Epithelial Metaplasia

Epithelial metaplasia is focal areas of transformed urothelium with normal nuclear and cellular architecture surrounded by normal urothelium usually located on the trigone and composed of squamous (squamous metaplasia) or glandular (glandular metaplasia) cells. Squamous metaplasia often has a knobby appearance and is covered by white, flaky, easily disrupted material lying on the trigone. Glandular metaplasia appears as clumps of raised red areas that appear inflammatory and are often confused for cancer. Approximately 40% of women and 5% of men have squamous metaplasia of the bladder, which is usually related to infection, trauma, and surgery (Ozbey et al, 1999). There are no racial differences, and squamous metaplasia is more common in women of childbearing age. Spinal cord injury is associated with squamous metaplasia most likely from catheter trauma and urinary tract infections (Vaidyanathan et al, 2003). Glandular metaplasia can extensively involve the bladder, particularly the trigone, but biopsy is not required. Treatment is unnecessary, and a preventive agent has not been identified.

Leukoplakia

Leukoplakia of the bladder is similar to squamous metaplasia with the addition of keratin deposition that appears as a white flaky substance floating in the bladder (Staack et al, 2006). Leukoplakia occurs in other organs that are covered by squamous epithelium and is often premalignant (Zhang et al, 2009). However, cytogenetic studies on bladder leukoplakia are consistent with a benign lesion, and no treatment is necessary (Staack et al, 2006).

Inverted Papilloma

An inverted papilloma is a benign proliferative lesion that is associated with chronic inflammation or bladder outlet obstruction and can be located throughout the bladder but most commonly on the trigone, comprising less than 1% of all bladder tumors (Sung et al, 2006; Jones et al, 2007; Kilciler et al, 2008). Inverted papillomas demonstrate an inverted growth pattern composed of anastomosing islands of histologically and cytologically normal urothelial cells invaginating from the surface urothelium into the lamina propria but not into the muscularis propria (Fig. 80–1) (Sung et al, 2006). When diagnosed according to strictly defined criteria (e.g., lack of cytologic atypia), inverted papillomas behave in a benign fashion with only a 1% incidence of tumor recurrence (Sung et al, 2006; Kilciler et al, 2008). Occasionally, inverted papillomas are present with coexistent urothelial cancer elsewhere in the urinary system, occurring more commonly in the upper tract than the bladder (Asano et al, 2003). The use of fluorescent in-situ hybridization (FISH) to evaluate chromosomal changes can distinguish between an inverted papilloma and a urothelial cancer with an inverted growth pattern (Jones et al, 2007). Transurethral resection is the treatment of choice.

Figure 80–1 Inverted papilloma.

Papilloma

Urothelial papilloma is a benign proliferative growth in the bladder that is composed of delicate stalks lined by normal-appearing urothelium (Fig. 80–2) (Montironi and Lopez-Beltran, 2005). Papillomas had previously been categorized as grade 1 Ta tumors of the bladder until the World Health Organization (WHO) changed the classification of noninvasive bladder cancer in 1998 (Epstein et al, 1998). Papillomas rarely have mitotic figures and lack markers of aggressive growth such as TP53 or RB mutations, but 75% of these tumors will have mutations in the fibroblast growth factor receptor-3 (FGFR-3) (van Rhijn et al, 2004). Papillomas may recur, but they do not progress or invade.

Figure 80–2 Papilloma.

