Unfortunately, there are many problems with the pathologic evaluation of these tumors, mostly due to the inherent subjectivity of the field and the lack of universal, standardized criteria for the evaluation of the above-mentioned morphologic parameters. Nowhere is this issue more apparent than in grading. In many, if not all, sites there is significant interobserver variability when it comes to grading. We tend to agree better at the extremes, that is to say that we agree with what is benign and what is high grade. We do less well segregating the degrees of dysplasia, separating "significant atypia" from low grade carcinoma, low grade from intermediate grade carcinoma, and intermediate grade from high grade carcinoma. In fact, in any classification scheme, the more options we are given the poorer the interobserver variability. These statements do not apply solely to bladder cancer but to most tumors.

Another issue that compounds the problem is the fact that multiple other factors such as age, recurrences, status of the adjacent mucosa, and size affect the biologic behavior of a tumor. As such, it is wise for us to look at our role in the morphological assessment of bladder tumors as but one component in risk prognostication.

Grading of Urothelial Tumors
Grading is a method by which pathologists evaluate the cytologic and/or growth pattern characteristics of a tumor in an attempt to predict its biologic potential. To this effect, multiple grading schemes have been developed and employed throughout the years. In all classifications, those lesions which cytologically resemble normal urothelium are low grade (well differentiated) while cytologic anaplasia characterized high grade or poorly differentiated carcinomas. Nevertheless, classifications differ in their recognition of a benign tumor counterpart and in the number of categories into which transitional cell carcinoma should be graded.

In October 1997, Dr. F.K. Mostofi assembled a group of pathologists, urologists, urologic oncologists, and basic scientists with an interest in bladder neoplasia at a meeting in Washington, D.C. with the purpose of discussing the terminology of bladder lesions and making recommendations to the World Health Organization (WHO) Committee on Urothelial Tumors. All in attendance agreed that it was imperative to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by pathologists, urologists, and oncologists. Following this meeting, a group of urologic pathologists who had attended the Washington meeting decided to broaden the representation of the group and arranged a meeting primarily of the members of the International Society of Urologic Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston, Massachusetts. At this meeting issues regarding terminology of bladder lesions ¾ primarily neoplastic and putative preneoplastic lesions ¾ were discussed, resulting in a consensus statement. In December 1998, barely 14 months from the beginning of this initiative, we published the WHO/ISUP consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder.

CLASSIFICATION OF UROTHELIAL (TRANSITIONAL CELL) NEOPLASMS

NORMAL Normal* HYPERPLASIA Flat Hyperplasia Papillary Hyperplasia FLAT LESIONS WITH ATYPIA Reactive (Inflammatory) Atypia Atypia of Unknown Significance Dysplasia (Low-grade Intraurothelial Neoplasia) Carcinoma In-Situ (High-grade Intraurothelial Neoplasia)** PAPILLARY NEOPLASMS Papilloma Inverted Papilloma Papillary Neoplasm of Low Malignant Potential Papillary Carcinoma, Low-grade Papillary Carcinoma, High-grade*** INVASIVE NEOPLASMS Lamina Propria Invasion Muscularis Propria (Detrusor Muscle) Invasion *May include cases formerly diagnosed as "mild dysplasia" ** Includes cases with "severe dysplasia" *** Option exists to add comment as to the presence of marked anaplasia

Normal Urothelium:

• Although the terms "urothelium" and "transitional epithelium" are synonymous and may be used interchangeably.
• Many pathologists overuse the diagnosis of "mild dysplasia". Flat lesions with minimal cytologic atypia and architectural disorder should be designated as normal rather than as mild dysplasia.

1. Flat Urothelial Hyperplasia
   • Flat urothelial hyperplasia consists of a markedly thickened mucosa without cytologic atypia.
   • This lesion may be seen adjacent to low grade papillary urothelial neoplasms, but there is no data as to its premalignant potential when seen by itself.
2. Papillary Urothelial Hyperplasia
   • This term in the past has been used imprecisely, frequently to describe polypoid cystitis, an inflammatory and reactive condition.
   • Characterized by urothelium of variable thickness without atypia and exhibiting a slight "tenting", undulating, or papillary growth. These areas lack fibrovascular cores but often have one or several dilated capillaries at its base.
   • The relationship between this lesion and papillary urothelial neoplasia is controversial, although it is frequently associated with either a prior or concurrent history of papillary bladder cancer.

