Neoplasms of the Urinary Bladder

Reactive Atypia

Reactive atypia is characterized by mild nuclear abnormalities occurring in acutely or chronically inflamed urothelium. In most cases there is a history of cystitis, instrumentation, infection, stones, or previous therapy. The epithelium may or may not be thickened in reactive atypia. The cells are often larger than normal, with more abundant cytoplasm than normal urothelial cells ( Fig. 6.10 ). These features occasionally impart a squamoid appearance. Nuclei are uniformly enlarged, vesicular, and may have prominent, usually centrally located nucleoli. Mitotic figures may be frequent but always occur in the lower epithelial layers ( Table 6.2 ). Inflammatory cells occupying the lamina propria and infiltrating into the urothelium are invariably present. CK20, CD44, p53, and p16 immunohistochemical stains may be particularly useful from a differential diagnosis perspective ( Table 6.3 ) (see Urothelial Dysplasia section).

Atypia of Unknown Significance

The term atypia of unknown significance was introduced by the International Society of Urological Pathology (ISUP) consensus group to describe lesions in which the pathologist was uncertain whether the changes were reactive or preneoplastic. Atypia of unknown significance is characterized by nuclear changes similar to those seen in reactive atypia. However, the degree of nuclear pleomorphism and hyperchromasia is greater than in reactive atypia, and dysplasia cannot be ruled out. Inflammation in the lamina propria with urothelial infiltration is often present. However, the cellular changes seem to be disproportionate to the degree of inflammation. Atypia of unknown significance is often seen in patients with a previous diagnosis of urothelial neoplasia. Progression to urothelial carcinoma has not been documented. No evidence currently supports a premalignant nature of such lesions. The clinical outcome of patients with atypia of unknown significance is identical to that of patients with reactive atypia. The utility of creating this diagnostic category has been questioned, and the use of the designation “atypia of unknown significance” is discouraged.

Primary Dysplasia

Primary dysplasia occurs in the absence of other urothelial tumors. Its prevalence in the general population is unknown due to lack of large-scale screening studies. In an autopsy series of 313 patients without gross lesions, urothelial dysplasia was present in 6.8% of males and 5.7% of females. Only a few studies provide clinical information on patients with primary dysplasia. These patients are predominantly middle-aged men with irritative symptoms with or without hematuria. The lesion has a predilection for posterior wall location. Dysplasia is not cystoscopically visible, although occasionally the urothelium may appear raised and irregular or mildly erythematous. It is estimated that de novo (primary) dysplasia progresses to bladder neoplasia in 14% to 19% of cases. Using modern criteria for urothelial dysplasia, Cheng et al. found a 19% progression rate in 36 patients with isolated urothelial dysplasia during a mean follow-up of 8.2 years. A similar progression rate (15%) was found in a different cohort of patients.

Secondary Dysplasia

Secondary dysplasia is seen in patients with a history of bladder neoplasia. The incidence of dysplasia in patients with established bladder neoplasia varies from 22% to 86% and approaches 100% in patients with invasive carcinoma. As many as 24% of random biopsies from patients with stage Ta and T1 carcinomas show epithelial abnormalities that include dysplasia and carcinoma in situ. The presence of urothelial dysplasia indicates urothelial instability and is a harbinger of recurrence and progression. Recurrence rate was 73% of patients with superficial neoplasia and concomitant dysplasia compared with 43% without coexisting dysplasia. Of the 30% of patients with superficial urothelial carcinoma who experienced muscle invasive cancer within 5 years after the initial diagnosis, most had dysplasia or carcinoma in situ adjacent to the primary tumor. Of the patients with dysplasia elsewhere in the bladder mucosa, 36% eventually had muscle-invasive tumors, whereas only 7% of patients with normal urothelium in adjacent biopsies subsequently had muscle-invasive cancer.

Microscopic Pathology

Urothelial carcinoma in situ is characterized by flat, disordered proliferation of urothelial cells with marked cytologic abnormalities ( Fig. 6.18 ). The morphologic diagnosis of carcinoma in situ requires severe cytologic atypia (anaplasia). Full-thickness change is not required, which may range from one cell layer to the thickness of hyperplasia (greater than seven cells). Superficial (umbrella) cells may or may not be present. Marked disorganization of cells is characteristic, with loss of cellular polarity and decreased cellular cohesiveness. The tumor cells tend to be large and pleomorphic, with moderate to abundant cytoplasm. Nevertheless, the cells of carcinoma in situ are sometimes small with a high nuclear-to-cytoplasmic ratio. The chromatin tends to be coarse and clumped. Nucleoli may be multiple, and they are large and prominent in at least some of the cells. Mitotic figures, which are often atypical, are seen in the uppermost layers of the urothelium. The adjacent mucosa often contains lesser degrees of cytologic abnormality. Tissue edema, vascular ectasia, and proliferation of small capillaries are frequently observed in the lamina propria ( Fig. 6.18 ).