Nephrogenic Adenoma

Nephrogenic adenoma is a rare tumor caused by chronic irritation of the urothelium; it arises from a variety of sources, including trauma, previous surgery, renal transplantation, intravesical chemotherapy, stones, catheters, and infection (Wood et al, 1988; Tse et al, 1997). Nephrogenic adenoma is composed of glandular-appearing tubules similar to renal tubules that involve the mucosa and submucosa of the bladder. These structures are covered by cuboidal cells with clear or eosinophilic cytoplasm with cytologically normal nuclei. The lesion may be vascular, which explains the presence of gross hematuria in most cases (Porcaro et al, 2001). There is no racial or gender association with the entity. The constant theme of chronic inflammation suggests metaplastic changes to the urothelium lead to nephrogenic adenoma, though some authors have proposed a theory that nephrogenic adenoma arises from nests of displaced mesonephric tissue in the urothelium that is activated with mucosal injury (Porcaro et al, 2001). The most frequent presenting symptom is gross hematuria, often in conjunction with a urinary tract infection. Treatment consists of transurethral resection and elimination of the chronic irritation.

Cystitis Cystica and Glandularis

Cystitis cystica and/or glandularis is a common finding in normal bladders, usually associated with inflammation or chronic obstruction (Semins and Schoenberg, 2007). These benign tumors represent cystic nests that are lined by columnar or cuboidal cells and are generally associated with proliferation of Von Brunn nests (Figs. 80-3 and 80-4). Cystitis glandularis can be associated with pelvic lipomatosis and may occupy the majority of the bladder (Buckley et al, 2007). Cystitis glandularis may develop into or coexist with intestinal metaplasia, which are benign tumors characterized by goblet cells that are histologically similar to colonic epithelium. There have been a few case reports of cystitis cystica or glandularis transforming into adenocarcinoma, and therefore regular endoscopic evaluation of patients with these entities is recommended (Smith et al, 2008). The most common presenting feature of cystitis cystica or glandularis is irritative voiding symptoms and hematuria. Treatment is transurethral resection and relief of the obstruction or inflammatory condition.

Figure 80–3 Von Brunn nest with cystitis cystica.

Figure 80–4 Cystitis glandularis.

Leiomyoma

Leiomyomas are the most common nonepithelial benign tumor of the bladder composed of benign smooth muscle. Several hundred cases have been reported, but this may under-represent the true prevalence. These tumors occur most commonly in women of childbearing age and are histologically similar to leiomyomas of the uterus (Castillo et al, 2008). Leiomyomas appear as smooth indentations of the bladder and can be confused with a bladder tumor except for the normal urothelium overlying the tumor (Fasih et al, 2008). Imaging, especially with magnetic resonance imaging (MRI), can confirm the diagnosis and spare invasive procedures (Fasih et al, 2008). Surgical resection is required if the leiomyoma is large or painful.

Epidemiology

The incidence rate of a cancer is defined as the number of new cancers diagnosed per 100,000 persons per year. The prevalence rate is the total number of cancers per 100,000 persons per year, not just new cases. Because urothelial cancer is a cancer of the environment and age, the incidence and prevalence rates increase with age, peaking in the 8th decade of life, and there is a strong association between environmental toxins and urothelial cancer formation (Jemal et al, 2008; Parkin, 2008). The incidence rate of urothelial cancer has been rising over the last 60 to 70 years, but the rate of rise has recently decreased significantly and in some geographic areas has leveled off (Parkin, 2008). Unfortunately, the incidence rate is rising the fastest in underdeveloped countries where industrialization has led to carcinogenic exposure.

According to the latest American Cancer Society statistics, there were 68,810 total cases diagnosed in the United States in 2007, comprising 51,230 men and 17,580 women and accounting for 7% of all cancers (Jemal et al, 2008). Bladder cancer is a lethal disease with 14,100 deaths recorded in 2007, comprising 9950 men and 4150 women and accounting for 3% of all cancer deaths. Importantly, there has been a 5% decrease in bladder cancer mortality from 1990 to 2004 despite a continued rise in the incidence of the disease. Bladder cancer contributes to 0.7% of the absolute decrease in the cancer death rate seen during this time, when all cancers are considered (Jemal et al, 2008). Globally, the incidence rate of bladder cancer has been increasing, but due to smoking cessation programs, at a slower rate over the last decade (Parkin, 2008). The mortality rate from bladder cancer has decreased significantly from 1990 to 2004 with both men and women recording a 18.4% decrease in mortality rate (Fig. 80–5). This decrease in mortality rate is more striking in men than women because of the earlier peak when men begin to smoke, which occurred approximately 20 years before women. Because of the latency period with urothelial cancer–causing agents in tobacco, we should see a commensurate decrease in the mortality rate in women in 15 to 20 years as their smoking cessation programs become more widespread.

