Pathology of bladder neoplasms

INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system. Urothelial carcinoma is the predominant histologic type in the United States and Europe, where it accounts for 90 percent of all bladder cancers. In other areas of the world, non-urothelial carcinomas are more frequent. Much less commonly, urothelial cancers can arise from other sites in the urinary tract, including the renal pelvis, ureter, or urethra. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

The pathology of bladder neoplasms will be reviewed here. Clinical aspects of these different tumor types are discussed separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer" and "Non-urothelial bladder cancer".)

The College of American Pathologists (CAP) bladder cancer checklists provide guidelines for diagnosis and reporting of bladder cancer in biopsy, transurethral resection, and cystectomy specimens.

CLASSIFICATION — Several systems have been used to grade and classify bladder neoplasms. The system proposed by the World Health Organization (WHO) in 1972 distinguished papillomas from grade I, II, and III papillary transitional cell carcinomas [1].

In 1998, WHO and the International Society of Urologic Pathologists (ISUP) published a consensus classification system for urothelial (transitional cell) neoplasms [2]. The clinical significance of this schema was validated by subsequent studies, and in 2004, it was accepted as the standard classification schema [3]. The WHO 2022 (fifth edition) adopted the same classification [4].

According to this system, urothelial carcinoma is classified as low grade and high grade based upon the degree of nuclear anaplasia and architectural abnormalities. With rare exceptions (eg, nested or tubular subtypes), invasive urothelial carcinoma is high grade in its cytological features.

Bladder anatomy — The wall of the bladder consists of four layers (picture 1):

●Urothelium – The urothelium is the innermost epithelial lining of the bladder. The urothelium is the site of origin for bladder carcinomas.

●Lamina propria – The lamina propria (subepithelial connective tissue) is separated from the urothelium by a thin basement membrane and is composed of abundant connective tissue containing vascular and neuronal structures [5-8]. Wispy fascicles of smooth muscle can be found within the mid lamina propria with vascular plexus, either isolated or forming a complete or incomplete muscularis mucosae [9].

●Muscularis propria – The muscularis propria (detrusor muscle) surrounds the lamina propria and consists of thick, irregularly arranged muscle bundles. In small biopsies, fascicles of hypertrophic muscularis mucosae in the lamina propria may be confused with the larger smooth-muscle bundles of the muscularis propria, potentially resulting in an error in tumor staging. Adipose tissue also can be present within the lamina propria and/or muscularis propria [2]. The presence of invasive tumor in fat, thus, is not always indicative of extravesical extension.

●Adventitia or serosa – The perivesical adipose tissue outside the muscularis propria is covered by a serosal layer.

Pathologic tumor staging — The most important element in the pathologic staging of urothelial carcinoma is the extent of invasion into deeper layers of the bladder and surrounding tissues (figure 1). The depth of invasion is incorporated into the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) classification schema (table 1). The staging of the primary bladder tumor (pT) in the eighth edition AJCC has not changed from the seventh edition. This information has major implications for both prognosis and treatment.

Most pT1 tumors are high-grade papillary urothelial carcinomas; low-grade tumors occur less frequently. More deeply invasive pT2 to pT4 urothelial carcinomas are high grade. Several studies showed that pT1 tumors have a less favorable prognosis than pTa neoplasms. However, pTa and pT1 neoplasms are grouped together as "non-muscle invasive" tumors because both pTa and pT1 lesions are managed conservatively, despite having different prognoses. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Lamina propria invasion — Recognition of lamina propria invasion by urothelial carcinoma can be difficult [10]. Biopsy specimens are often poorly oriented, fragmented, and/or cauterized. In pT1 disease, foci of invasion are characterized by urothelial nests, clusters, or single cells within the papillary cores and/or lamina propria (picture 2) [6,11].

The invasive nests can induce a desmoplastic stromal response that mimics a malignant spindle cell component, a feature known as pseudosarcomatous stromal reaction (picture 2). In addition, foci of invasive tumor may be associated with retraction artifact, mimicking vascular invasion (picture 2) [12,13].

Although the WHO classification does not substage pT1 tumors according to the depth of lamina propria invasion, some studies have demonstrated prognostic differences in tumors with invasion above and below the muscularis mucosae [14]. In a meta-analysis of 15,215 patients with high-grade T1 tumors, substaging was the most important prognostic factor for recurrence and progression [15]. The maximum size of the invasive focus seems to confer additional prognostic value [16]. Therefore, pathologists should provide the extent of lamina propria invasion if such assessment is possible [2,17].

Muscularis propria invasion — In more advanced stages, urothelial carcinoma infiltrates the muscularis propria (pT2) (picture 3), or perivesical adipose tissue and adjacent organs (pT3 and pT4) (picture 4). Muscularis propria invasion is diagnosed when urothelial carcinoma infiltrates between thick, distinct fascicles of muscle bundles (picture 3). Muscle invasion by urothelial carcinoma may or may not elicit a desmoplastic stromal response [6].