An immunohistochemical panel, consisting of CK20, CD44, p53, and Ki67, may be helpful in differential diagnosis. Carcinoma in situ shows intense CK20 and p53 positivity in most malignant cells. Increased Ki67 labeling is noted in carcinoma in situ, but this can be seen also in reactive atypia of the urothelium, thus limiting its usefulness in practice. The neoplastic cells are uniformly negative for CD44 immunostaining. In contrast, CK20 staining shows patchy cytoplasmic immunoreactivity only in the superficial umbrella cell layer, and CD44 stains only the basal cells in the adjacent normal urothelium. p16 and racemase have been reported as variably positive in urothelial carcinoma in situ and negative to weak and focal in reactive urothelium.

Histologic Variants of Carcinoma In Situ

Several morphologic variants and growth patterns of carcinoma in situ have been recognized over the years ( Figs. 6.19 to 6.21 ; Table 6.4 ). Variations in subtype of urothelial carcinoma in situ do not alter patient prognosis. Although it is not necessary to mention these specific growth patterns or morphologic variants in the surgical pathology report, awareness of the histologic diversity of carcinoma in situ may aid in the diagnosis of this therapeutically and biologically important lesion. These lesions may be associated with microinvasion, sometimes clinically unsuspected and histologically subtle.

Carcinoma In Situ With Squamous or Glandular Differentiation

Rare cases of carcinoma in situ may exhibit squamous differentiation characterized by intercellular bridges. Carcinoma in situ with squamous features is most often observed in association with urothelial carcinoma showing extensive squamous differentiation elsewhere in the bladder ( Fig. 6.21 A). A much less frequently encountered pattern is carcinoma in situ with morphologic and immunohistochemical evidence of glandular differentiation ( Fig. 6.21 B). Some authors refer to this as adenocarcinoma in situ; such lesions may show papillary, cribriform, or flat morphology. Carcinoma in situ involving von Brunn nests ( Fig. 6.22 ), cystitis glandularis, or cystitis cystica may be difficult to distinguish from adenocarcinoma in situ in the absence of concurrent invasive adenocarcinoma. A recent report based on 25 cases of urothelial carcinoma in situ with glandular differentiation showed high Ki67 index and p53 accumulation, high nuclear and cytoplasmic p16 expression, and diffuse PTEN expression, a phenotype that also characterized concurrent conventional carcinoma in situ. MUC5A, MUC2, CK20, and HER2 were positive in all 25 cases of urothelial carcinoma in situ with glandular differentiation, and CDX2 was present in 19 cases; MUC1, CK7, or 34βE12 was focally present in 21, 19, and 18 cases, respectively. The authors concluded that urothelial carcinoma in situ with glandular differentiation is a variant of carcinoma in situ that follows the natural history of conventional urothelial carcinoma in situ. The immunophenotype suggests urothelial origin with the expression of MUC5A and CDX2 as signature for glandular differentiation.

Carcinoma In Situ With Micropapillary Pattern

On rare occasions, urothelial carcinoma in situ may have a micropapillary architecture, characterized by a flat surface with micropapillae (pseudopapillae without vascular cores) lined by markedly atypical cells ( Fig. 6.23 ). This morphology is seen in the context of conventional urothelial carcinoma and seems to be unrelated to invasive micropapillary urothelial carcinoma.

Carcinoma In Situ With Microinvasion

Carcinoma in situ with microinvasion was initially defined by Farrow and Utz as invasion into the lamina propria to a depth ≤ 5 mm from the basement membrane. At a recent consensus it was suggested that cases with more than 20 cells measured from the stroma-epithelial interface should be classified as fully invasive. Microinvasion appears as direct extension in cords (tentacular), single cells, or single cells and clusters of cells ( Fig. 6.24 ). The clusters of cells may have retraction artifact that mimics vascular invasion. Stromal response may be present, but in most cases it is absent. In cases with a prominent stromal inflammatory response the invasive neoplastic cells may be interspersed among lymphocytes, making them inconspicuous. In these circumstances, immunohistochemical staining with antibodies against CKs, such as AE1/AE3, highlights the invading cells.