Figure 80–5 Age-Standardized Rates (ASR) of global mortality from bladder cancer.

(From Parkin DM. The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl 2008;218:12–20.)

Gender/Racial/Age Differences

Males are 3 to 4 times more likely to develop bladder cancer than females, presumably because of an increased prevalence of smoking and exposure to environmental toxins (Jemal et al, 2008; Parkin, 2008). African-American males have a 19% higher incidence rate than white males for all cancers and a 37% higher death rate. However, for urothelial cancer, white males have a higher incidence and death rate than African-Americans (Jemal et al, 2008; Parkin, 2008). African-American women have a 6% lower incidence but a 17% higher death rate than white women in all cancers (Jemal et al, 2008). However, bladder cancer is roughly times more common in white women than in African-American women. A white male has a 3.7% chance of developing urothelial cancer in his lifetime, which is roughly 3 times the probability for white females or African-American males and more than times the probability for African-American females (Hayat et al, 2007; Jemal et al, 2008). The risk of developing invasive bladder cancer is age dependant (Jemal et al, 2008). For men from birth to age 39 years, the incidence rate of invasive bladder cancer is 0.02%; ages 40 to 59 years, 0.41%; ages 60 to 69 years, 0.96%; ages 70 years and older, 3.5%; and from birth to death, 3.7%. The bladder cancer incidence for women from birth to age 39 years is 0.1%; ages 40 to 59 years, 0.13%; ages 60 to 69 years, 0.26%; ages 70 years and older, 0.99%; and from birth to death, 1.17%. In general, adolescents and young adults (less than age 40 years) tend to develop well-differentiated noninvasive, rather than invasive, bladder cancer (Linn et al, 1998). Unlike many other cancers where younger patients tend to develop more aggressive disease, the opposite appears to be true in bladder cancer, because they present more frequently with noninvasive low-grade tumors. However, the death rate, stage for stage, from bladder cancer is the same across all age groups (Wan and Grossman, 1989).

Global Burden of Bladder Cancer

There is a geographic difference in bladder cancer incidence rates across the world with the highest occurring in Southern and Eastern Europe parts of Africa, the Middle East, and North America and the lowest occurring in Asia and underdeveloped areas in Africa (Ferlay et al, 2007). Bladder cancer is the 9th most common cancer worldwide, with 357,000 cases recorded in 2002 (Parkin, 2008). Bladder cancer is the 13th most common cause of death, accounting for 145,000 deaths worldwide (Ferlay et al, 2007; Parkin, 2008). The incidence rate of bladder cancer has been rising in Asia and Russia because of an increased prevalence of smoking. Sixty-three percent of all bladder cancer cases occur in developed countries, with 55% from North America and Europe. In the United States, the highest bladder cancer incidence rate is in Rhode Island and the lowest is in the District of Columbia (Jemal et al, 2008). The histologic cell type of bladder cancer is very geographically dependent, but urothelial cancer is the most common. In North America and Europe, 95% to 97% of cases are urothelial carcinoma; in Africa 60% to 90% are urothelial and 10% to 40% are squamous cell; and Egypt has the highest rate of squamous cell carcinoma because of the endemic infections with Schistosoma species (Parkin, 2008).