Uncertainty about the depth of invasion should be explicitly stated in the pathology report [5]. Even in cases of noninvasive disease, the pathologist should note whether muscularis propria was present in the biopsy specimen to provide information regarding the adequacy of resection. The absence of muscularis propria in transurethral resection specimens with tumor has been associated with an increased risk of residual disease, recurrence, and understaging [18]. Repeat transurethral resection of bladder tumor might be needed when muscularis propria is not present in the biopsy, as this information impacts treatment decisions for patients with bladder cancer. (See "Overview of the initial approach and management of urothelial bladder cancer".)

Adipose tissue is often present between detrusor muscle bundles. Thus, the mere presence of tumor in fat in a biopsy does not necessarily equate with involvement of perivesical fat.

Bladder cancer may invade the prostate gland. Involvement of the prostate gland may occur in several different patterns. Tumors (flat carcinoma in situ, papillary or invasive carcinoma) can first spread along the prostatic urethral mucosa and prostate glands, and subsequently invade prostatic stroma (transurethral mucosal route; this type of prostatic stroma invasion is staged based on the prostatic urethral staging as pT2). Tumors may also invade through the bladder wall and the base of the prostate directly into the prostate gland. Tumors can also invade into extravesical fat and then extend back into the prostate gland. The last two routes are considered direct transmural invasion.

The AJCC eighth edition staging manual defines direct transmural extension of urinary bladder cancer into the prostate gland as T4 disease and excludes transurethral, mucosal, prostatic stroma invasion from the pT4a staging status. However, there are limited data on the best methodology to stage urothelial carcinoma that concurrently involves the urinary bladder and the prostatic urethra. In patients who have a large urinary bladder carcinoma that has invaded through the full thickness of the bladder wall and, thereby, secondarily involves the prostatic stroma, a T4 stage should be assigned to urinary bladder staging. In other circumstances in which involvement by urothelial carcinoma is seen in both sites, separate urinary bladder and prostatic urethral staging should be assigned.

Vascular invasion — Vascular invasion detected at transurethral resection is associated with adverse pathological features and upstaging at radical cystectomy [19] and is therefore important to recognize. Establishing the presence of vascular invasion is difficult (picture 5) [5,13]. Urothelial carcinomas are commonly associated with a stromal retraction artifact that mimics vascular invasion. Caution is warranted, and strict criteria should be applied. Immunostains for endothelial markers may be used in difficult and ambiguous cases.

NONINVASIVE UROTHELIAL NEOPLASMS — The normal urothelial mucosa is flat and consists of a layer of three to seven cells, although the thickness depends upon the extent of bladder distension at the time of biopsy. Normal urothelial cells are approximately two to three times the size of stromal lymphocytes (picture 6).

Noninvasive urothelial lesions are divided into flat and papillary subgroups.

Flat lesions — Flat noninvasive lesions of the urothelium include dysplasia and carcinoma in situ (CIS).

Dysplasia/atypia — Dysplasia (low-grade intraurothelial neoplasia) is diagnosed when atypical dysplastic changes in urothelial cells do not meet the criteria for CIS. Some urologic pathologists combine "dysplasia" with the category of "urothelial atypia cannot exclude dysplasia" due to their similar clinical management strategy and the known reproducibility problems in diagnosing definitive flat neoplasia that fall short of the threshold for CIS. Areas of dysplasia are commonly associated with higher-grade bladder neoplasia, and the incidence of dysplasia approaches 100 percent in patients with invasive urothelial carcinoma. Primary (de novo) dysplasia without CIS or invasive urothelial carcinoma is seen predominantly in middle-aged men, who present with symptoms of bladder irritation with or without hematuria.

Dysplastic lesions show a variable loss of cell polarity with nuclear crowding and cytologic atypia (picture 7A-C). The cells may have slightly enlarged nuclei, inconspicuous nucleoli, and rare mitoses (picture 7A). The degree of atypia is comparable to that seen in low-grade papillary urothelial carcinoma (LGPUC). (See 'LGPUC' below.)

The thickness of the urothelium in dysplastic lesions is usually normal (picture 7A-C), although it may be increased (picture 7B) or decreased. Urothelial dysplasia may involve von Brunn nests. Comparison with normal-appearing urothelium may help assess nucleomegaly and loss of polarity. The presence of pleomorphism, prominent nucleoli, and increased numbers of mitoses suggests a diagnosis of CIS.

The finding of dysplasia in patients with noninvasive papillary neoplasms indicates urothelial instability and is a marker for potential progression or recurrence. De novo dysplasia progresses to CIS or invasive carcinoma in between 5 and 20 percent of cases [20-23]. (See 'Papillary lesions' below.)

Carcinoma in situ — CIS is a flat lesion in which the surface epithelium contains cells that are cytologically malignant. CIS is synonymous with high-grade intraurothelial neoplasia.

De novo (primary) CIS accounts for less than 1 to 3 percent of urothelial neoplasms. Areas of CIS are also identified in 45 to 65 percent of patients with invasive urothelial carcinomas. Patients with primary CIS are typically in their 40s or 50s, and may be asymptomatic or have dysuria, frequency, urgency, or hematuria. Multifocal involvement of the urinary tract with CIS is common and may be synchronous or metachronous (picture 8). Endoscopically, CIS is characterized by irregularly hyperemic mucosa (picture 9).