Epidemiology and Risk Factors

Bladder cancer is the seventh most common cancer worldwide, accounting for an estimated 330,380 new cases globally in 2012. There are significant variations in incidence, morbidity, recurrence, progression, and mortality rates of bladder cancer in different countries and ethnicity groups. African American men have a much lower incidence of bladder cancer, but their mortality rates are similar to Caucasians. Bladder cancer occurs two to five times more frequently in men than in women. This has been attributed to different smoking and occupational exposure between men and women.

Multiple risk factors have been linked to bladder cancer. Exogenous factors, such as tobacco smoking, occupational risk, and lifestyle exposure to carcinogens, all play important roles. Smokers have two to four times the risk for urothelial cancer as the general population, and heavy smokers have five times the risk. It is estimated that 20 years of smoking is needed for development of bladder cancer, and the probability of this event is directly correlated with the lifetime number of cigarettes consumed. The relative risk for active smokers experiencing development of bladder cancer compared with never smokers is 3:1 and for previous smokers is 1.9:1. Although the exact mechanism by which tobacco causes bladder cancer is not known, many known carcinogens in cigarette smoke, such as acrolein, 4-amino-biphenyl, arylamine, and oxygen free radicals, have been implicated. Furthermore, increased duration, intensity of tobacco consumption, and degree of inhalation significantly contribute to cancer development. The beneficial effects of smoking cessation, in contrast, include an almost immediate decline in risk for bladder cancer. Continued smokers have a worse recurrence-free survival than those who quit at the time of diagnosis. Ex-smokers and current smokers also have a significantly shorter recurrence-free survival after treatment for bladder cancer.

Occupational exposure to aniline dyes and aromatic amines such as 2-naphthylamine and benzidine is the second most prevalent risk factor for bladder cancer. Benzidine, the most carcinogenic aromatic amine, is used in dye production and as a hardener in the rubber industry. The degree of carcinogenesis caused by occupational exposure varies with the degree of industrialization, but in heavily industrialized nations, occupational exposure may account for up to one-fourth of all urothelial cancers. The latency period between exposure and tumor development is usually prolonged. Occupational bladder cancer has also been observed in gas workers, painters, and hairdressers. Nutrition may also play a role. Vitamin A supplementation apparently reduces the risk for bladder cancer, whereas fried food and fat ingestion increases the risk. A high fluid intake reduced the risk for bladder cancer in one study, but this remains controversial. Epidemiologic studies in Taiwan and Chile have shown an increased risk for urothelial cancer in people whose drinking water has a high content of arsenic. Other water contaminants with putative toxic effects on urothelium are also being actively investigated.

Additional factors implicated in the development and progression of bladder cancer include analgesic use, urinary tract infections (bacterial, parasitic, fungal, or viral), urinary lithiasis, pelvic radiation, and chemotherapeutic agents such as cyclophosphamide. Although caffeine ingestion has been implicated as a risk factor for bladder cancer, risk estimates for this association decrease after controlling for concomitant tobacco use. Similarly, saccharin-containing artificial sweeteners have induced bladder neoplasia in rats, but human epidemiologic studies have failed to establish this relationship in humans. There is a relationship between the parasite Bilharzia (schistosomiasis) and squamous cell cancer in the bladder, more frequently seen in the Middle East, where waterborne flatworms are endemic.

Signs and Symptoms

The majority of patients with bladder cancer present with hematuria. Approximately 20% of patients being evaluated for gross hematuria will subsequently be diagnosed with bladder cancer. Similarly, of patients presenting with microscopic hematuria, up to 10% will be diagnosed with bladder cancer. A significant proportion of patients also have irritative voiding symptoms including urgency, frequency, and dysuria; their symptoms are mistakenly attributed to urinary tract infection.

The initial evaluation and management for patients with suspected bladder cancer involve cystoscopic evaluation of the bladder and prostatic urethra for mucosal lesions. Small lesions and flat lesions worrisome for carcinoma in situ can be sampled with cold-cup biopsy forceps, whereas larger suspicious lesions are resected transurethrally as completely as possible. Transurethral resections and biopsies should include muscularis propria if possible. Tumor recurrence is a significant risk factor for cancer progression. New guidelines of the International Consultation on Urological Diseases were recently published. Advances in multiparametric magnetic resonance imaging are likely to change the clinical approach to bladder cancer diagnosis in years to come.

