Reactive (inflammatory) atypia consists of nuclear abnormalities occurring in acutely or chronically inflamed urothelium.

This term is reserved for situations when it is difficult to differentiate between reactive and neoplastic atypia. There may be a greater degree of pleomorphism and/or hyperchromatism out of proportion to the extent of the inflammation. This designation allows patients to be followed more closely for reevaluation.

Dysplastic urothelium has appreciable cytologic and architectural changes felt to be preneoplastic, yet falling short of the diagnostic threshold for urothelial carcinoma in situ. This term is controversial due to problems with interobserver reproducibility, lack of a uniform definition, and confusing reports in the literature.

Urothelial carcinoma in situ (CIS) is a flat lesion of the urothelium that is a documented precursor of invasive cancer in many cases. It is characterized by the presence of cells with large, irregular, hyperchromatic nuclei that may be present throughout either the entire thickness of the epithelium or only part of it (Fig. 16.1). Mitoses are commonly seen in the mid to upper urothelium. CIS cells may be found scattered within the urothelium, have a pagetoid spread, or present as isolated cells in a partially denuded surface. CIS is a high-grade lesion and is most often found in association with
papillary or invasive carcinoma, where it has been reported in as many as 90% of cases (17,18,19,20,21); or in patients with a history of prior tumors. A substantial proportion of patients with CIS alone are asymptomatic. Symptoms, when they appear, suggest cystitis: dysuria, frequency, and nocturia (19,20,22,23,24,25,26,27). Gross hematuria, usually associated with tumor, is rare; however, most patients with CIS do have microscopic hematuria. Cystoscopically, the mucosa appears to be inflamed, with an erythematous, velvety, or cobblestone appearance. It differs from banal cystitis only by its discrete gross boundaries compared with the diffuseness of cystitis. The epithelium in areas of CIS is only loosely cohesive, cells readily desquamate, and the epithelium has a rapid turnover rate. Thus, there is extensive exfoliation from even limited areas of CIS and it is common for biopsied areas of CIS to exhibit a predominantly denuded bladder wall (so-called erosive cystitis), making urine cytology a very important and sensitive means to establish the correct diagnosis. Although some patients may have only a limited focus of CIS, the majority will have multifocal or diffuse involvement.

If left untreated, most cases of CIS will progress to invasive carcinoma, and in patients who underwent cystectomy for CIS, invasion was detected in approximately one third of them (27,28,29). Nevertheless, not all patients with CIS develop subsequent invasive disease (30).

The most common tumors of the urinary tract (excluding prostate) are papillary tumors of urothelial origin. They frequently are multiple, and often recur after being removed, yet most of these tumors are easily managed by local resection. Patients who have had papillary tumors of the bladder are at risk of developing invasive carcinoma, and some very experienced pathologists regard nearly all papillary tumors as carcinoma (31,32). The issue of grading papillary urothelial tumors has been vigorously debated among urologic pathologists, but in this chapter, we follow the classification adopted by the WHO/ISUP (Table 16.1). This classification system relies on changes in the architectural and cytologic features within the urothelium.

This is a rare benign condition typically occurring as a small, isolated growth seen primarily, but not exclusively, in younger patients. Morphologically it is a discrete, exophytic papillary growth with a central fibrovascular core lined by urothelium of normal thickness and cytology (Fig. 16.2A). Recurrences are rare and progression to carcinoma is exceedingly rare (33,34). Inverted Urothelial Papilloma is, by definition, an endophytic mass that shares several features with exophytic urothelial papilloma (Fig. 16.2B). Inverted papillomas have a low risk of recurrence when completely excised. Rarely, hybrid cases exist with portions of the lesion being endophytic and others exophytic. They may be seen in patients with a history of urothelial carcinoma, and rarely, urothelial carcinoma may arise within inverted urothelial papilloma.

This term describes a papillary urothelial neoplasm with an orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear atypia,
irrespective of cell thickness (Fig. 16.3). Mitoses are infrequent and usually limited to the basal layer. When strictly defined, PUNLMP is not associated with invasion or metastasis. Nevertheless, these patients are at risk of developing new bladder tumors (recurrence), usually of similar histology. Occasionally (7%-10%), these subsequent lesions manifest as urothelial carcinoma, such that follow-up of the patient is warranted.

Low-grade carcinomas maintain an overall orderly appearance but exhibit architectural or cytologic atypia that is easily recognizable at scanning magnification (Fig. 16.4). Variability in polarity, nuclear size, shape, and chromatin texture are minimal but comprise the hallmarks of the cytologic atypia seen in low-grade papillary urothelial carcinoma. Mitotic figures are infrequent. Although mitoses may be seen at any level of the urothelium, they are not atypical and usually are limited to the lower half. These tumors frequently recur and have a low (less than 5%) risk of progression.

High-grade carcinomas are characterized by a disorderly appearance because of marked architectural and cytologic abnormalities, recognizable at low magnification (Fig. 16.5). Cellular pleomorphism ranges from moderate to marked, and mitotic figures, including atypical forms, frequently are seen at all levels of the urothelium. They are commonly associated with invasive carcinoma at the time of initial presentation and the adjacent mucosa may show evidence of carcinoma in situ. Progression rate varies from 15% to 40%, much higher than low-grade lesions.