Severe cytologic atypia is required to diagnose CIS (picture 10A-D). The degree of nuclear anaplasia is identical to high-grade papillary urothelial carcinoma (HGPUC), although a spectrum of severity may exist. There may be complete loss of polarity, marked crowding, and pleomorphism (picture 10B-D). The nuclei are enlarged, frequently hyperchromatic, and have coarse or condensed chromatin. Most nuclei in CIS are at least four to five times the size of adjacent stromal lymphocytes. Large nucleoli may be present. Mitoses are common, may be atypical, and can extend into the upper cell layers.

The neoplastic changes may or may not involve the entire thickness of the epithelial layer, and umbrella cells may be present [23,24]. The urothelium may be denuded, diminished in thickness, of normal thickness, or even hyperplastic (picture 10A-B).

Different cytologic and architectural patterns are recognized in CIS. These include lesions characterized by pleomorphic large cells, nonpleomorphic large cells, small cells, clinging, and pagetoid features. Cystitis cystica and von Brunn nests may be completely or partially replaced by cytologically malignant cells, often after intravesical treatment (picture 10C-D). Loss of intercellular cohesion may result in a denuded surface (clinging CIS or denuding cystitis), and shedding of malignant cells into urine and positive urine cytology (picture 11A-B) [25].

Data suggest that de novo CIS is less likely to progress to invasive urothelial carcinoma than secondary CIS. Patients with CIS and concomitant invasive tumors have a higher mortality than patients with CIS and concomitant noninvasive tumor.

Papillary lesions — Noninvasive papillary lesions of the bladder can be benign (urothelial papilloma, inverted papilloma), have malignant potential (papillary urothelial neoplasm of low malignant potential [PUNLMP]), or contain noninvasive LGPUC or HGPUC. PUNLMP, LGPUC, and HGPUC typically present with hematuria and are more common in men, with a mean age at diagnosis in the 60s.

Grade heterogeneity is encountered in approximately one-third of noninvasive papillary urothelial neoplasms. The 1998 World Health Organization (WHO) and International Society of Urologic Pathology (ISUP) system assigns the grade of heterogeneous tumors based on the highest grade present in a tumor (of note, this system was republished in 2004 without major changes and has been adopted by the WHO) [26].

Despite this, there is no widely accepted definition or criteria to provide a quantitative estimate of size of the smallest focus required to "upgrade" a lesion. Arbitrary criteria used include the presence of high-grade histology in at least 5 to 10 percent being sufficient to upstage an otherwise low-grade lesion. Using a threshold of 5 percent of cells that are high-grade (defined as mixed grade), clinical outcomes in patients with mixed-grade tumors are similar to those with uniformly low-grade tumors and better than those with uniformly high-grade tumors [27]. As an example, in a study of 642 patients, a threshold of <10 percent of high-grade cells was used to define mixed-grade carcinomas. Progression-free and recurrence-free survival at five years for patients with mixed tumors was similar to those with low-grade tumors and significantly better than those with high-grade tumors [28].

However, the prognostic impact of lesions that do not meet these criteria is unknown. In addition, low-quality data suggest that pure high-grade papillary carcinoma has a different biologic behavior, including a higher risk of disease progression, than mixed high-grade and low-grade tumors [29]. Additional studies with long-term follow-up are needed to determine the prognostic impact of heterogenous lesions and to inform a consensus definition of the allowable extent or percentage cutoff when a high-grade focus is identified within a heterogeneous papillary urothelial neoplasm.

Urothelial papilloma — Urothelial papillomas are benign exophytic lesions characterized by simple nonbranching papillary fronds lined by normal-appearing urothelium lacking atypia. Urothelial papillomas account for 1 to 4 percent of bladder tumors; the male to female ratio is 1.9:1. Papillomas tend to occur in young patients and can be seen in children [30]. The typical presenting symptom is hematuria.

Most urothelial papillomas are located on the posterior or lateral walls of the bladder, close to the ureteral orifices or in the urethra. The lesions are usually relatively small and single, although multifocal tumors can be present. The cystoscopic appearance is identical to other low-grade papillary urothelial neoplasms.

Most papillomas have slender fibrovascular stalks (picture 12). Superficial umbrella cells are often prominent. Eosinophilic cytoplasm and prominent vacuolization are common findings. Urothelial atypia other than that in umbrella cells excludes the diagnosis of papilloma [31,32]. Mitoses are rare or absent.

One study found that urothelial papilloma and inverted papilloma are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial carcinomas [33]. (See 'Inverted papilloma' below.)

Urothelial papillomas rarely recur and progress to higher-grade disease [34]. As such, the clinical course is typically favorable.

Inverted papilloma — Inverted papillomas are benign tumors that originate from the overlying mucosa and grow into the stroma.

Inverted papillomas comprise less than 1 percent of urothelial neoplasms and are typically diagnosed in men in their 50s and 60s [35]. Hematuria or irritative symptoms are typical, although occasionally, these tumors produce symptoms of obstruction. Most inverted papillomas are solitary and can vary in size up to 8 cm. Approximately 70 percent occur in the bladder, typically in the trigone. Inverted papillomas can also occur in the ureter, renal pelvis, and urethra. Cystoscopically, these are sessile, pedunculated, or rarely, polypoid lesions with a smooth surface.

