Papillary Urothelial Neoplasms and their Precursors

The World Health Organization (WHO)/International Society of Urological Pathologists (ISUP) classification of noninvasive papillary urothelial lesions is outlined in Table 3.1 (1). The diagnosis of lesions within this classification takes into account architectural and cytologic features within the urothelium (Table 3.2).

PAPILLARY UROTHELIAL HYPERPLASIA

Papillary urothelial hyperplasia is a likely precursor lesion to low-grade papillary urothelial neoplasms (2). Typically, it is discovered on routine follow-up cystoscopy for papillary urothelial neoplasms and less frequently in the workup for microhematuria or urinary obstructive symptoms. In most cases at cystoscopy, a focal elevated lesion is identified that is variably described as “bleblike,” “papillary,” “raised,” “sessile,” or “frondular.”

Histologically, papillary hyperplasia consists of undulating urothelium arranged into mucosal narrow papillary folds of varying heights (Figs. 3.1, 3.2, 3.3 and 3.4) (efigs 3.1-3.7). Both the urothelium within papillary hyperplasia and the adjacent flat mucosa are often thicker than normal. In addition to the diagnostic mucosal folds, in some cases, there are also tent-shaped, somewhat broader folds that lack the edema and inflammation typical of polypoid cystitis. The cytologic findings in typical papillary hyperplasia are similar to those in normal urothelium. Some cases show increased vascularity in the stroma at the base of the papillary folds. An occasional case may also demonstrate early slight branching beginning at the top of one of the folds of papillary hyperplasia. Papillary hyperplasia is distinguished from papillary urothelial neoplasms by a lack of complex arborization and hence the absence of the appearance of “detached” papillary fronds (Figs. 3.5, 3.6).

Large studies with sufficient follow-up to evaluate the clinical significance of de novo papillary hyperplasia are lacking. Nevertheless, even though de novo papillary hyperplasia will not inevitably progress to urothelial neoplasia, it is reasonable to suggest that patients should be followed
up more closely than individuals in the general population. If papillary hyperplasia is diagnosed in someone with a history of urothelial neoplasia, it most likely indicates early recurrence of papillary neoplasia and warrants continued close follow-up. Molecular data also demonstrate that at least a proportion of papillary hyperplasia represents precancerous lesions of the bladder that subsequently progress to papillary bladder cancer (3).

TABLE 3.1 The WHO/International Society of Urological Pathology Consensus Classification of Papillary Urothelial (Transitional Cell) Lesions

Hyperplasia
	Papillary hyperplasia
Papillary neoplasms
	Papilloma
	Papillary neoplasm of low malignant potential
	Papillary carcinoma, low-grade
	Papillary carcinoma, high-grade

Less commonly, the overlying urothelium in a lesion with the architectural pattern of papillary hyperplasia reveals varying degrees of cytologic atypia ranging from dysplasia to CIS (4) (Fig. 3.7) (efigs 3.8, 3.9). One hypothesis is that, in some cases, CIS or dysplasia may evolve into a papillary lesion, with further progression to a high-grade papillary cancer. This process is analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms. In cases of CIS or dysplasia with the architecture of papillary hyperplasia, reasonable diagnoses are “CIS with early papillary formation” and “dysplasia with early papillary formation.” Patients will be treated for CIS or dysplasia, respectively, yet the diagnoses correlate with the cystoscopic appearance of a slightly papillary lesion.

PAPILLARY UROTHELIAL NEOPLASMS

Background

The classification and grading of papillary urothelial neoplasms have been a long-standing source of controversy (5). There are numerous grading systems, most of which have poor interobserver reproducibility, with most cases falling into an intermediate category (6, 7, 8, 9, 10, 11, 12, 13). The most commonly used grading systems for bladder tumors have been those proposed by the WHO. In 1973, the WHO system proposed that tumors be categorized into benign urothelial papillomas and three grades of carcinoma (grades 1, 2, and 3) (8). A major limitation of the WHO (1973) grading system was its vague definition of the various grades and its lack of specific histologic criteria. The following statement is the sole description of the difference among WHO grades 1, 2, and 3 as written in the original WHO (1973) system: “Grade 1 tumors have the least degree of anaplasia compatible with the diagnosis of malignancy. Grade 3 applies to tumors with the most severe degrees of cellular anaplasia, and Grade 2 lies in between.” In December 1998, members of WHO and ISUP published the WHO/ISUP consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder (1). This new classification system arose out of the need to develop a more detailed classification system for bladder neoplasia and because many of the tumors classified as “transitional cell carcinoma, grade 1” had no potential for malignant behavior once completely excised. In 2004, WHO revised its classification of urothelial tumors, adopting the WHO/ISUP system, resulting in a unified grading system for urothelial tumors (14). Because these systems are identical, in this text, the grading system is referred to as the WHO/ISUP system.