In a papillary urothelial neoplasm with variable histology, the tumor should be graded according to the highest grade, although it is not uncommon for minuscule areas of higher grade morphology to be ignored in a tumor with overwhelming low-grade component. It is yet to be determined how significant a minor component must be in order to have an impact on prognosis.

Urothelial carcinomas, particularly high-grade tumors, have a propensity for divergent differentiation and may contain variable proportions of different histologic patterns, including a number of variants of urothelial carcinoma that have been recognized by the WHO (Table 16.3). This feature is seen primarily in invasive tumors but may occasionally be present in in situ disease (35). In a series of 300 consecutive cystectomies performed at Memorial Sloan-Kettering Cancer Center, 27% of cancer-bearing specimens contained some form of divergent differentiation. This incidence, however, was lower in transurethral resection specimens at approximately 7%. When divergent differentiation is seen together with usual urothelial carcinoma, the pathologist should use the terminology urothelial carcinoma with ____ differentiation, inserting the type of differentiation observed.

The diagnosis of squamous cell carcinoma (SCC) should be reserved for urothelial tumors that exhibit exclusive or predominant squamous differentiation (Fig. 16.7). For urothelial tumors with variable amounts of squamous differentiation, the term urothelial carcinoma with squamous differentiation should be used. Overall, squamous cell carcinomas constitute 2% to 7% of urothelial cancers except in West African regions and along the Nile Valley where, as a consequence of the endemic schistosomal infections, they are the most common form of cancer (36,37,38). Risk factors associated with the development of bladder squamous cell carcinoma include long-term indwelling catheterization, a nonfunctioning bladder, bladder calculi, urinary obstruction, and chronic infection with Schistosoma hematobium (39,40). Squamous carcinoma of the urothelial tract is thought to arise through a process of metaplasia of the urothelium. A large percentage of patients with SCC have squamous metaplasia of the adjacent urothelium. Many have a history of severe, long-term chronic inflammation associated with stones, chronic infection, bilharziasis and, in a few examples, prior systemic chemotherapy with cyclophosphamide (41). A number of morphologic alteration in the urothelial lining have been associated with the development of bladder squamous cell carcinoma including keratinizing squamous metaplasia, verrucous squamous hyperplasia, condyloma acuminatum, and squamous cell carcinoma in situ (42,43).

Squamous cell carcinoma of the bladder tends to be sessile, ulcerated, and infiltrative at the time of diagnosis. The histologic hallmarks of pearl formation, intercellular bridges, and keratotic cellular debris are those of squamous carcinoma at any site. With the exception of the verrucous variant, most of these carcinomas are moderately or poorly differentiated and more deeply invasive at the time of diagnosis than the majority of transitional cell carcinomas, which may contribute to the generally poor prognosis of these tumors. When these tumors are evaluated stage for stage, however, the prognosis is similar to that of “usual” urothelial carcinoma (38,44,45).

Primary pure adenocarcinomas of the bladder are rare, representing no more than 2.5% of all malignant vesical neoplasms (46,47). By definition, the tumor should be composed entirely, or virtually entirely, of glandular elements. As with squamous carcinoma, they arise through a process of metaplasia of the urothelium and frequently are associated with long-standing local irritation, nonfunctioning bladder, and obstruction (48,49,50,51,52,53,54). Up to 90% of carcinomas associated with bladder extrophy are of adenocarcinoma type and this tumor is more frequently encountered in a setting of schistosomiasis (55,56). They can arise anywhere on the bladder surface, although a large percentage originates from the trigone and posterior wall. A major clinical difference as compared to usual urothelial carcinoma is that two thirds of adenocarcinomas are single discrete lesions, whereas TCC tends to be multifocal (48,49). Grossly the tumors can be papillary, nodular, or flat and ulcerated. Microscopically, the tumor is most often composed of colonic-type glandular epithelium (Fig. 16.8) and may contain abundant extracellular mucin. Regardless of histologic pattern, cystitis cystica et glandularis or surface glandular metaplasia is commonly present in the adjacent benign urothelium. At the time of initial diagnosis, most adenocarcinomas are locally advanced and infiltrated deeply, most likely accounting for their poor prognosis. Stage for stage, however, they appear to have similar survival to TCC (46,52,53,54,57,58).

It is important to consider the possibility of metastasis or direct invasion from another primary site in the differential diagnosis of an adenocarcinoma involving the bladder. Tumors that directly invade the bladder and mimic primary vesical adenocarcinoma include those arising in rectum, prostate, appendix, and endometrium (59,60,61). For this reason, we have routinely added the following disclaimer to our pathology report of the biopsy specimen: We would accept as primary at this site if a metastasis or direct extension from an adjacent organ can be ruled out clinically. The treating clinician is in the best position to evaluate the patient and consider other primary sites.