Inverted papillomas are characterized by anastomosing islands and cords of normal urothelial cells (picture 13). The base of the lesion is well circumscribed. Urothelial cells may invaginate extensively into the lamina propria but not into the muscular bladder wall. In contrast to other papillary urothelial neoplasms, the peripheral portion of the cords demonstrates palisading basal cells (picture 13). The stromal component is minimal and lacks inflammation. Foci of nonkeratinizing squamous metaplasia are often present. Cytologic atypia is minimal to absent [36-39]. Mitotic figures are rare and only seen at the periphery of the trabeculae.

If these criteria are strictly applied in establishing the diagnosis, inverted papillomas are benign and only infrequently recur [35,40]. In several studies, inverted papilloma is occasionally associated with a history of urothelial tumors and with a slight increased risk of concomitant or subsequent urothelial tumors [41,42].

PUNLMP — Papillary urothelial neoplasm of low malignant potential (PUNLMP) resembles urothelial papilloma but is distinguished from the latter by thickening of the urothelium. PUNLMP occurs predominantly in the lateral and posterior walls of the bladder, close to the ureteral orifices [3,6].

The papillae of PUNLMP are discrete, slender, and lined by a thickened, multilayered urothelium with minimal to absent cytologic atypia (picture 14). The cell density is increased compared with normal. The polarity and the umbrella cell layer are preserved (picture 14). Rare mitoses may be present but are confined to the basal layers. In contrast to noninvasive LGPUC, PUNLMP is characterized by a proliferation of monotonous, bland-appearing cells lacking enlarged hyperchromatic nuclei.

PUNLMP frequently recur (in 30 to 40 percent of patients). Progression to LGPUC and HGPUC is also frequently seen (29 percent), although stage progression and mortality due to the disease are exceedingly rare [43].

LGPUC — Noninvasive low-grade papillary urothelial carcinoma (LGPUC) is characterized by an orderly overall appearance of the urothelium lining papillary fronds, but with easily recognizable variation in architectural and cytologic atypia. LGPUC predominantly involves the posterior or lateral wall of the bladder. In the majority of the cases, the tumor is single, but two or more lesions can be present [3,6].

LGPUC is characterized by slender, frequently branching, papillary fronds with minimal fusion (picture 15). The nuclei are uniformly enlarged, with mild differences in shape, contour, and chromatin distribution (picture 15). Inconspicuous nucleoli may be present. Mitoses are infrequent and may occur at any level, but they usually are limited to the lower half. The finding of scattered hyperchromatic nuclei and more than rare mitotic figures best distinguishes LGPUC from PUNLMP.

If a tumor contains a high-grade component of more than 5 percent, the lesion should be classified as HGPUC. In the rare cases with a high-grade component comprising less than 5 percent, the lesion is diagnosed as LGPUC with a comment indicating the presence of focal high-grade tumor, the significance of which is unknown. Progression to invasion is rare, although recurrence is common [44]. Grade heterogeneity is not uncommonly encountered in papillary urothelial neoplasms. The WHO 2022 (fifth edition) recommends grading of heterogeneous tumor be based on the highest grade present in a tumor [4]. There is no current widely acceptable definition or criteria to provide a quantitative estimate of size of the smallest focus required to "upgrade" a lesion. While arbitrary criteria of ignoring less than 5 percent have been proposed, the prognostic impact of this criterion is unknown. From the few studies available, there is evidence to suggest that pure high-grade papillary carcinoma has a different biologic behavior or has higher disease progression than mixed high-grade and low-grade tumors. (See 'HGPUC' below.)

Additional studies with long-term follow-up are needed to determine the prognostic impact and define the allowable extent or percentage cutoff of high-grade focus in a heterogeneous papillary urothelial neoplasm [45].

Compared with PUNLMP, LGPUC have a higher rate of recurrence (48 to 77 versus 25 to 47 percent) and progression (3 to 11 versus 0 percent) [44].

HGPUC — Noninvasive high-grade papillary urothelial carcinoma (HGPUC) is characterized by a disorderly appearance of urothelium lining papillary fronds resulting from marked architectural and cytologic abnormalities. The endoscopic appearance varies from papillary to nodular/solid sessile lesion. Single or multiple lesions may be present.

The architectural disorder and cytologic atypia characteristic of HGPUC are easily recognizable at low magnification. The papillae are frequently fused and branching (picture 16). The thickness of the urothelium lining the papillae may vary considerably. The cells typically are not cohesive. The spectrum of cytologic pleomorphism ranges from moderate to marked (picture 16). There is marked variation in nuclear polarity, size, shape, and chromatin pattern, in contrast to LGPUC; nucleoli may be prominent. Mitotic figures frequently are seen at all levels of the urothelium (picture 16). Invasion into the lamina propria, both within the papillary cores and at the base of the lesions, is common and should be sought [3,6].

One analysis using next-generation sequencing suggested that detailed genetic analyses of HGT1 bladder tumors might be able to identify features that correlate with outcome, eg, high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures being associated with good outcome [46].

HGPUC has a high risk of progression; it is often associated with invasive disease at the time of presentation.

INVASIVE UROTHELIAL CARCINOMA — Invasive urothelial carcinoma is characterized by invasion into the lamina propria and into the muscularis propria (picture 17 and picture 3). Urothelial carcinomas with invasion into lamina propria is grouped with noninvasive carcinomas as non-muscle invasive bladder cancer (NMIBC) for management purposes.