Mortality

The mortality rate from bladder cancer in Egypt is 3 times higher than in Europe and 8 times greater than in North America because of the aggressive nature of squamous cell carcinoma that is highly prevalent in Egypt (Parekh et al, 2002). In the United States, death rates for all cancer sites combined decreased by 2.6% per year in males and by 1.8% in females from 2002 to 2004 compared with 1.5% and 0.8% per year in males and females, respectively, from 1992 to 2002 (Jemal et al, 2008). The mortality rate for bladder cancer has decreased by 5% during this period primarily because of smoking cessation, changes in environmental carcinogens, and healthier lifestyles. Mortality from bladder cancer is highest in elderly persons, particularly those over the age of 80 years, accounting for the third most common cause of cancer deaths in men older than age 80 years (Jemal et al, 2008). Whether this increase in mortality rate is related to tumor biology or changes in physician practices with the elderly is unclear. Recent evidence suggests that physician practices may be related to bladder cancer deaths in the elderly (Morris et al, 2009). These authors estimated that 31% of all bladder cancer deaths were avoidable, more commonly in noninvasive rather than invasive disease. Better chemotherapy has improved the survival rate in patients with metastatic bladder cancer, but changes in physician practices related to more timely care and more aggressive treatment in healthy patients could well lead to improvement in overall survival. Lee and colleagues (2006) reported that a delay of more than 12 weeks from the diagnosis of bladder cancer to cystectomy treatment was associated with a decrease in overall and cancer-specific survival. However, more intensive treatment (intravesical chemotherapy and cystoscopy) for patients with noninvasive bladder cancer did not correlate with the better survival or less need for invasive treatment (Hollenbeck et al, 2009; Morris et al, 2009).

Etiology

Bladder cancer is caused by genetic abnormalities and external risk factors, including carcinogen exposure, nutritional factors, fluid intake, alcohol, inflammation, infection, chemotherapy, radiation, and possibly artificial sweeteners.

Genetic

The higher incidence of bladder cancer in white compared with African-American males is probably not genetic but environmental, or it may be related to differential susceptibility to carcinogens (Bouchardy et al, 1995, 1996; Wanner et al, 1995). There are several polymorphisms that seem to be related to the formation of bladder cancer, in particular the susceptibility to environmental carcinogens. N-acetyl transferase (NAT) detoxifies nitrosamines, a known bladder carcinogen. Specifically, NAT-2 regulates the rate of acetylation of compounds such as caffeine, which are related to bladder cancer formation. The slow NAT-2 polymorphism is related to bladder cancer with an odds ratio of 1.4 compared with the fast polymorphism (Garcia-Closas et al, 2005). Glutathione-S-transferase (GSTM1) conjugates several reactive chemicals, including arylamines and nitrosamines. The null GSTM1 polymorphism is associated with an increased bladder risk with a relative risk of 1.5 (Garcia-Closas et al, 2005). The null GSTM1 and slow NAT-2 lead to high levels of 3-aminobiphenyl and higher risk of bladder cancer. These polymorphisms are present in 27% of white, 15% of African-American, and 3% of Asian males, thus partially explaining the different bladder cancer incidence rates across ethnic groups.

External Risk Factors

In addition to the skin and lungs, the bladder is the main internal organ affected by occupational carcinogens. The primary culprits are the aromatic amines that bind to DNA (Delclos and Lerner, 2008; Reulen et al, 2008). Twenty percent to 27% of all bladder cancers are associated with industrial exposure of some type, primarily in areas with a heavy concentration of chemical industries (Case and Hosker, 1954; Blot and Fraumeni, 1978; Reulen et al, 2008). Among the first chemical agents implicated in the formation of bladder cancer in dye and rubber workers were benzidine and β-naphthylamine (Case and Hosker, 1954). Activation of these amines to allow DNA binding occurs with enzymes that are selectively expressed in the population, making some subjects more susceptible to cancer formation as described above for the NAT-2 and GSTM1 polymorphisms. There are 11 specific aromatic amines implicated in bladder cancer formation; they are broken into three groups—definite, probable, and possible—as seen in Table 80–1. Other industrial agents implicated in bladder cancer formation include polycyclic aromatic hydrocarbons (PAH), diesel exhaust, and paint substances (Zeegers et al, 2001a).