Field Cancerization and Tumor Multicentricity

Development of multifocal tumors in the same patient, either synchronous or metachronous, is a common characteristic of urothelial malignancy ( Fig. 6.25 ). Multiple coexisting tumors have often arisen before clinical symptoms are apparent. The separate tumors may or may not share a similar histology. Two theories have been proposed to explain the frequency of urothelial tumor multifocality. The monoclonal theory suggests that the multiple tumors arise from a single transformed cell that proliferates and spreads throughout the urothelium either by intraluminal implantation or by intraepithelial migration. The field effect theory explains tumor multifocality as a development secondary to field cancerization effect. Chemical carcinogens cause independent transforming genetic alterations at different sites in the urothelial lining, leading to multiple genetically unrelated tumors.

The issue of monoclonal versus oligoclonal origin of multifocal urothelial carcinomas is clinically important for understanding patterns of early tumor development when planning treatment and surgical strategies, and when molecular diagnostic techniques are used in the detection of recurrent or residual disease. The cause of multifocality also influences test design for genetic detection of recurrent or residual tumor cells in posttreatment urine samples. No consensus currently exists concerning which theory is most important in the development of multifocal urothelial carcinoma. Many studies have suggested a monoclonal origin for multifocal urothelial carcinoma, but other studies have shown an independent origin for some multicentric urothelial tumors using similar methods. A recent study suggests that both field cancerization and monoclonal tumor spread may coexist in the same patient. Molecular evidence supporting an oligoclonal origin for multifocal urothelial carcinomas in the majority of cases was found, consistent with the field cancerization theory for multicentric urothelial carcinogenesis.

Field cancerization, which is an important cause of multicentric squamous cell carcinomas of the head and neck, postulates that multifocal urothelial carcinomas arise in the same way. In the field cancerization process, simultaneous or sequential tumors result from numerous independent mutational events at different sites in the urothelial tract. These independent transformations are a consequence of external cancer-causing influences. In support of the field effect theory is the frequent finding of genetic instability in normal-appearing bladder mucosa in patients with bladder cancer in the adjacent urothelium. Premalignant changes, such as dysplasia or carcinoma in situ, often are found in urothelial mucosa away from an invasive bladder cancer ( Fig. 6.26 ). Many genetic comparisons and mapping of atypia in cystectomy specimens have emphasized the role of oligoclonality and field cancerization in the development of multifocal urothelial tumors, especially in early-stage disease. Because the monoclonal and oligoclonal theories to explain urothelial tumor multifocality are not mutually exclusive, various theories have been proposed to combine the two mechanisms. It has been suggested that oligoclonality is more common in early lesions with progression to higher stages leading to the overgrowth of one clone and pseudomonoclonality. Thus early or preneoplastic lesions may arise independently with a specific clone undergoing malignant transformation, which subsequently spreads through the urothelium by either an intraluminal or intraepithelial dissemination. Whereas tumor multifocality seems to be an oligoclonal phenomenon in the majority of cases, there is undeniable support for the monoclonal hypothesis in some cases.

Molecular Taxonomy

Recent studies have sought to better define the molecular characteristics of urothelial carcinoma using broad-based genomic and transcriptomic approaches to differentiate distinct molecular classes of urothelial carcinoma. Historically, a dual-pathway model was developed in which noninvasive lesions (low-grade papillary Ta) are associated with frequent HRAS and FGFR3 alterations, and frequent TP53 and RB alterations characterize high-grade urothelial carcinomas. The findings in more recent studies suggest that this model may somewhat oversimplify the genomic complexity of urothelial cancer. Based on complex gene expression studies, the number of bladder cancer subtypes has been reappraised. One group of investigators identified five categories of tumors that demonstrated differential expression of CK, FGFR3 mutational status, cell adhesion gene profiles, and cell-cycle regulator gene profiles. These five categories include the so-called urobasal A, urobasal B, genomically unstable, squamous cell carcinoma–like, and infiltrated. Three major subtypes—urobasal, genomically unstable, and squamous cell carcinoma–like—can also be distinguished based on immunohistochemical profile, enabling identification of such cases in daily pathology practice.