Histologic subtypes and divergent differentiation — The World Health Organization (WHO) classifies invasive urothelial carcinoma into histologic subtypes and divergent differentiation, due to its propensity for multidirectional differentiation.

●Histologic subtypes – Histologic subtypes describe a distinct clinical or histomorphologic category within a certain type of neoplasm with prognostic significance. In the WHO 2022 (fifth edition), the term "subtype" has replaced "variant" [4]. The spectrum of microscopic forms of urothelial carcinoma has now been expanded to include several unusual histologic subtypes. Awareness of these unusual patterns may be critical to avoid diagnostic misinterpretations. (See 'Histologic subtypes' below.)

Accurate identification of distinct histology subtype is also important for management decisions, as some subtypes harbor genetic alterations that are amenable to targeted therapies. In general, high-grade papillary urothelial carcinoma (HGPUC) with subtype histology does not impact the prognosis. However, some tumor subtypes exhibit more aggressive biologic behavior and present with advanced disease; for example, such tumors have a higher risk for muscularis propria invasion and upstaging at radical cystectomy [47]. Furthermore, clinicians should always evaluate for metastatic disease in patients with bladder tumors with distinct subtype histology. However, with appropriate treatment, survival outcomes are not significantly different compared with those for tumors of pure urothelial carcinoma and similar stage [48-50]. Plasmacytoid, small cell, sarcomatoid, and micropapillary subtypes might be exceptions to this statement. The WHO 2022 (fifth edition) classification of urothelial carcinomas is shown in the table (table 2).

●Divergent differentiation – Urothelial carcinomas often exhibit divergent differentiation, or elements of squamous, glandular, or trophoblastic differentiation (divergent differentiation). Divergent differentiation is more common in high-grade and high-stage lesions [51-53]. (See 'Divergent differentiation' below.)

Histologic subtypes

Nested subtype — The nested subtype of urothelial carcinoma is an uncommon aggressive neoplasm with a deceptively benign appearance that closely resembles von Brunn nests infiltrating the lamina propria. Useful features in recognizing this lesion as malignant include the presence of muscle invasion, irregularly invading crowded nests, and the tendency for increasing atypia in the deeper portion of the lesion (picture 18). There is a marked male predominance. Despite treatment, 70 percent of cases are dead within three to four years of diagnosis [54,55].

Large nested subtype — In some cases, the invasive nests are medium to large, and they are often deeply invasive into detrusor muscles. The tumor cells are deceptively bland, similar to nested subtype urothelial carcinoma. These tumors are termed large nested urothelial carcinoma. They are clinically similar to other HGPUC [56].

Tubular and microcystic subtype — Urothelial carcinomas occasionally show a striking microcystic or tubular pattern (picture 19). Cysts can range from microscopic up to 1 to 2 mm in diameter and may contain necrotic material or pink pale secretions (picture 19). The cyst lining may be absent, flattened, or urothelial and may show differentiation toward mucinous cells. The cytology, by definition, is bland. The microcystic subtype of urothelial carcinoma often coexists with the nested subtype and is unrelated to primary adenocarcinoma of the bladder [57]. There is no apparent striking biologic significance associated with this pattern of urothelial carcinoma.

Micropapillary subtype — The micropapillary subtype of urothelial carcinoma is rare. These tumors typically are high grade, present at an advanced stage, and carry a poor prognosis [58-60]. There is a male predominance, and the median age of diagnosis is approximately 70 years. Micropapillary urothelial carcinomas are tumors that harbor at least 10 percent of a micropapillary component, as measured by semiquantitative (visual) estimation on histology [61].

This rare subtype of urothelial carcinoma resembles serous carcinoma of the ovary. The surface of the tumors shows slender, delicate papillary and villiform processes, often without a central vascular core (picture 20). The invasive component is characterized by multiple minute nests of cells or delicate papillae contained within tissue retraction spaces, simulating lymphatic spaces.

To increase interobserver diagnostic reproducibility, the criteria have been refined. The features that have the highest association with an accurate diagnosis of invasive micropapillary urothelial carcinoma include the presence of multiple small nests without vascular cores within the same retracted lacunar spaces, extensive retraction, and back-to-back lacunae. Other important diagnostic features are peripherally oriented nuclei with high-grade atypia and intracytoplasmic vacuoles with distortion of the nuclear contour (ring forms) [62].

Invasive micropapillary urothelial carcinoma invariably invades muscle muscularis propria (picture 20) and has a high incidence of metastasis. The percentage of the micropapillary component has been shown to be a significant adverse prognostic factor [63]. A high frequency of activating extracellular domain human epidermal growth factor 2 (ERBB2 [HER2]) mutation was reported in this tumor, raising the possibility of targeted treatment using ERBB2 inhibitors [64].

Lymphoepithelioma-like subtype — A few cases of urothelial carcinoma resembling lymphoepithelioma of the nasopharynx have been reported (picture 21). These tumors show a male predominance and tend to occur in late adulthood. Unlike lymphoepithelioma of the nasopharynx, association with Epstein-Barr virus (EBV) infection has not been documented, either by immunohistochemistry or by in situ hybridization [65-67].