Table 80–1 Aromatic Amines Associated with Urothelial Cancer Formation

Environmental carcinogens can enter the system and cause bladder cancer from inhalation or through skin absorption. In general, there is a long latency period of 10 to 20 years between the industrial exposure and the formation of the bladder cancer, thus proving definitive causative relationships is difficult (Dryson et al, 2008). However, there are a variety of occupations statistically associated with bladder cancer formation, and all are industrial in nature (Table 80–2) (Reulen et al, 2008). The overall increased risk of bladder cancer formation in industrial workers is 30%, with agriculture workers having the lowest and rubber workers the highest risk of bladder cancer formation.

Table 80–2 Relative Risk of Occupations Associated with Urothelial Cancer Formation

Pathology

Histologically, 90% of bladder cancers are of urothelial origin, 5% are squamous cell carcinomas, and less than 2% are adenocarcinoma or other variants (Lopez-Beltran, 2008). Urothelial carcinoma is the most common malignancy of the urinary tract and is the second most common cause of death among genitourinary tumors. At initial presentation, 80% of urothelial tumors are non–muscle invasive. There are multiple growth patterns of urothelial cancer, including flat carcinoma in situ (CIS), papillary tumors that can be low or high grade, and sessile tumors with a solid growth pattern. Non–muscle-invasive cancers can be very large because of lack of genetic alterations required for invasion. Likewise, invasive tumors can be quite small if early genetic changes occur within the tumor cell, allowing for an invasive phenotype.

The World Health Organization (WHO) first determined nomenclature for the histologic classification of urothelial cancer in 1973. In 1998, the International Society of Urological Pathology (ISUP) developed a new nomenclature to better reflect the recurrence and progression rates of urothelial cancer (Epstein et al, 1998). The two main changes were recognition that papillary Ta grade 1 urothelial cancers should not be considered cancers because of their indolent growth and lack of invasion, and the second was elimination of “grade 2” cancers, which became a grey zone encompassing grade 1 and grade 3 cancers causing interobserver variation. In 2004, the WHO adopted the ISUP recommended staging system and is the standard histologic nomenclature for urothelial carcinoma (Sauter et al, 2004). The clinical pattern of presentation is related to the cytologic and architectural alterations that occur within the tumor. Table 80–3 lists the histologic changes that occur from normal epithelium to high-grade muscle-invasive disease. Table 80–4 lists the neoplasms that can occur in the bladder, and Table 80–5 lists the WHO 2004 classification of urothelial neoplasms (Sauter et al, 2004; Montironi and Lopez-Beltran, 2005).

Table 80–3 Histologic Characteristics of Noninvasive Papillary Urothelial Tumors of the Bladder According to the WHO 2004 Classification

Table 80–4 Histologic Type of Tumors of the Urinary Bladder (World Health Organization, 2004)

* Refers to tumors that are undifferentiated by light microscopy.

Table 80–5 2004 World Health Organization Classification of Noninvasive and Invasive Urothelial Neoplasia

Precursor Lesions to Urothelial Cancer

Normal bladder urothelium is multilayered and less than seven cells thick (Epstein et al, 1998; Montironi and Lopez-Beltran, 2005) (Fig. 80–6). The cells mature from the basement membrane to the surface cells in an orderly fashion. The surface has large umbrella cells that may have nuclear atypia and form asymmetrical units. Their membrane is composed of uroplakin proteins and is rigid. These umbrella cells are part of the urine bladder barrier preventing toxins within the urine from transforming urothelial cells. Previously, normal urothelium was called “transitional cells” because of their ability to transition into other cell types, including squamous cells and adenocolumnar cells.

Figure 80–6 Normal urothelium.