TABLE 3.2 Histologic Features of Papillary Urothelial Lesions

		Papilloma	Papillary Neoplasm of Low Malignant Potential	Low-Grade Papillary Carcinoma	High-Grade Papillary Carcinoma
Architecture of papillae		Delicate	Delicate; occasionally fused	Fused; branching; delicate	Fused; branching; delicate
Organization of cells		Identical to normal	Polarity identical to normal; any thickness; cohesive	Predominantly ordered, yet minimal crowding and minimal loss of polarity; any thickness; cohesive	Predominantly disordered with frequent loss of polarity; any thickness; often discohesive
Cytology
	Nuclear size	Identical to normal	May be uniformly enlarged	Enlarged with variation in size	Enlarged with variation in size
	Nuclear shape	Identical to normal	Elongated; round-oval; uniform	Round-oval; slight variation in shape and contour	Moderate—marked pleomorphism
	Nuclear chromatin	Fine	Fine	Mild variation within and between cells	Moderate—marked variation within and between cells with hyperchromasia
	Nucleoli	Absent	Absent to inconspicuous	Usually inconspicuous^a	Multiple prominent nucleoli may be present
	Mitoses	Absent	Rare; basal	Occasional, at any level	Usually frequent, at any level; may be atypical
	Umbrella cells	Uniformly present	Present	Usually present	May be present
^aIf present, small and regular and not accompanied by other features of high-grade carcinoma.

FIGURE 3.1 Papillary urothelial hyperplasia.

FIGURE 3.2 Papillary urothelial hyperplasia.

FIGURE 3.3 Papillary urothelial hyperplasia.

FIGURE 3.4 Papillary urothelial hyperplasia with tall folds. Some would regard as early papilloma.

FIGURE 3.5 Papillary urothelial hyperplasia (right and inset) adjacent to urothelial papilloma (left).

FIGURE 3.6 Papillary urothelial hyperplasia starting to develop branched fronds and “detached-appearing” papillary fronds diagnostic of early urothelial papilloma.

WHO/ISUP System

The WHO/ISUP system is a modified version of the scheme proposed by Malmström et al. (11) One of the major contributions of the WHO/ISUP system is a detailed histologic description of the various grades, using specific cytologic and architectural criteria. These criteria are based on
the architectural features relating to the histology of the papillae and the overall organization of the cells. Cytologic features encompassed in the WHO/ISUP system include nuclear size, nuclear shape, chromatin content, nucleoli, mitoses, and umbrella cells. Papillary tumors may show heterogeneity of grade. Tumors are graded based on the highest grade exhibited, although it remains to be defined what percentage is minimally needed to place tumors in a higher category when the highest grade is focal (see “High grade papillary carcinoma”). The terminology used in the WHO/ISUP system for carcinomas is consistent with that used in urine cytology.

FIGURE 3.7 CIS with early papillary formation.

Relation of WHO (1973) to WHO/ISUP

A major misconception in the application of the WHO/ISUP classification is that there is a one-to-one translation between it and the WHO (1973) classification system (Fig. 3.8). Only at the extremes of grades in the WHO (1973) classification does this one-to-one correlation hold true. Lesions called papilloma in the WHO (1973) classification system are also called papilloma in the WHO/ISUP system. At the other end of the grading extreme, lesions called WHO (1973) grade 3 are, by definition, high-grade carcinoma in the WHO/ISUP system. However, for WHO (1973) grades 1 and 2, there is no direct translation to WHO/ISUP classification system. Rather, lesions must be analyzed using the criteria of the WHO/ISUP classification system without regard to how they were diagnosed in WHO (1973) system. Lesions formerly called WHO (1973) grade 1, which upon review show no cytologic atypia and merely thickened urothelium with, at most, nuclear enlargement, would be called
papillary urothelial neoplasms of low malignant potential (PUNLMP). However, other WHO (1973) grade 1 lesions with definite yet slight cytologic atypia would be diagnosed in the WHO/ISUP system as low-grade urothelial carcinomas.

FIGURE 3.8 Relationship of WHO (1973) to WHO (2003)/ISUP classification of papillary urothelial tumors.