The epithelial tumor cells are large and arranged in syncytia with individual undifferentiated neoplastic cells with indistinct cell borders, pleomorphic vesicular nuclei, prominent nucleoli, and numerous mitoses. The background consists of a prominent lymphoid infiltrate. The differential diagnosis includes malignant lymphoma, poorly differentiated urothelial carcinoma with lymphoid stroma, and poorly differentiated squamous cell carcinoma. In limited biopsy material, florid chronic cystitis may be confused with lymphoepithelioma-like carcinoma.

When only focal lymphoepithelioma-like carcinoma is present, the proportion of lymphoepithelioma-like carcinoma should be reported; the behavior of such tumors is similar to conventional urothelial carcinoma of the same grade and stage [68]. The lymphoepithelioma-like component is responsive to chemotherapy [69,70]. This tumor has a basal molecular type and increased programmed cell death ligand 1 (PD-L1) expression, a target for potential therapy with checkpoint inhibitor immunotherapy [71]. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

Plasmacytoid subtype — In the lymphoma-like and plasmacytoid subtype of urothelial carcinoma, malignant cells resemble those of malignant lymphoma or plasmacytoma (picture 22).

The histologic features of this tumor subtype are characterized by the presence of discohesive, oval to round malignant cells in a loose or myxoid stroma (picture 22). The tumor cells have eccentrically placed nuclei and abundant eosinophilic cytoplasm. In addition to the plasmacytoid morphology, a variable number of single cells with vacuoles imparting an appearance of signet ring cells, with or without intracytoplasmic mucin, can be seen. Some cases that were reported in the literature as signet ring cell carcinoma of the bladder, specifically those not associated with extracellular mucin, would now be classified as plasmacytoid carcinoma (WHO 2022) [4]. These tumors are not associated with extracellular mucin production, unlike what is seen in mucinous adenocarcinoma with signet ring cells. The tumor cells express the usual plasma cell marker syndecan-1 (CD138), but they also express urothelial markers such as GATA binding protein 3 (GATA3). E-cadherin is often completely lost. The differential diagnosis includes lymphoma (plasmacytoid type), multiple myeloma, malignant melanoma, metastatic carcinoma, paraganglioma, neuroendocrine carcinoma, and rhabdomyosarcoma. The prognosis of those tumors is poor and related to the pathologic stage [72-76]. Most patients have locally advanced disease at presentation and are at increased risk for intraperitoneal spread, which makes frozen section interpretation of ureteral or urethral margins challenging [77]. Progression to metastatic disease is frequent, and survival tends to be short.

Plasmacytoid bladder cancer is an aggressive histologic subtype with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, truncating somatic alterations in the CDH1 gene occur in 84 percent of plasmacytoid carcinomas and are specific to this histologic subtype [78].

Sarcomatoid subtype — The term sarcomatoid subtype of urothelial carcinoma should be used for all biphasic malignant neoplasms exhibiting morphologic and/or immunohistochemical evidence of both epithelial and mesenchymal differentiation [79]. Sarcomatoid urothelial carcinoma is rare, as less than one percent of all bladder carcinomas are sarcomatoid carcinomas or carcinosarcomas. Aside from sarcomatoid carcinoma, other rare histologic subtypes of infiltrating urothelial carcinoma include giant-cell, poorly differentiated, lipid-rich, and clear-cell types (table 2).

Molecular studies strongly argue for a monoclonal origin of both the epithelial and mesenchymal components in sarcomatoid carcinoma and carcinosarcoma, and progression from basal subtype of conventional urothelial carcinoma with enrichment of TP53, RB1, and PIK3CA mutations [80]. The mesenchymal component most frequently observed is an undifferentiated, high-grade spindle cell neoplasm. The most common heterologous element is osteosarcoma, followed by chondrosarcoma (picture 23), rhabdomyosarcoma, and leiomyosarcoma.

Sarcomatoid carcinoma has a poor prognosis [81-86]. In observational cohort studies of patients with sarcomatoid carcinoma, median disease-specific and overall survival were 16 and 18 months, respectively [79,87]. Sarcomatoid carcinoma often presents with advanced disease, and nodal and distant organ metastases at diagnosis are common [86,88]. While aggressive treatment improves outcomes, the role of multimodality therapy is unclear. This tumor has increased PD-L1 expression and may benefit from immune checkpoint inhibitors [80]. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder" and "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

Divergent differentiation

Squamous divergent differentiation — Squamous differentiation is present in approximately 20 percent of urothelial carcinomas of the bladder and 44 percent of tumors of the renal pelvis (picture 24). True squamous differentiation requires evidence of keratinization, intercellular bridges, or both and should be obvious on routine hematoxylin and eosin (H&E) staining. The presence of squamous differentiation does not seem to affect prognosis, although these tumors may be less likely to respond to chemotherapy and radiation treatment [3,52], although more recent studies have challenged this notion [89].