Precursor lesions are a continuum from hyperplasia to atypia to dysplasia and finally cancer. Different pathologists have their own interpretation of important cellular or structural changes that separate these histologic changes into different categories. Hyperplasia is characterized by markedly thicker mucosa with or without atypia (Fig. 80–7). The urothelium is more than seven cells thick, and there is some disorganization of the cellular architecture. Hyperplasia is often adjacent to low-grade tumors and thought to be a precursor lesion (Epstein et al, 1998). Loss of parts of chromosome 9 can occur in hyperplasia, particularly if adjacent to low-grade tumors (Hartmann et al, 1999). Urothelial hyperplasia appears as undulating or papillary growths that are best seen on flexible cystoscopy (Sauter et al, 2004). The presence of hyperplasia does not increase the risk of developing cancer; however, if present in someone with a history of urothelial carcinoma, it may herald a recurrence in the future (Montironi and Lopez-Beltran, 2005; Lopez-Beltran, 2008).

Figure 80–7 Papillary urothelial hyperplasia.

Reactive atypia can have nuclear changes associated with inflammation, regeneration, or reaction from noxious stimuli and is characterized by large cells with prominent nucleoli (Lopez-Beltran et al, 2002). Mitotic activity without abnormal forms can be present. Endoscopically, reactive atypia is edematous, especially in the lamina propria and associated with previous urinary instrumentation, stones, infection, or intravesical therapy (Lopez-Beltran, 2008).

Urothelial dysplasia has abnormal cytologic and nuclear changes that are preneoplastic but are not sufficient to be characterized as CIS (Sauter et al, 2004). Dysplasia is characterized by cohesive cells with mildly abnormal nuclear changes. There is nuclear crowding, prominent nucleoli, and abnormal mitotic figures may be present. Umbrella cells can be present with dysplasia, but not with CIS. Most cellular abnormalities are in the basal or early cell layers, with appropriate maturation toward the luminal surface. The urothelium is more than seven cells thick at times, but there can be sloughing of the more mature urothelium, exposing the less mature early cell layers. There is allelic loss of chromosome 9 and occasional TP53 abnormalities (Harnden et al, 1996; Hartmann et al, 1999). It is difficult to quantitate the clinical significance of dysplasia secondary to the interobserver reproducibility of this entity (Montironi and Lopez-Beltran, 2005). However, dysplasia is a good indication of urothelial instability and a marker of recurrence and progression in those with known urothelial cancer. Isolated dysplasia progressing to CIS occurs in approximately 19% of cases, but dysplasia in the face of previous history of urothelial cancer will form CIS in approximately 60% of cases (Cheng et al, 1999a).

Urothelial Cancer Histology

Non–muscle-invasive bladder cancer (NMIBC) includes CIS, papillary urothelial neoplasia of low-malignant potential (PUNLMP), and low- and high-grade urothelial cancer that previously had been called “superficial bladder cancer,” which is a misnomer. The clinical significance of the WHO grading classification is shown in Table 80–6. The grade distribution of NMIBC is 25% PUNLMP, 50% low grade, and 25% high grade (including CIS) (Holmang et al, 2001; Samaratunga et al, 2002). CIS is characterized as nonpapillary, flat, high-grade tumors in which the surface epithelium contains cancer cells (Fig. 80–8) (Sauter et al, 2004). There is severe nuclear atypia, loss of cellular polarity, and a noncohesive cellular structure. The cells are large, pleomorphic, chromatin clumping, and abnormal mitotic figures are common. Loss of umbrella cells is a characteristic, separating CIS from dysplasia. All CIS is high grade by definition. The genetic abnormalities associated with CIS include alterations to the RB, TP53, and PTEN genes (Cordon-Cardo et al, 2000; Lopez-Beltran et al, 2002; Cordon-Cardo, 2008). CIS is immunoreactive for cytokeratin 20, and NMP22 is present in the cells. CIS is a precursor lesion for invasive cancer and can spread to the distal ureters and prostatic urethra on the surface or in a pagetoid manner, undermining normal adjacent urothelium (Montironi et al, 2002). Endoscopically, CIS is reddish with heaped-up mucosa and can be mistaken for inflammatory changes or radiation cystitis. CIS in association with invasive tumors have a worse prognosis, with a 45% to 65% 5-year death rate (Lopez-Beltran et al, 2002).