1. Reactive atypia
   
   • Reactive (inflammatory) atypia consists of nuclear abnormalities occurring in acutely or chronically inflamed urothelium.
   • This lesion should not be considered neoplastic.
2. Atypia of unknown significance
   • In some cases it is difficult to differentiate between reactive and neoplastic atypia, due to a greater degree of pleomorphism and/or hyperchromatism out of proportion with the extent of inflammation.
   • This designation will allow patients to be followed more closely and re-evaluated once the inflammation subsides.
3. Dysplasia: Low-grade Intraurothelial Neoplasia
   • Dysplastic urothelium (low-grade intraurothelial neoplasia) has appreciable cytologic and architectural abnormalities felt to be neoplastic, yet falling short of the diagnostic threshold for urothelial carcinoma in situ.
   • Because of problems with interobserver reproducibility, the lack of a uniform definition, and confusing reports in the literature, the natural history of dysplasia in humans is poorly understood.
   • There is some evidence along several lines of investigation that dysplasia may be a precursor of invasive carcinoma.
4. Carcinoma in situ (High-grade Intraurothelial Neoplasia)
   • Carcinoma in situ (CIS) is a flat lesion of the urothelium that is a documented precursor of invasive cancer in many cases.
   • Characterized by the presence of cells with large, irregular, hyperchromatic nuclei that may be either present the entire thickness of the epithelium or only part of it.
   • Urothelial carcinoma in situ is frequently underdiagnosed and described as moderate dysplasia or atypia.
   • CIS cells may be found scattered within the urothelium, have a pagetoid spread, or present as isolated cells in a partially denuded surface; b) high nuclear to cytoplasmic ratio is not necessarily seen in CIS; c) umbrella cells may still be present overlying; and, d) there is a wide spectrum of cytologic features and degree of cytologic atypia, despite the fact that, by definition, all CIS are high grade lesions.

Another source of controversy lies in the grading of papillary urothelial carcinomas. There are numerous grading systems, all of which have poor interobserver reproducibility with most cases falling into the intermediate category. One system, which is a modified version of the scheme proposed by Malstrom et al., was recently evaluated by a group of the consensus committee and found to be fairly reproducible. It is described below.

1. Urothelial Papilloma
   • Discrete, exophytic papillary growth with a central fibrovascular core lined by urothelium of normal thickness and cytology.
   • It is a rare benign condition typically occurring as a small, isolated growth seen primarily, but not exclusively, in younger patients.
2. Inverted Urothelial Papilloma
   • Endophytic lesion which shares several features with exophytic urothelial papilloma.
   • Rarely, hybrid cases exist with portions of the lesion resembling exophytic urothelial papilloma and others inverted urothelial papilloma.
   • Inverted papillomas have a low risk of recurrence when completely excised.
   • May be seen in patients with a history of urothelial carcinoma, and rarely, urothelial carcinoma may arise within inverted urothelial papilloma.
3. Papillary Urothelial Neoplasm of Low Malignant Potential
   • 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.
   • Mitoses are infrequent and usually limited to the basal layer.
   • But in exceptional cases, a papillary urothelial neoplasm of low malignant potential is not associated with invasion or metastasis.
   • It is a clinically important lesion because patients are at an increased risk of developing recurrent or new papillary lesions.
   • Patients with papillary urothelial neoplasms of low malignant potential are at risk of developing new bladder tumors ("recurrence"), usually of similar histology. However, occasionally these subsequent lesions manifest as urothelial carcinoma, such that follow-up of the patient is warranted.
4. Papillary Urothelial Carcinoma, Low Grade
   • Exhibit an overall orderly appearance but have variability in architecture and/or cytologic features which are easily recognizable at scanning magnification.
   • 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 usually limited to the lower half.
   • Common to see fusion of adjacent papillae, a feature that may lead to overgrading due to an appearance of disorder.
   • Frequently recur, may invade the bladder wall, and have a low (<5%) risk of progression.
5. Papillary Urothelial Carcinoma, High Grade
   • Characterized by a disorderly appearance due to marked architectural and cytologic abnormalities, recognizable at low magnification.
   • Cellular pleomorphism ranges from moderate to marked.
   • Mitotic figures, including atypical forms, are frequently seen at all levels of the urothelium.
   • Pathologists are free to comment on the presence of "anaplasia".
   • Progression rate varies from 15% to 40%, much higher than low grade lesions.
   • Commonly associated with invasive disease at the time of initial presentation and the adjacent mucosa may show evidence of CIS.

What has happened since the publication of this "consensus" classification has not been pretty. Suffice it to say that it has not been universally accepted with pockets of resistance within the pathology as well as urology communities. In fact some of the members of the panel that participated in the original paper went on to discredit it. One of the major sources of criticism was the fact that the classification was not based on hard data but rather the "experience" of seasoned pathologists. Several papers, including well-designed studies from the Malström group in fact validated the classification, whereas others questioned several aspects, particularly lumping a variety of tumors into a high grade category. The 1999 edition of the World Health Organization International Classification of Tumors subclassified tumors into LMP, grades 1, 2, and 3 disease.

There was a meeting held in Ancona, Italy in 2001 which was promulgated as a "consensus meeting" regarding grading, which suggested reverting to 1973 WHO classification but, quite frankly, all sides of the debate were not represented so it is difficult to give their conclusions much significance. Luckily, relief may be on the horizon. Late last year and under the auspices of the WHO, a group of urologic pathologists met in Lyon to discuss and finalize the new "Blue Book" on the pathology and genetics of tumors of the urinary system. I understand that the 1998 WHO/ISUP classification was accepted with few changes and few dissenting votes. It is imperative that we move on to more important issues if we are to move ahead as a field. Rather than arguing about classification, we should be participating in multidiciplinary studies evaluating multiple risk factors, including molecular markers, to stratify patients into prognostic groups better.