Glandular divergent differentiation — Glandular differentiation is present in approximately 6 percent of cases and is defined as the presence of true glandular spaces within the urothelial component of the tumor (picture 25). It may consist of tubular or enteric glands with mucin secretions. Intracytoplasmic mucin does not indicate glandular differentiation. A pure adenocarcinoma should always raise suspicion for metastatic or direct extension of an adenocarcinoma from another primary site, such as the colorectum, endocervix, uterus, or prostate. The presence of glandular differentiation and mucin positivity in urothelial carcinomas does not affect the prognosis for any given stage [3,52]. Its impact on therapy remains unclear [89].

Trophoblastic divergent differentiation — Trophoblastic differentiation is very rare and can be indistinguishable from choriocarcinoma.

Differential diagnosis — Specific problems that can arise in the differential diagnosis of urothelial carcinoma include the following:

●The nested subtype of urothelial carcinoma can be difficult to differentiate from von Brunn nests. (See 'Nested subtype' above.)

●In limited crushed biopsies, florid chronic cystitis may be confused with lymphoepithelioma-like carcinoma. (See 'Lymphoepithelioma-like subtype' above.)

●The glandular component of urothelial carcinoma with glandular divergent differentiation in rare cases raises the possibility of a nephrogenic adenoma.

●A poorly differentiated bladder cancer in a male should raise the possibility of prostate carcinoma, particularly if the specimen is obtained from the trigone or bladder neck. Immunoperoxidase staining may be very helpful. Positive staining for GATA3, high molecular weight cytokeratin, p63, and both cytokeratin 7 (CK7) and even more cytokeratin 20 (CK20) favors the diagnosis of urothelial carcinoma (picture 26), while reactivity for prostate markers, including prostate-specific antigen (PSA), prostatic-specific acid phosphatase (PSAP), prostate-specific membrane antigen (PSMA), prostein (P501S), and NKX3.1, favors the diagnosis of prostate carcinoma.

SQUAMOUS CELL CARCINOMA — Squamous cell carcinomas (SCCs) of the bladder are derived from the urothelium and characterized by a pure squamous cell phenotype. In North America and Europe, SCCs comprise less than 5 percent of bladder cancers. In contrast, bladder cancer is significantly more common overall, and SCCs comprise approximately 75 percent of cases in areas of the world where Schistosoma haematobium infection is endemic. (See "Non-urothelial bladder cancer", section on 'Squamous cell carcinoma' and "Non-urothelial bladder cancer", section on 'Schistosomal bladder cancer'.)

Pathologic findings — Most SCCs are bulky, polypoid, solid, necrotic masses that fill the bladder lumen. The presence of necrotic material and keratin debris on the surface is typical.

SCC of the bladder is morphologically indistinguishable from SCC of other sites. The invasive component may be well differentiated, with islands of squamous cells demonstrating keratinization, prominent intercellular bridges, and minimal nuclear pleomorphism (picture 27). Poorly differentiated tumors are characterized by marked nuclear pleomorphism and only focal evidence of squamous differentiation. The presence of keratinizing squamous metaplasia in the adjacent flat epithelium supports the diagnosis of SCC [90]. Most studies show that human papillomavirus has a very limited role in its pathogenesis [91,92].

SCC often presents at an advanced stage. However, radical cystectomy with lymph node dissection appears to offer a significant benefit in survival in a subset of patients [93].

ADENOCARCINOMA — Adenocarcinoma of the bladder is characterized histologically by a pure glandular phenotype. These tumors most often are derived from the urothelium of the bladder ("nonurachal adenocarcinoma") and less often arise from a remnant of the urachus ("urachal adenocarcinoma") [94-96].

Nonurachal adenocarcinoma — Nonurachal adenocarcinomas typically occur in the bladder base or dome, but they can appear anywhere in the bladder (picture 28). (See "Non-urothelial bladder cancer", section on 'Non-urachal adenocarcinoma'.)

The urothelial mucosa is replaced by glandular structures with definite nuclear atypia. Based on histology, the adenocarcinoma of the bladder is subdivided into various subtypes, including mucinous (24 percent), enteric (19 percent), signet ring cell (17 percent), and mixed (13 percent); in 28 percent of cases, no specific subtype is specified. The enteric type resembles adenocarcinoma of the colon. Tumors with abundant mucin and tumor cells floating within the mucin are classified as mucinous or colloid type. Adenocarcinoma in situ may be found alone or in combination with invasive adenocarcinoma [3,94].

Urachal adenocarcinoma — Urachal adenocarcinoma is derived from remnants of the urachus and, thus, typically involves the bladder dome [97-101]. Although the tumor may be discrete, it can involve urachal remnants, forming a large mass in the anterior abdominal wall. Calcified mucinous lesions may be identified on a plain radiograph film of the abdomen. (See "Non-urothelial bladder cancer", section on 'Urachal adenocarcinoma'.)

Clinical correlation is required to differentiate urachal from nonurachal adenocarcinoma of the bladder. The criteria for diagnosing urachal adenocarcinoma include:

●Location in the dome or anterior wall of the bladder

●Sharp demarcation between the tumor and the normal surface epithelium

●Lack of an in situ adenocarcinoma component

●Adjacent mucosa lacks prominent cystitis glandularis

●Bulk of the tumor is in the bladder wall rather than luminal

●Exclusion of primary adenocarcinoma located elsewhere that has spread secondarily to the bladder

Differential diagnosis — The differential diagnosis of bladder adenocarcinoma includes metastatic disease or direct extension, commonly from either the colorectum or prostate. Secondary involvement is more common than a primary lesion [102-104]. (See 'Metastatic cancers from other sites' below.)

