Ask the Doctor

Fall 2008

Our questions for this issue of Outlook are answered by Dr. Donna Hansel, Assistant Professor, Department of Pathology and Laboratory Medicine at Taussig Cancer Center at Cleveland Clinic. We sincerely appreciate her sharing her expertise in explaining terminology commonly used in urine cytology and biopsy reports.

Q. In reviewing a urine cytology report, the terms “negative” or “positive” are easy to understand. Sometimes, however, the results are not so definitive, and the terms “atypical” or “suspicious for TCC” are used. What do these terms mean, and how should such results be interpreted by the patient and his/her doctor?

A. Urine cytology is commonly used in patients who have hematuria (blood in the urine) or other urinary tract symptoms that raise the suspicion for urothelial cancer. The cytologic examination is a microscopic examination performed by a pathologist with subspecialty training in cytopathology and is extremely useful for identifying a variety of conditions ranging from inflammation to cancer. The general cytopathologic evaluation considers cells that are shed from the lining of the bladder into the urine and generally includes either single cells or small groups of cells.

Urine cytology is most useful in the diagnosis of high-grade papillary urothelial carcinoma, flat urothelial carcinoma in situ (CIS) or invasive urothelial carcinoma; these forms of high-grade bladder cancer are often characterized by loss of cell adhesion molecules – factors that normally allow cells to maintain binding to the bladder surface and to one another – resulting in cancer cells shed into the urine. In contrast, low-grade tumors present more of a challenge due to their ability to cytologically resemble normal urothelial cells and lower incidence in the urine.

On occasion, atypical cells are present in the urine that defy further characterization, either due to low numbers of cells to examine or lack of definitive features for high-grade malignancy. In addition, a variety of non-cancerous conditions can cytologically mimic high-grade cancer, including viral infection, reactive changes due to urinary tract stones or infection, radiation treatment, among many others. As a good example, human polyoma virus (BK virus) cytologically resembles cells of flat CIS and these cells have been termed “decoy” cells for obvious reasons. Fortunately, for many of the mimickers specific microscopic features or additional tests will lead to a definitive diagnosis. Yet despite this, there are still a small number of cases that share some – but not all – of the features of high-grade urothelial cancer that cannot be definitively diagnosed. These cases are termed “atypical cells” that may be “suspicious for urothelial carcinoma.” Patients with this diagnosis are often followed closely for the development of urothelial carcinoma, often with repeated urine cytologies. Although several molecular tests for urothelial cancer on urine cytology currently exist (one of the most common is the UroVysion test), these are typically used in a supporting role to the microscopic urine cytology rather than in lieu of it. Ongoing research in this field will hopefully yield more specific tests that will reduce the percentage of “atypical” cases and provide a more complete and detailed picture of the underlying changes in the urothelial lining.

Q: Please explain the difference between the “stage” and “grade” of a bladder tumor. Why is it possible for two different pathologists to arrive at different conclusions as to the stage and grade of one specific bladder tumor?

A. Over the past several decades, the terminology of bladder tumors has undergone tremendous changes based on our improved knowledge of the molecular changes that define this group of entities. The most recent classification scheme is based on the 1998 World Heath Organization/International Society of Urologic Pathology, which outlines microscopic criteria for the classification of urothelial (formerly, “transitional”) tumors. In this classification scheme, urothelial tumors are defined by both stage (pT) and grade (e.g., low- and high-grade), among other features.

Stage represents the depth of invasion into the bladder wall, including (in order of increasing stage) lamina propria, muscularis propria (detrusor muscle), perivesical fat and adjacent organs. Typically, there is fairly good concordance between different pathologists in the identification of pathologic stage, with the caveat that there is occasional difficulty in the distinction of the muscularis propria (detrusor muscle) layer. This layer of the bladder wall consists of large bundles of smooth muscle that are readily identifiable in normal bladder specimens, but can become markedly distorted and disrupted when invaded by urothelial carcinoma. In addition, smaller bundles of smooth muscle (”muscularis mucosa”) are present in the superficial layers of the bladder that may also be difficult to distinguish from muscularis propria in small biopsy material. The identification of the muscularis propria is critically important in the setting of transurethral resection specimens and biopsies, where invasion into the muscularis propria indicates the need for radical cystectomy in most cases. Due to the critical importance of recognizing this part of the bladder wall, many researchers have recently focused on identifying markers specific for the muscularis propria, with the hope that within the next several years new techniques to aid in the diagnosis of this layer of the bladder wall will be developed.

The grade of a urothelial tumor is determined at the microscopic level by a defined set of criteria. In general, the distinction has been made between low-grade and high-grade tumors, with the latter representing entities with an increased propensity for invasive and metastatic disease on numerous patient follow-up studies. The non-invasive neoplastic entities are divided into flat lesions (urothelial dysplasia, flat urothelial carcinoma in situ) and papillary lesions (papilloma, papillary urothelial neoplasm of uncertain malignant potential, low-grade papillary urothelial carcinoma, high-grade papillary urothelial carcinoma). Invasive urothelial carcinomas are typically considered high-grade lesions. The new classification scheme has been validated in part by molecular evidence suggesting different oncogenic pathways in these microscopically defined entities, including FGFR3 mutations in low-grade lesions and p53 mutations in high-grade lesions.

Despite the rigorous microscopic criteria set forth in the definition of these numerous forms of bladder cancer, the diagnosis often is challenging for a number of common reasons that include small size of some biopsy specimens, procedural artifact in obtaining the biopsy and limited orientation of specimens received for analysis. In some instances, these additional factors impact the interpretation of biopsy material, thus leading to discrepancy in staging and grading. Fortunately, with careful clinical follow-up and discussion with the consulting pathologist, proper patient care is ensured.