Invasive Urothelial Neoplasms:

Staging of Bladder Cancer:
In invasive disease, the most powerful prognostic factor is stage. Both the Jewett-Marshall and the AJCC classifications are able to stratify patients based on the depth of invasion; superficial disease (Ta,T₁) has an excellent prognosis while survival greatly decreases in deeply invasive tumors (T₂-T₃b). Pathologic staging takes on greater importance since we know that clinical over- or understaging may occur in up to 40% of cases. Unfortunately, pathologic staging also has its problems. Pathologists do not agree as to what constitutes lamina propria invasion. There are many cases of T₁ disease which are unequivocal but there are an equal number in which invasion is minimal or not existent. Pathologists' interpretations in the latter group are inconsistent and not reproducible. This lack of consistency is responsible, in great part, for the clinicians' lumping of TA and T₁ tumors together into one prognostic group ("superficial disease"). Obviously, better parameters are needed to make this distinction and furthermore, should be adhered to by all pathologists. Studies evaluating the biologic differences between pTa and clear-cut pT₁ lesions would be interesting and very informative.

Accurate pathologic staging requires knowledge of the basic histology of the organ in question. In the urinary bladder, transitional epithelium (urothelium) overlies a basement membrane and lamina propria composed of connective tissue, vascular and neural structures. The lamina propria in turn is enveloped by a muscularis propria with its thick but poorly oriented muscle bundles. In transurethral biopsy material the tissue chips are frequently poorly oriented (not cut perpendicular to the bladder wall). This fact by itself may make it difficult to establish depth of invasion. Also, it is evident that the urinary bladder wall thickness is not uniform. In fact, even in the undistended bladder, the lamina propria is much attenuated (and consequently the muscularis propria is closer to the epithelial surface) in the area of the trigone, bladder neck and adjacent to the ureteral orifices.

The lamina propria is a connective tissue layer that lies directly under the urothelium, which commonly contains interrupted fascicles of smooth muscle known as muscularis mucosae. The larger smooth muscle bundles beneath the lamina propria are referred to as either the muscularis propria or detrusor muscle. The term "superficial bladder cancer" should not be used as it lumps together three morphologically and biologically distinct lesions: CIS, noninvasive papillary neoplasia, and carcinoma with lamina propria invasion. The terms "superficial muscle invasion" and "deep muscle invasion" should not be used since these terms are employed by some to indicate the extent of muscularis propria invasion and by others to denote muscularis mucosae and muscularis propria invasion, respectively. Invasive tumors should be graded as low or high, analogous to the scheme used for grading noninvasive papillary lesions.

a) Lamina Propria Invasion

• Characterized by the presence of urothelial nests, clusters, or single cells within the lamina propria.
• Tumor cells may have abundant eosinophilic cytoplasm at the advancing edge of the infiltrating nests (so-called "paradoxical differentiation").
• Often associated with a desmoplastic or inflammatory stromal response that is not always conspicuous.
• Nests of invasive tumor within the lamina propria may exhibit prominent retraction artefact which is frequently overdiagnosed as vascular invasion. Vascular invasion in cases with lamina propria invasion is uncommon and the diagnosis should be reserved for unequivocal cases or those confirmed by immunohistochemistry.

In slightly over 50% of transurethral resection specimens it is possible to identify the mid level of the lamina propria characterized by the presence of muscularis mucosae and/or medium caliber thick-walled vessels. While some investigators have shown that it is possible to substage tumor invading the lamina propria based on these anatomic landmarks, pathologists should not universally adopt this practice. It is often difficult to identify the depth of lamina propria invasion due to the lack of orientation in the TUR chips or because of the absence of muscularis mucosae and thick-walled vessels. Nevertheless, pathologists are encouraged to provide some assessment as to the extent of lamina propria invasion. If the tumor invades muscularis mucosae, this fact may (but need not) be mentioned in the report. If it is mentioned, the wording should be unambiguous so that the urologist does not confuse muscularis mucosae with muscularis propria. The presence or absence of muscularis propria in the specimen should always be mentioned, even in cases of noninvasive disease, with the purpose of giving feedback to the urologist as to the depth of their biopsy.

b) Muscularis propria (Detrusor Muscle) Invasion

• Characterized by tumor cells which infiltrate thick muscle bundles.
• In cases where there is uncertainty as to the depth of invasion, this fact should be conveyed to the urologist so that a restaging TUR be performed.
• In a TUR specimen there should be no attempt to substage the depth of muscularis propria invasion.
• The presence of tumor in fat is not diagnostic of extra-vesicle disease, as adipose tissue may be seen within the lamina propria.

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