**3. Non-Urothelial Variants**

Non-urothelial BC can be categorized as epithelial and non-epithelial tumors. Approximately 90% are epithelial, including squamous cell carcinoma, adenocarcinoma and small-cell carcinoma. Non-epithelial tumors are rare, and include sarcoma, corinosarcoma, paraganglioma, melanoma and lymphoma [41]. In this section we will restrict our description to the most common subtypes.

### **4. Squamous Cell Carcinoma**

Squamous Cell Carcinoma (SCC) represents the most common non-urothelial histologic variant, accounting for almost 2–5% of all BC in the western world and approximately 30% in endemic regions (Egypt and other parts of Africa) due to the parasite *Schistosoma haematobium* infection, which causes bilharzial SCC [42]. Non-bilharzial SCC is associated with chronic inflammation of the urothelium as a result of chronic urinary tract infection, long-term indwelling catheters and bladder calculi. In contrast to UC, the relationship between SCC and cigarette smoking in not clearly established [43].

In terms of histological characteristics, SCC contains keratin pearl inclusions and granules (**Figure 11**). Moreover, microscopic analysis shows that most SCC tumors are moderately to poorly differentiated tumors.

SCC tends to appear in the seventh decade of life, except for spinal cord injured patients which can present at younger ages and is characterized by a slight male predominance with a higher proportion of non-Caucasians [44]. SCC is associated with more advanced disease at presentation compared to UC, with 70% of cases showing muscle-invasiveness at time of diagnosis, with a higher propensity for nodal involvement and metastatic disease [45]. Even in patients with T1 staging at diagnosis, pure SCC has been identified as an independent predictor of mortality in patients who did not undergo early cystectomy [46]. However, data from studies has also reported that, in cases in which the tumor was confined to the bladder wall and the bladder was surgically removed as part of the initial treatment, SCC histologic features were not associated with increased mortality when compared to UC [41, 47].

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

#### **Figure 11.**

*The image shows presence of keratin pearls and copious keratin production, unequivocal for squamous differentiation (HE × 100).*

This histological subtype has been associated with poorer OS, even when adjusted for stage. However, bilharzial-associated SCC, which usually presents at a younger age, is associated with lower stages at diagnosis, and a more indolent disease course with subsequent better survival outcomes [48].

In opposition to UC, NAC has not demonstrated a statistically significant improvement in OS among patients with the SCC histology, treated with RC [49].

Regarding radiation therapy, there is some evidence that treatment with preoperative RT may improve disease-free survival comparing with RC alone [49]. Moreover, since SCC histology subtype is notoriously chemo-resistant to most regiments used for metastatic UC, radiotherapy can have an important therapeutic role [50]. This data was, however, obtained from retrospective studies with a very limited number of cases, suggesting that conclusions must be further evaluated.

Based on the best published evidence, early RC remains the mainstay therapy in patients with high-risk SCC, even when non-muscle invasive staging is observed [28]. It is important to note that, unlike other histologic subtypes, pelvic lymph node dissection (PLND) was associated with an improvement in OS [51].

#### **5. Adenocarcinoma**

Adenocarcinoma (AC) of the bladder can be primary or secondary [if it results from a contiguous invasion from other organs such as prostate, colon or uterus (endometrium and cervix), or metastatic spread (lung)]. Primary AC accounts for roughly 2% of all BCs and is divided into two subtypes: Urachal (10%) and nonurachal AC. There are also different types of adenocarcinomas that have been described, including glandular (**Figure 12**), colloid, papillary, signet ring and clear cell. Known risk factors include bilharziasis, chronic inflammation and bladder exstrophy (even in patients who have undergone correction in the neonatal period) [43, 51]. The diagnosis of primary AC of the bladder should only be made if secondary involvement from other organs is excluded. This entity has been shown to be more common in females, with a higher proportion among non-caucasians [52].

**Figure 12.** *Intestinal-type adenocarcinoma shows malignant colonic glands with high-grade columnar cells and necrosis in the lumens (HE × 40).*

Bladder AC usually presents at an advanced stage, with muscle-invasive or metastatic disease. For localized disease, RC is currently the treatment of choice. However, when matched for stage, primary AC appears to have similar outcomes to UC [53]. In patients with NMIBC disease, a SEER analysis reports that, in non-urachal AC, transurethral resection (TUR) alone increased mortality risk, compared with early cystectomy [54]. There is currently no evidence available regarding the effect of immuno- or chemotherapy.

Urachal AC seems to present more favorable prognosis compared with nonurachal AC. Partial cystectomy (with en bloc resection of the bladder dome and umbilical ligament) is an alternative option to RC, in selected patients [55, 56]. Although urachal AC also seems more likely to present as metastatic disease in comparison to UC, the previous mentioned better prognosis is most probably partly due to be diagnosed among younger patients, with less co-morbidities [28].

Current data about NAC or AC in adenocarcinoma patients, although very scarce, suggests that neither therapy confers an improvement in survival [57].

#### **5.1 Small Cell Carcinoma**

The urinary bladder is the most common site for genitourinary extra-pulmonary neuroendocrine/small cell carcinomas. Small cell carcinoma (SmCC) accounts for less than 1% of BCs. It is a neuroendocrine tumour characterized by nests or solid sheets of small cells with enlarged nuclei, evenly dispersed chromatin with a "salt and pepper" pattern (**Figure 13**), with abundant resemblance to its pulmonary counterpart. It often co-exists with conventional UC, SCC and AC. Neuroendocrine markers such as chromogranin, synaptophysin and CD56 are expressed in SmCC [43]. Mean age presentation sits in the seventh-decade of life, with a strong male predominance (5:1) [55]. SmCC also shows similar characteristics to small cell carcinomas of the lung including ectopic hormone production, which can lead to clinically relevant hyperkalemia and hypophosphatemia [56, 58].

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

#### **Figure 13.** *Small cells with artifacts that make it difficult to distinguish between cytoplasm and nucleus (HE × 100).*

This histologic variant is also characterized by its aggressiveness, exhibiting rapid growth with a predilection for early metastases, and a particularly high propensity for brain metastasis [59].

Contrarily to many of other histologic variants, a treatment strategy based on NAC followed by RC or RT represents the optimal strategy, based on several studies that demonstrated the chemosensitivity (with platinum-based therapy) of SmCC with an improvement in survival [59].

In terms of prognosis, SmCC presents a similar outcome to pure UC at same stages, except in the setting of diffuse metastatic disease in which it presents worse outcomes [60].