Within the WHO (1973) system, grade 2 is a very broad category. It includes lesions that are relatively bland, which, in some places, are diagnosed as WHO (1973) grade 1-2; these lesions in the WHO/ISUP system would be called papillary urothelial low-grade carcinoma. In other cases, WHO (1973) grade 2 lesions border on higher grade lesions and, in many institutions, are called WHO (1973) grade 2-3; these lesions in the WHO/ISUP classification system would be called high-grade carcinoma. In the old WHO (1973) system, a large percentage of patients with noninvasive papillary urothelial carcinomas were called grade 2, an ambiguous group that the urologists did not know how to treat. In the WHO/ISUP grading system, these grade 2 tumors can be segregated roughly equally into low- and high-grade cancers with correspondingly low and high risks of progression (15, 16, 17). When WHO (1973) grade 2 tumors are reclassified as high-grade tumors, they show molecular aberrations usually associated with cancers of higher grade and poor outcome, further supporting that WHO (1973) grade 2 tumors form a heterogeneous group that can be subdivided into low- and high-grade cancers (18).

There have been several studies comparing WHO (1973) and the current WHO/ISUP system. Most have demonstrated a superiority of WHO/ISUP in predicting recurrence and progression or interobserver reproducibility (15, 19, 20, 21, 22). Whether routine ancillary studies such as immunohistochemical or molecular markers will aid us in better stratifying these tumors into distinct risk groups remains to be proven.

Others have reported no difference in interobserver reproducibility of WHO/ISUP compared to WHO (1973), although in some of these works, the WHO/ISUP grade was merely translated from the WHO (1973) grade, which, as described earlier, is inaccurate (23, 24, 25). In another study comparing the two grading systems, there was no difference in survival, yet one would not expect a difference in survival as the vast majority of papillary urothelial neoplasms do not result in the death of the patient; the more appropriate endpoints to evaluate are progression (in grade or stage) and recurrence (26).

Papilloma

Using the WHO (1973) system, some experts applied very restrictive criteria for the diagnosis of urothelial papilloma, in part based on the number of cell layers, and regarded all other papillary neoplasms as carcinomas. Others applied a broader definition of “urothelial papilloma” so as not to label all patients with papillary lesions with minimal cytologic and architectural atypia as having carcinoma.

The WHO/ISUP system has very restrictive histologic features for the diagnosis of papilloma, requiring papillary fronds to be lined by normal
appearing urothelium (Figs. 3.9, 3.10, 3.11, 3.12, 3.13 and 3.14) (efigs 3.10-3.45). Most papillomas present as single lesions that are relatively small. However, multifocal tumors and larger lesions may be seen.

FIGURE 3.9 Urothelial papilloma with atypical umbrella cells.

Most papillomas have a simple nonbranching or minimally branching arrangement, slender fibrovascular stalks, and a predominantly exophytic pattern. In some papillomas, more complex anastomosing papillae, marked stromal edema within the papillae, and endophytic areas (areas of inverted papilloma) can be identified (Figs. 3.15, 3.16).

Within the limits of normal urothelial thickness, there is some variability. Uncommon cases may be composed of only one to two cell layers of urothelium. There is no need to count the maximum number of cell layers, as long as it is not obviously thicker than the normal urothelial lining. In most cases, the urothelium is tightly cohesive, although in some cases, there may be the appearance of discohesion. Umbrella cells vary in their morphology from being inconspicuous to being cuboidal with slightly enlarged nuclei and paler cytoplasm to having a hobnail appearance with abundant eosinophilic cytoplasm. Occasional cases of urothelial papilloma have an umbrella cell layer with prominent vacuolization. Single, enlarged umbrella cells may also drape themselves over several underlying urothelial cells, where the umbrella cell nuclei may demonstrate degenerative atypia. Urothelial atypia, other than that which can be seen in umbrella cells, excludes the diagnosis of papilloma. Mitotic figures are absent.

FIGURE 3.10 Urothelial papilloma. There is a consistent umbrella cell layer in which the cells appear slightly enlarged: this feature does not argue against a diagnosis of papilloma.

FIGURE 3.11 Urothelial papilloma.

FIGURE 3.12 Urothelial papilloma with cuboidal umbrella cells with clear cytoplasm.

FIGURE 3.13 Urothelial papilloma with vacuolated umbrella cells. Note foam cells in a papillary core.

Papillomas are rare and typically, but not exclusively, occur in younger patients. Papillomas may occur in association with a prior or concurrent history of other urothelial tumors. However, if a papilloma is the first manifestation of urothelial neoplasia, only about 7% to 8% recur, typically within 5 years of the initial diagnosis (16, 25, 27, 28, 29, 30). Lesions typically recur as papilloma and less commonly as PUNLMP or noninvasive low-grade papillary urothelial carcinoma. Of the three largest series on papillomas totaling 112 patients, only one patient experienced stage
progression; invasive urothelial carcinoma was found extending out of the bladder 4 years after the diagnosis of papilloma (27, 28, 30). A caveat to this exceptional case is that the patient was immunosuppressed following renal transplantation.