A simplified classification system was recently published that divides urothelial carcinoma into “luminal” and “basal-like” categories. Whereas luminal (CK20 ⁺ , GATA3 ⁺ ) carcinomas expressed genes frequently associated with superficial umbrella cells and appeared similar to superficial papillary tumors, basal-like (CK5/6 ⁺ , CD44 ⁺ , CK20 ^- ) carcinomas expressed genes more characteristic of urothelial basal cells and also had a significantly worse prognosis but may be more responsive to neoadjuvant chemotherapy. In addition to the luminal and basal-like tumors, some classification systems have identified a third group of tumors, “p53-like,” which are associated with resistance to neoadjuvant chemotherapy.

Immune Checkpoint Inhibitor Therapy

Immunotherapeutic strategies to target the programmed cell death-1/ programmed cell death-1 ligand (PD-1/PD-L1) axis represent a breakthrough in the treatment of bladder cancer. These agents act on T-cell–inhibitory pathways, unleashing profound antitumor effects. Drug options for patients with bladder cancer now include atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab. The suggested cutoffs for evaluating available immunohistochemical markers associated with a specific drug are summarized in Table 6.5 .

Histologic Grading According to the 1973 World Health Organization Classification

Histologic grading is one of the most important prognostic factors in bladder cancer. The first widely accepted grading system for papillary urothelial neoplasms was the 1973 WHO classification system, which divided urothelial tumors into four categories: papilloma, grade 1 carcinoma, grade 2 carcinoma, and grade 3 carcinoma. Histologic grading is based on the degree of cellular anaplasia, with grade 1 tumors having the least degree of anaplasia compatible with a diagnosis of malignancy, grade 3 tumors having the most severe degree of anaplasia, and grade 2 tumors having an intermediate degree of cellular anaplasia ( Fig. 6.27 ). Anaplasia is further defined by the authors of the 1973 WHO classification as increased cellularity, nuclear crowding, disturbed cellular polarity, failure of differentiation from the base to the surface, nuclear polymorphism, irregular cell size, variations in nuclear shape and chromatin pattern, displaced or abnormal mitotic figures, and giant cells.

The 1973 WHO histologic grading of bladder cancer is one of most successful grading systems among all organ sites and has been validated since its introduction three decades ago. The 1973 WHO grading system has been accepted by pathologists, urologists, oncologists, and cancer registrars in the United States and elsewhere. An enormous amount of data have been accumulated using this system in studies of the morphologic properties, clinical behavior, treatment, and follow-up of urothelial tumors. Because of its relative simplicity and its well-documented powerful predictive value, it has been well accepted by urologists and used globally for several decades in making clinical decisions for management of patients with urothelial cancer.

A recent systematic review surveyed 3593 published articles and compared the prognostic performance and reproducibility of the 1973 WHO and 2004/2016 WHO grading systems. They found that higher tumor grade in both classifications was associated with higher disease progression and recurrence rates. Progression rates in grade 1 patients were similar to those in low-grade patients. However, the 1973 system identifies more aggressive tumors. Reproducibility of the 2004/2016 system was marginally better than that of the 1973 system. The authors could not confirm that the 2004/2016 classification outperforms the 1973 classification in prediction of recurrence and progression.

The European Association of Urology (EAU) guidelines on non–muscle-invasive urothelial carcinoma of the bladder recommend the use of both 1973 and 2004/2016 WHO classifications ( Table 6.6 ) (see further discussion later in this chapter).

Histologic Grading According to the 2004/2016 World Health Organization Classification

The first widely accepted grading system for papillary urothelial neoplasms was the 1973 WHO classification system. In 1998 a revised system of classifying noninvasive papillary urothelial neoplasms of the urinary bladder was proposed by the ISUP ( Table 6.8 ). This system was formally adopted by the WHO in 1999 and was published in Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs (3rd and 4th editions), which is part of a series of WHO “Blue Books” for the classification of tumors. This system separates noninvasive papillary urothelial neoplasms into four categories, designated papilloma, PUNLMP, low-grade carcinoma, and high-grade carcinoma ( Fig. 6.28 ; Table 6.8 ).

Histologic Grading of Urothelial Carcinoma: The Four-Tier Proposal

A four-tier grading categorization of urothelial carcinomas was proposed in 2012. In this system noninvasive papillary urothelial carcinomas are separated into four categories: grade 1 urothelial carcinoma (low grade), grade 2 urothelial carcinoma (low grade), grade 3 urothelial carcinoma (high grade), and grade 4 urothelial carcinoma (high grade) ( Table 6.9 ; Figs. 6.29 and 6.30 ). PUNLMP is classified as “grade 1 urothelial carcinoma (low grade)” in the four-tier grading scheme. Urothelial papilloma remains as a benign urothelial tumor following identical diagnostic criteria and terminology to those defined in the 1973 and 2004/2016 WHO classifications.

