC, there have been reports showing no statistically significant differences in overall survival (OS) between the group who have undergone NAC plus RC vs. RC only [27]. A recent study analyzed the impact of adjuvant chemotherapy (AC) in the OS among patients with MPUC and the results demonstrated that, in contrast to pure UC, no survival benefit was observed in patients with this histology subtype [28]. Nevertheless, although these results could be explained by the more aggressive clinical behavior of this histologic variant, they can also be a consequence of small samples size, short follow-up periods and lack of risk stratification in most studies.

#### **2.8 Lymphoepithelioma-like UC**

Lymphoepithelioma-like UC (LLUC) resembles lymphoepithelioma of the nasopharynx and is characterized by a prominent lymphoid stroma (**Figure 7**) with T (predominantly CD3) and B lymphocytes, plasma cells, histiocytes, neutrophils and eosinophils. Major differential diagnosis comprises poorly differentiated UC with lymphoid inflammatory response or lymphoma [29, 30].

This histologic variant has been found to have a similar prognosis to conventional UC as well as similar chemosensitivity and response to immunotherapy [31].

#### **2.9 Plasmocytoid**

Plasmacytoid UC is a rare histopathological variant of UC, comprising 1–3% of all UCs and is characterized by the presence of discohesive cells with eccentrically placed nuclei surrounded by abundant eosinophilic cytoplasm (**Figure 8**). This variant usually displays a diffusely infiltrative growth pattern, inducing minimal stromal reaction [32]. This morphology is not exclusive to UC, thus plasmacytoid UC (PUC) must be distinguished from melanoma and lymphoma. Immunohistochemical markers such as CK7, CK20 uroplakin II, and GATA-3 can be useful in the differentiation in doubtful situations [33]. It is also characterized by a distinct growth pattern in which tumour cells can manifest distant from macroscopic disease with the absence of a desmoplastic reaction making it more challenging to determine the plane between the tumour and normal tissue. A wide margin of resection is therefore mandatory to ensure an adequate resection at the time of RC [32].

#### **Figure 7.**

*Characterized by syncytial sheets of tumor cells and a prominent chronic inflammatory infiltrate in the stroma. The infiltrate is composed largely of lymphocytes, plasma cells, eosinophils, and other inflammatory cells which may create an appearance of chronic cystitis or malignant lymphoma (HE × 100).*

#### **Figure 8.**

*PUC usually displays single tumor cells with plasmacytoid features infiltrating loose myxoid stroma. It shows discohesive tumour cells with eccentrically located nuclei and abundant eosinophilic cytoplasm (HE* **×** *200).*

Mutations in CDH1 are pathognomonic of PUC and result in the loss of E-cadherin expression in its tumour cells, this is thought to explain the higher rates of tumour cell migration observed [34, 35].

Plasmacytoid UC response to intravesical BCG has not been clearly defined yet but given the fact that these tumors display a strong predilection for recurrence, especially in peritoneal lining, even in cases when non-muscle invasiveness is encountered, early RC seems to provide a more effective control of the disease [36].

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

The role of NAC/AC is still unclear in PUC, although initial evidence suggested this histologic variant was chemosensitive, more recent data suggests that platin based regimens confer no survival enhancement and that even in patients who achieve pT0 stage after cystectomy after RC, poor prognosis is maintained in PUC [36, 37].

## **2.10 Sarcomatoid**

Sarcomatoid UC accounts for approximately 0.3% of all UCs. This histologic variant is characterized highly variable morphology exhibiting both epithelial and mesenchymal differentiation with high-grade spindle cells (**Figure 9**). Previous exposure to radiotherapy (RT) and intravesical cyclophosphamide are known risk factors [38].

Sarcomatoid differentiation has been associated with a very poor prognosis, since it usually presents at an advanced stage [38]. However recent series demonstrated no differences in comparison with same stage pure UC, regarding diseasespecific, all-cause mortality and overall survival [28]. A survival benefit was not found in patients undergoing NAC or AC, suggesting this variant might be particularly resistant to chemotherapy [39].
