Elsevier

European Urology

Volume 51, Issue 4, April 2007, Pages 889-898
European Urology

Review – Bladder Cancer
Histologic Grading of Noninvasive Papillary Urothelial Neoplasms

https://doi.org/10.1016/j.eururo.2006.10.037Get rights and content

Abstract

Objectives

In 1998, a revised system of classifying noninvasive papillary urothelial neoplasms of the urinary bladder was proposed and subsequently formally adopted by the World Health Organization (WHO). The introduction of this new system was justified as being potentially superior on a number of levels to the 1973 WHO classification system that it replaced. Specifically, a new category of neoplasms, designated papillary urothelial neoplasm of low malignant potential (PUNLMP), was considered advantageous for several reasons. The new system was expected to gain widespread acceptance, improve reproducibility of diagnoses among pathologists, and enhance the correlation between urine cytology and tumor histology. We examine the history of the changes in terminology for these lesions, the relative merits of PUNLMP terminology, the extent to which the expectations accompanying the new grading system have been met, and the extent to which the new system has enhanced the management of patients with noninvasive papillary urothelial neoplasms of the bladder.

Methods

A PubMed literature search after the introduction of this new classification was performed and relevant papers reviewed.

Results and Conclusions

The 2004 WHO classification is a positive initiative in attempting to standardize urothelial tumor grading by expanding and clearly defining the morphologic characteristics of noninvasive papillary urothelial neoplasms. The new terminology used in this system is of questionable validity and utility. Full-genome searches for prognostic and predictive molecular gene expression signatures, GeneChip technology and proteomics techniques, and several new biomarkers and molecular tests may be useful in future grading schemes after their clinical utility is better established.

Introduction

Nearly half of all bladder tumors are noninvasive (stage pTa) papillary neoplasms of urothelial origin. These tumors have been intensively investigated for many decades, and a number of concepts regarding their biologic behavior and prognosis have been well established. Prognosis for these tumors is influenced by tumor size, tumor multifocality, recurrence status, coexistence of carcinoma in situ, and histologic tumor grade [1]. The first four elements are straightforward. However, there has been a long-standing lack of agreement among pathologists concerning the ideal system for grading these tumors. In this review, we examine this controversy, limiting our discussion to two grading systems, one of which (1973 World Health Organization [WHO]) was extensively used for several decades, and the other of which (2004 WHO) has been recommended as its replacement.

Section snippets

Historical perspective

In the 1973 WHO classification of urothelial tumors, papillary urothelial neoplasms were separated into four categories: papilloma, and carcinoma grades 1–3 [2]. Papillomas were defined as exophytic tumors consisting of delicate fibrovascular cores covered by normal-looking urothelium with intact umbrella cells and virtually lacking mitotic activity. Clinically, these tumors are typically solitary and <1.0 cm in diameter, occur in patients <50 yr old, and have a negligible recurrence rate [3].

Are the 1973 WHO and 2004 WHO classification systems interchangeable?

The 2004 WHO classification system divides noninvasive papillary urothelial tumors into four categories as noted above. The definition for papilloma is the same in both the 1973 WHO and the 2004 WHO systems [6]. The authors of the new classification system have emphasized that the three newly introduced categories (PUNLMP, low-grade carcinoma, and high-grade carcinoma) are not directly interchangeable with the three 1973 WHO grades of carcinoma. The 1973 WHO grade 1 carcinomas are reassigned,

What is a PUNLMP and what is its biologic behavior?

This lesion is histologically defined by the 2004 WHO classification system as a papillary urothelial tumor that resembles the exophytic urothelial papilloma but shows increased cellular proliferation exceeding the thickness of normal urothelium (Fig. 1) [7]. It is characterized by papillary structures lined by an orderly arrangement of urothelial cells with minimal architectural abnormalities and minimal nuclear atypia [8]. Most, if not all, of these tumors would be diagnosed as grade 1

Is PUNLMP actually carcinoma?

Considering these studies of the biologic behavior and the molecular characteristics of PUNLMP, it seems evident that PUNLMP is an indolent variety of what we generally regard as “carcinoma.” A diagnosis of PUNLMP implies a real and significant potential for an adverse clinical outcome that does not differ greatly from that of 2004 WHO low-grade noninvasive urothelial carcinomas. By convention, appropriately or otherwise, the term “carcinoma” is routinely used to describe noninvasive neoplasms

Does the 2004 WHO classification system improve reproducibility?

All grading systems are hampered by varying degrees of subjectivity that affect interobserver reproducibility. For example, Coblentz et al. found that 18% of bladder specimens with a referring diagnosis of urothelial carcinoma were found to have significant differences in diagnosis, stage, grade, or histologic tumor types when a second pathologist rendered an opinion [20]. Published reports of the reproducibility of grading systems are often derived from the efforts of small groups of

Has the 2004 WHO grading system enhanced diagnostic accuracy in urine cytology?

The authors of the 2004 WHO classification acknowledged that PUNLMP tumors would be difficult to diagnose by urinary cytopathology because of their minimal cytologic atypia. They postulated that the majority of 2004 WHO low-grade carcinomas could be diagnosed by this method [8]. Whisnant et al. correlated histologic findings in 86 transurethrally resected specimens representing a wide spectrum of papillary urothelial neoplasms with their corresponding urine cytology specimens [24]. They

Has the 2004 WHO classification system facilitated changes in clinical management of papillary urothelial neoplasms?

In the past few decades it has been and still is well understood by most practicing urologists that noninvasive papillary urothelial tumors of all WHO 1973 grades require follow-up to detect recurrence or progression, despite the fact that grade 1 tumors are characteristically associated with an excellent prognosis. The length of clinical follow-up, the frequency of surveillance cystoscopy, and the adjunctive use of intravesical instillations of bacillus Calmette-Guérin (BCG) or a variety of

Conclusions

The new 2004 WHO classification is a positive initiative in attempting to standardize urothelial tumor grading by expanding and clearly defining the morphologic characteristics of noninvasive papillary urothelial neoplasms. The new terminology used in this system is of questionable validity and utility. The creation of the category of “papillary urothelial neoplasm of low malignant potential” (PUNLMP) is especially contentious. It is unproven that this designation is any less a “psychosocial

Conflicts of interest

None of the authors (Gregory T. MacLennan, MD, Ziya Kirkali, MD, Liang Cheng, MD) have any commercial relationship such as consultancies, stock ownership or other equity interests, patents received and/or pending, or any commercial relationship which might be in any way considered related to a submitted article.

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