Elsevier

The Lancet

Volume 353, Issue 9157, 20 March 1999, Pages 974-977
The Lancet

Early Report
Expression of cytokeratin 20 redefines urothelial papillomas of the bladder

https://doi.org/10.1016/S0140-6736(98)05383-5Get rights and content

Summary

Background

Most non-invasive urothelial tumours of the bladder are diagnosed as papillary carcinomas in accordance with the WHO classification and because the identification of papillomas is difficult by routine histology; some patients are therefore misdiagnosed. This practice is associated with psychological morbidity for the patient and may also skew cancer statistics. Cytokeratin 20 (CK20) is a sensitive marker of urothelial differentiation. We investigated whether this marker could be used in the identification of urothelial papillomas and used the rate of recurrence as an indicator to assess the biological behaviour of such tumours.

Methods

In a prospective study, immunocytochemistry for CK20 was done on tumours of all patients who presented for the first time with non-invasive papillary bladder tumours. We classified the expression pattern of CK20 as normal or abnormal at the time of initial diagnosis. We recorded time to first biopsy-proven recurrence or length of follow-up when no recurrence was observed.

Findings

Of 58 consecutive patients, ten had tumours with a normal pattern of CK20 expression. No patients developed further tumours during the follow-up (median 18 [range 13–28] months). By contrast, 30 (73%) of the 41 evaluable patients with tumours that showed abnormal CK20 expression developed further tumours; the median time to a second tumour was 6 (2–24) months. The only factor that had a significant effect on the outcome of patients in terms of recurrence was expression of CK20 (p<0·0001).

Interpretation

Normal urothelial differentiation, as evidenced by a normal pattern of CK20 expression, is retained in a proportion of non-invasive papillary urothelial tumours and thus justifies use of the term urothelial papilloma. A large-scale study is needed to investigate the outcome of patients with such tumours.

Introduction

The nomenclature of urothelial tumours is unique in that the WHO classification1 recognises non-invasive urothelial carcinomas, despite the fact that it is the invasive behaviour of tumours that leads to local and distant spread, which is the hallmark of the cancer. The definition and diagnosis of urothelial papillomas as benign tumours that do not require further intervention is controversial,2, 3, 4, 5 and in practice is seldom used. The term carcinoma is preferentially used because it triggers a follow-up protocol of regular cystoscopies aimed at the prevention or early identification of invasive disease, which occurs in a small proportion of patients.6 Because it is difficult to reliably identify this small group of patients by means of clinical criteria or standard morphology, all patients are given a diagnosis of cancer. This practice has profound practical and psychological effects for the patient and may also affect cancer statistics. In the Netherlands between 1975 and 1989, there was an increase in age-adjusted incidence of bladder cancer per 100 000 person-years from 25·9 to 40·7 in men and from 3·1 to 8·5 in women. This increase has been attributed to the inclusion of non-invasive tumours after the adoption of the WHO classification and changes in reporting procedures.7

If standard morphology is a poor predictor of outcome in individual patients, it is important to explore more sensitive ways to classify tumours. In normal urothelium, the expression of intermediate filament cytokeratin 20 (CK20) is related to differentiation and is limited to superficial and occasional intermediate cells (figure 1). Abnormalities of urothelial differentiation are accompanied by loss of this restriction, so that expression of CK20 is seen in all cell layers (figure 1).8 We postulated that if a papillary non-invasive tumour retained a normal pattern of CK20 expression, it would fulfil the criteria for the diagnosis of a benign tumour, because of the evidence of normal urothelial organisation and the absence of invasion. If this normal pattern of expression could be associated with low rates of recurrence and no progression, we could then identify a clinically meaningful category of tumours. We have previously identified a subgroup of patients with non-invasive urothelial tumours with a normal pattern of CK20 expression who had no recurrence during 5 years in a retrospective study.9 The study we report aimed to confirm this finding prospectively by an investigation of all new non-invasive tumours with the CK20 marker.

Section snippets

Methods

Between 1994 and 1995, we did immunocytochemistry for CK20 on the tumours of all consecutive patients who presented for the first time with non-invasive papillary tumours (pTa). We expected to recruit 100 patients but only 58 new patients had non-invasive tumours in that period.

The immunolabelling was done on paired sections of the tumour where levels had been cut and on every block of the larger tumours. During the study period, we also stained 167 non-invasive tumours from patients with a

Results

Of the 58 new patients who presented during the study period, seven were given additional intravesical chemotherapy or immunotherapy after diagnosis of a grade 3 tumour. These patients formed a heterogeneous group and were not included in our assessment of recurrence patterns. The other 51 patients (16 women, 35 men, median age 67 [range 34–86] years) were treated according to standard practice by resection and one instillation of mitomycinC (40 mg/40 mL).10 17 patients had grade 1 tumours and

Discussion

Dysregulation of CK20 expression seems to be an early event in the disturbance of urothelial maturation, and can identify mild dysplasia more readily than morphology alone.8 Therefore, retention of a normal pattern, as we have found in a proportion of non-invasive urothelial tumours, is a powerful indicator of normal differentiation, and justifies the terminology of papilloma. In our retrospective series9 with a follow-up of 5 years, there were no instances of recurrence and, therefore, no

References (16)

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    There are many reports supporting a prognostic role of CK20 expression in non-invasive urothelial tumors, with nonrecurrence rates varying from 45% to 100% in the presence of normal CK20 immunoexpression [6,7,11,27,39]. Harnden et al. [6,11] found an abnormal CK20 expression (i.e. expression in all cell layers) to be an independent (p < 0.0001) predictor of tumor recurrence in primary non-invasive papillary LGUCs. Similar results have been showed by Desai et al. [27], who recorded a 44.9% rate of nonrecurrence when a normal CK20 expression pattern was ascertained, as compared to the 63.2% recurrence rate related to an abnormal staining profile.

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