The immunohistochemical profile of bladder adenocarcinoma is variable and is similar to that of adenocarcinoma of the colon; therefore, it is not helpful for the diagnosis in most cases. Cytokeratin 20 (CK20) is positive in most bladder adenocarcinomas, while cytokeratin 7 (CK7) positivity is variable. The most common molecular alterations that occur in both bladder and colon adenocarcinomas include TP53, APC (in the Wnt pathway), and KRAS (in the MAPK pathway) mutations [96].

Immunoreactivity for beta-catenin has been detected in the majority of colorectal adenocarcinomas secondarily involving the bladder, but not in primary bladder tumors.

SMALL CELL CARCINOMA — Small cell carcinoma of the bladder is a malignant, poorly differentiated neuroendocrine neoplasm that mimics small cell carcinoma of the lung. A molecular study has indicated that small cell carcinoma and urothelial carcinoma are derived from the same clonal population [105]. Therefore, most authors consider small cell carcinoma of the urinary bladder to be a special subtype of urothelial carcinoma. Small cell carcinoma of the urinary bladder is characterized by an aggressive clinical course and poor prognosis. (See "Small cell carcinoma of the bladder".)

Small cell carcinomas sometimes present as an isolated polypoid or nodular mass, but they can extensively infiltrate the bladder wall. The dome and lateral walls of the bladder are the most frequent locations, although they arise in a bladder diverticulum in approximately 5 percent of cases.

The cells are small and uniform with scant cytoplasm, nuclear molding, and nuclei with finely stippled chromatin and inconspicuous nucleoli. Mitoses may be frequent, and apoptosis is common (picture 29). Approximately one-half of small cell carcinomas are associated with areas of urothelial carcinoma, and they are associated less frequently squamous cell carcinoma (picture 29) and/or adenocarcinoma.

Most small cell carcinomas express synaptophysin, neuronal-specific enolase (NSE), and CD56; chromogranin is seen in approximately one-third. Thyroid transcription factor-1 (TTF-1) is frequently positive in bladder small cell carcinoma. The differential diagnosis includes metastatic small cell carcinoma from another site, malignant lymphoma, lymphoepithelioma-like carcinoma, plasmacytoid carcinoma, and poorly differentiated urothelial carcinoma. The presence of TMPRSS2-ERG gene fusion indicates prostatic origin, while the presence of TERT promoter mutations suggests a urothelial origin [106,107].

METASTATIC CANCERS FROM OTHER SITES — The urinary bladder may be involved by direct extension of tumors from adjacent sites (secondary involvement) or by metastases from a distant site [108,109]. Secondary tumors account for approximately 15 percent of malignant bladder tumors. Cancers extending from the colon or rectum (picture 30), prostate, and uterine cervix are most common and are most frequently identified in the bladder neck and trigone. Metastatic lesions from melanomas and stomach, breast, and lung cancers are less frequent.

The lesions may mimic a primary urothelial carcinoma or may manifest as multiple submucosal nodules. Multifocality, prominent vascular involvement, absence of mucosal abnormality, and unusual morphology should raise suspicion of metastatic tumors. Tumors with less characteristic histologic features, such as poorly or undifferentiated high-grade tumors, require immunohistochemical workup.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Bladder cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Bladder cancer diagnosis and staging (Beyond the Basics)" and "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)" and "Patient education: Bladder cancer treatment; non-muscle invasive (superficial) cancer (Beyond the Basics)")

SUMMARY

●Pathologic classification – Bladder tumors are classified according to the World Health Organization (WHO) 2022 (fifth edition). Within the WHO system, urothelial cancer is classified as either low grade or high grade based upon the degree of nuclear anaplasia and architectural abnormalities. (See 'Classification' above.)

●Staging – The most important element in the pathologic staging of urothelial cancer is the extent of invasion into deeper layers of the bladder and surrounding tissues. This information has major implications for both prognosis and treatment and is incorporated into the Tumor, Nodes, Metastasis (TNM) staging system. (See 'Pathologic tumor staging' above and "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Staging'.)

●Common bladder histologies – The most common bladder tumor histologies are urothelial, squamous cell, and adenocarcinoma:

•Urothelial carcinoma – Invasive urothelial carcinoma is characterized by invasion into the muscularis propria. Urothelial carcinoma is the most common form of bladder cancer in the United States and Europe. (See 'Invasive urothelial carcinoma' above.)

•Squamous cell carcinoma – Squamous cell carcinomas of the bladder are derived from the urothelium and are characterized by a pure squamous cell phenotype. In North America and Europe, squamous cell carcinomas comprise less than 5 percent of bladder cancers. (See 'Squamous cell carcinoma' above and "Non-urothelial bladder cancer".)

•Adenocarcinoma – Adenocarcinoma of the bladder is characterized histologically by a pure glandular phenotype. These tumors, which constitute approximately 2 percent of bladder cancers, most often are derived from the urothelium of the bladder and less often arise from a remnant of the urachus. (See 'Adenocarcinoma' above and "Non-urothelial bladder cancer".)