Table 80–6 Clinical Significance of Different Non–Muscle-Invasive Urothelial Cancer Categories in WHO 2004 Grading System

Figure 80–8 Carcinoma in situ.

PUNLMP is a papillary growth with minimal cytological atypia that is more than seven cells thick and is generally solitary and located on the trigone (Fig. 80–9) (Holmang et al, 2001; Sauter et al, 2004). PUNLMP is composed of thin papillary stalks, where the polarity of the cells is maintained and the nuclei are minimally enlarged. PUNLMP has a low proliferation rate and is not associated with invasion or metastases, but almost 80% will have loss of chromosome 9 (Cheng et al, 2004). PUNLMP is different from a benign papilloma in that a PUNLMP has a thicker cell layer and large nuclei with occasionally mitotic figures. The male to female ratio for PUNLMP is 5 : 1, and the mean age is 65 (Holmang et al, 2001). PUNLMP can recur within the bladder in 35% of cases, but progression is rare, occurring in less than 4% (Oosterhuis et al, 2002).

Figure 80–9 Papillary urothelial neoplasm of low malignant potential.

Low-grade urothelial carcinoma is typically papillary in nature with a fibrovascular stalk and frequent papillary branching with increased cellular size, some nuclear atypia (more than in PUNLMP), and occasional mitotic figures (Fig. 80–10) (Epstein et al, 1998). Genetic abnormalities associated with low-grade cancer include deletion of 9q and alterations of FGFR-3, HRAS, and PI3K (Holmang et al, 2001; Cordon-Cardo, 2008). Low-grade carcinomas are immunoreactive for cytokeratin-20 and CD-44. The architectural and histologic changes that separate low-grade urothelial carcinoma from a PUNLMP include multiple stalks, more cytologic atypia, and the multifocal nature of low-grade carcinomas compared with the solitary PUNLMP.

Figure 80–10 Low-grade papillary urothelial neoplasm.

High-grade papillary urothelial cancer is composed of fused papillary stalks with high-grade cancer in the urothelial layer. There is a disordered growth pattern, numerous mitotic figures present, and there are pleomorphic cells with exaggerated nuclei. Over 80% of high-grade cancers will invade the underlying stroma if left untreated. Genetic abnormalities associated with high-grade papillary urothelial cancer include similar abnormalities seen in the low-grade type plus alterations in the INK4A gene (Cordon-Cardo, 2008). In addition, there can be deletions of 2q, 5q, 10q, 18q, and gains of 5q and 20q (Knowles, 2008b). Alterations of TP21 and TP27 along with TP53 have been reported (Simon et al, 2004). High-grade urothelial carcinoma stains are immunoreactive for cytokeratin-20 and are likely aneuploid.

There are key genetic and phenotypic changes that occur in cancer cells, thus providing the ability to invade the underlying stroma. Invasive urothelial carcinoma is divided into two groups: lamina propria and deep muscle invasion. Lamina propria invasive tumors are high-grade cancers that can be in clusters or in single cells, with single-cell invasion having a worse prognosis (Fig. 80–11). Rarely, low-grade cancers can invade the lamina propria. Vascular invasion can occur within the lamina propria because of the large vascular network within this tissue layer; however, it is frequently overcalled because of retraction artifact around tumor nests. There is a subdivision of lamina propria invasion into T1a (invasion above muscularis mucosa) and T1b (invasion below the muscularis mucosa). This subject will be dealt with more extensively in the Staging section.

Figure 80–11 High-grade urothelial cancer invading the lamina propria.