Other Proposals for Bladder Cancer Grading and Tumor Heterogeneity

Tumor Heterogeneity: Implications for Grading

Papillary urothelial neoplasms encompass a spectrum of morphologic findings including tumors that behave aggressively and tumors that are biologically benign. Attempting to differentiate biologic behavior based solely on subtle histopathologic criteria is fraught with difficulties and perils, especially considering the significant interobserver variability that has been documented in numerous studies with all classification schemes. The 2004/2016 WHO/ISUP system provides clearly defined histologic criteria for each of its diagnostic categories; however, urothelial neoplasms frequently demonstrate features of more than one grade ( Fig. 6.31 ). The grading of papillary urothelial tumors is typically based on the worst grade present. However, cancer heterogeneity could have a significant impact on patient outcome. Cheng et al. examined 164 patients with stage Ta urothelial tumors and found that approximately one-third of tumors had morphologic tumor heterogeneity consistent with more than one histologic grade. They graded both the primary and secondary patterns of tumor growth by the 2004/2016 WHO/ISUP criteria with PUNLMP, low-grade carcinoma, and high-grade carcinoma patterns receiving scores of 1, 2, and 3, respectively. Each tumor was then evaluated by a combined scoring system on a scale of 2 to 6. With a median follow-up of 9.2 years, the prognosis of patients with a combined score of 6 (the entire tumor consisting of high-grade carcinoma) is considerably worse than those with a combined score of 5 (a tumor consisting of low- and high-grade carcinoma) (26% versus 68% 10-year progression-free survival; P = 0.02). The significant survival difference (42%) between score 5 and score 6 groups may suffice to warrant different management strategies in appropriate settings. Subsequent studies have also suggested that combined scoring systems may be useful in the grading of bladder tumors. Grading should take cancer heterogeneity into consideration, because prognostic accuracy was increased when the combined primary and secondary grades were applied. This finding (two-numbered grading system) was recently validated.

Neither the 2004/2016 WHO/ISUP system nor the 1973 WHO system takes tumor heterogeneity into account; however, the 1973 WHO system does allow a greater amount of diagnostic flexibility in that tumors are frequently classified as grade 1 to 2 or grade 2 to 3. This added flexibility may give a more accurate representation of the tumor histology than attempting to force a lesion into a single diagnostic category. It appears that prognostic accuracy is improved when heterogeneity is considered. Future investigations are needed to fully address the impact of tumor heterogeneity on clinical outcome.

General Features of Invasive Urothelial Carcinoma

At gross examination, most tumors present as a single, solid, polypoid mass with or without ulceration, and may also appear sessile and extensively infiltrate the bladder wall ( Fig. 6.32 ). Histologically, the neoplastic cells invade the bladder wall as nests, cords, trabeculae, small clusters, or single cells that are often separated by a desmoplastic stroma. The tumor sometimes grows in a more diffuse, sheetlike pattern, but even in these cases, focal nests and clusters are generally present. The cells show moderate to abundant amphophilic or eosinophilic cytoplasm and large hyperchromatic nuclei. In larger nests, palisading of nuclei may be seen at the edges of the nests. The nuclei are typically pleomorphic and have irregular contours with angular profiles. Nuclear grooves may be identified in some cells. Nucleoli are highly variable in number and appearance. Some cells contain single or multiple small nucleoli, and others have large eosinophilic nucleoli. Foci of marked pleomorphism may be seen, with bizarre and multinuclear tumor cells present. Mitotic figures are common, including many abnormal forms. Invasive tumors are most commonly high grade, usually showing marked anaplasia with focal giant cell formation.

Pathologic stage is most critical for assessing patient prognosis. The 2017 TNM (tumor, lymph node, and metastasis) staging information should be provided in the pathology report ( Figs. 6.33 and 6.34 ; Table 6.10 ).

Stage pT1 Tumor

Infiltrating urothelial carcinoma is defined by the WHO as a urothelial tumor that invades beyond the basement membrane. The 2017 TNM staging system defines pT1 tumors of the bladder as those invading the lamina propria, but not the muscularis propria. The recognition of lamina propria invasion by urothelial carcinoma is one of the most challenging fields in surgical pathology, and the pathologist should follow strict criteria in its assessment ( Table 6.11 ; Fig. 6.35 ).