Signet ring cell carcinoma of the bladder is a rare variant of adenocarcinoma with fewer than 70 cases reported in the English literature, which tends to infiltrate the bladder wall diffusely, giving it an indurated and thickened quality similar to the “linitis plastica” seen in gastric signet ring cell carcinomas (Fig. 16.9). Most of these tumors additionally exhibit morphology in which tumor cells have eccentrically situated nuclei and abundant eosinophilic cytoplasm giving them the appearance of plasma cells and hence the term “plasmacytoid” urothelial carcinoma. The tumor also commonly infiltrates extensively throughout adjacent soft tissue, making primary resection for cure virtually impossible. In the differential diagnosis, one must rule out direct extension, usually from a rectal or prostatic carcinoma, or metastasis from stomach or lobular carcinoma of the breast, or other organs (62,63,64,65,66,67,68,69).

Clear cell adenocarcinoma is another rare variant that is characterized by cuboidal tumor cells forming duct or tubulelike structures that resemble its müllerian counterpart in the female genital tract. These tumors were initially thought to arise from mesonephric nests in the trigone area, but are now considered to arise through a process of metaplasia of the surface urothelium or from müllerian rest (69,70,71,72,73). This tumor has a strong female predominance, which is unusual for urothelial tumors and suggests that müllerian origin may account for an even larger percent of these cases. Immunohistochemical studies are not useful in establishing histogenesis (72). Histologically, these tumors are characterized by tubular and papillary structures that are generally lined by flat, cuboidal, or rarely columnar cells; with hobnail cells present in most tumors (Fig. 16.10). Clear cells are abundant in most tumors, but cells with abundant eosinophilic cytoplasm are also common.

Urachal carcinoma is a primary carcinoma of the bladder arising from urachal remnants, the vast majority of which is adenocarcinoma. Urachal remnants have been found in up to 35% of bladders at the time of autopsy; usually in the dome, but also along the anterior and rarely along the posterior bladder wall (78,79). Although their epithelial lining usually is transitional in type, it can be glandular in 33% of cases. Urachal carcinoma is rare and comprises 0.35% to 0.7% of all bladder cancers and 22% to 35% of vesical adenocarcinomas (79,80,81). Most of these carcinomas have enteric features and may be mucinous (Fig. 16.12); however, rare examples containing signet ring cell, micropapillary, squamous cell, small cell/neuroendocrine, lymphoepithelioma-like, usual urothelial and anaplastic carcinoma components have been reported (79,82,83,84). Adenomatous changes have been identified in the adjacent urachal remnant in 37% of cases in one study (79).

Although the criteria for a diagnosis of urachal carcinoma are somewhat controversial, most investigators agree with those set forth by Sheldon et al. (85) and Mostofi et al. (49). These include (a) tumor in the dome of the bladder; (b) absence of cystitis cystica and cystitis glandularis; (c) predominant invasion of the muscularis or deeper tissues with a sharp demarcation between the tumor and surface bladder urothelium that is free of glandular or polypoid proliferation; (d) presence of urachal remnants within the tumor; (e) extension of tumor into the bladder wall with involvement of the space of Retzius, anterior abdominal wall, or umbilicus; and (f) no evidence of a primary neoplasm elsewhere.

A few staging systems have recently been proposed (84,86), but commonly followed is that proposed by Sheldon et al. (85): pT1—no invasion beyond the urachal mucosa; pT2—invasion confined to the urachus; pT3—local extension to the (a) bladder, (b) abdominal wall, and (c) viscera other than the bladder; and pT4—metastasis to (a) regional lymph nodes and (b) distant sites.

Because the urachus usually is found along the free surface of the bladder, urachal carcinomas frequently are amenable to partial cystectomy. The entire length of the median umbilical ligament may harbor urachal remnants that may develop carcinoma synchronously or metachronously (87). For this reason, the surgery of choice should include en bloc resection of the entire length of the ligament, including the umbilicus (84,88).

The differential diagnosis includes metastatic adenocarcinoma and adenocarcinoma arising in the bladder surface. The latter usually is associated with an intraluminal mass and the diagnosis is established by finding CIS or extensive glandular metaplasia of the adjacent urothelium. Because these features are rarely seen on a TUR specimen of an ulcerated lesion, we include the following note in the pathology report of any solitary glandular lesion involving the dome of the bladder: We would accept as primary at this site, including the possibility of urachal origin, if a metastasis or
direct extension from an adjacent organ has been ruled out. Once again, the urologist is in the best position to make this determination.

Small cell carcinoma is a malignant neuroendocrine neoplasm derived from the urothelium that histologically resembles its pulmonary counterpart (16,89,90,91,92). It consists of small cells with nuclear molding, scant cytoplasm, and dark nuclei containing finely stippled chromatin and inconspicuous nucleoli (Fig. 16.13). By immunohistochemical studies, most tumors express chromogranin and synaptophysin. In most cases, they are associated with CIS of the urothelium and show microscopically foci of other divergent histologic patterns, usually transitional cell carcinoma, but also adenocarcinoma, squamous cell carcinoma, or spindle cell carcinoma (89,93,94). Small cell or neuroendocrine carcinomas should be considered high-grade tumors. They usually present at an advanced stage; up to one third of patients have metastases at the time of diagnosis.