Muscle-invasive urothelial carcinoma is by definition high grade and is composed of cancerous cells extending through the lamina propria into the deep muscle bundles. There are rare cases of metastases to the deep muscle, but the overwhelming majority of cases are a direct extension from a surface urothelial carcinoma through the lamina propria into the deep muscle.

Staging

The American Joint Commission on Cancer in combination with the International Union Cancer Consortium meets on a regular basis to determine the tumor, nodes, and metastases (TNM) staging classifications. The 2009 staging system is shown in Table 80–7 (Edge et al, 2010). Ta and CIS disease have no invasion of the basement membrane, but endophytic growth of low-grade tumors into the lamina propria is possible, and cancer can occur in Von Brunn nests (Sung et al, 2006, Jones et al, 2007). T1 disease, as mentioned earlier, can be divided into T1a and T1b disease (Smits et al, 1998). The subdivision is based on the muscularis mucosa, which comprises thin wavy vesicles of muscle within the lamina propria that are associated with large vessels and lymphatics (Fig. 80–12). Some investigators substitute the presence of this large-vessel lymphatic layer for the muscularis mucosa when dividing T1a and T1b disease (Lopez-Beltran and Cheng, 2003). Unfortunately, muscularis mucosa is only identified in 15% to 80% of bladder biopsy specimens and in 90% of radical cystectomy specimens (Cheng et al, 1999; Sozen et al, 2002; Lopez-Beltran and Cheng, 2003; Lopez-Beltran, 2008). The prognostic significance of T1a and T1b disease is inconsistent because of the lack of muscularis mucosa in many bladder biopsy specimens. Essentially, the T1a and T1b stratifications suggest that the deeper the tumor invades in the lamina propria, the worse the survival.

Table 80–7 Definition of TNM

Figure 80–12 High-grade T1a (left) and T1b (right) urothelial cancer.

Muscle-invasive disease is subdivided into T2a and T2b. T2a includes invasion into the inner half of the muscularis propria, while T2b is deeper into the outer half. Analysis of the American Joint Committee on Cancer (AJCC) data would suggest that there is a disease-free survival difference between T2a and T2b disease (Edge et al, 2010). On the contrary, Cheng and colleagues (1999b) showed that depth of muscle invasion was not predictive of disease-free survival, but the size of the tumor was the key element. T3 disease constitutes invasion outside the bladder proper into the periadipose tissue. T3a disease involves microscopic extension, while T3b involves macroscopic extension. Clinically, T3a disease is identified by a palpable mass at the time of examination under anesthesia during the initial transurethral resection and subsequently is nonpalpable after the tumor is resected. T3b disease has a persistent palpable mass after transurethral resection of the tumor. Pathologically, T3a disease is microscopic extension into the periadipose tissue, while T3b disease is macroscopic extension. T4a disease is invasion of the prostatic stroma, uterus, or vagina, and T4b disease is invasion of the pelvic wall or abdominal wall. Extension of the tumor into the prostatic urethra without stromal invasion is currently classified under the prostatic urethral section and does not carry an adverse prognosis for patients with known bladder cancer (Pagano et al, 1996; Edge et al, 2010). Prostatic stromal invasion, however, particularly if it is a direct extension from the bladder through the muscle into the prostate, does have a poor prognostic factor, with a 5-year overall survival of less than 25% (Esrig et al, 1996; Pagano et al, 1996).

A major problem in bladder cancer is understaging, occurring in 34% to 64% of cases. Chang and colleagues (2001) reported that 27% of T1 tumors were upstaged after radical cystectomy, and 49% of T2 tumors were upstaged to T3. Because of this understaging, the American Urological Association (AUA) guidelines call for a repeat transurethral resection in patients with T1 tumors to assess for muscle invasive disease even if muscle was present in the specimen (Hall et al, 2007). The significance of this restaging is shown in an article by Herr and colleagues (2007)

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