A review of upper urinary tract cytology performance before and after the implementation of The Paris System

Urinary cytology (UC) is one of the primary diagnostic modalities used for the screening and surveillance of urothelial carcinoma. Despite its widespread use, UC has suffered from a lack of standardized or reproducible criteria and wide interobserver variability, particularly of the designation of atypical urothelial cells. The Paris System for Reporting Urinary Cytology (TPS), published in 2016, aimed to provide a standardized approach for evaluating UC by creating diagnostic categories with specific cytomorphologic criteria. Recent studies have primarily investigated the application of TPS on lower urinary tract specimens and have mostly shown that TPS implementation has improved the performance of UC specimens. Only a few studies have reported the impact of TPS on upper urinary tract (UUT) cytology. Additionally, there is uncertainty as to which cytological features are most predictive of high-grade urothelial carcinoma (HGUC) in the UUT. This review summarizes the literature regarding the utility and performance of UUT cytology and highlights findings before and after the implementation of TPS.     

Value of p16(INK4a) in the diagnosis of low-grade urothelial carcinoma of the urinary bladder in urinary cytology

BACKGROUND:

The sensitivity of urinary cytology for the diagnosis of urothelial carcinomas is low, particularly in low‐grade carcinomas. The UroVysion test is a fluorescent in situ hybridization multiprobe assay that increases the sensitivity of urinary cytology. However, this test is not widely available. P16^INK4a, a protein involved in cell cycle progression, is overexpressed in urothelial carcinoma. Immunocytochemical expression of p16^INK4a has been examined in biopsy samples from urothelial carcinomas, but few studies have addressed this protein in urine cytology.

METHODS:

The authors compared the results of p16^INK4a immunoreactivity in cytology and biopsy samples from 83 cases, including low‐grade urothelial carcinomas, reactive epithelial lesions, and negative cases.

RESULTS:

p16^INK4a assessment of in urine cytology samples showed a sensitivity of 66.7% and a specificity of 82.8% in the diagnosis of low‐grade urothelial carcinomas.

CONCLUSIONS:

On the basis of these results, the authors propose that immunocytochemical detection of p16^INK4a is a reliable tool in urine cytology, both for the diagnosis of low‐grade urothelial carcinomas and for follow‐up purposes. More retrospective and prospective studies are required to verify these results. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.     

Reflex UroVysion testing in suspicious urine cytology cases

BACKGROUND:

UroVysion is a US Food and Drug Administration–approved fluorescence in situ hybridization (FISH) probe set for use in the detection of recurrent urothelial carcinoma and in patients with hematuria. The objective of the current study was to evaluate the usefulness of UroVysion as a reflex test in patients with a suspicious urine cytology diagnosis. The rationale was that a more aggressive workup might be indicated in patients with a suspicious cytology diagnosis and positive UroVysion test.

METHODS:

The study population included 161 urine specimens diagnosed as suspicious over a period of 12 months. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (NPV) were calculated based on the histologic and cystoscopic correlation.

RESULTS:

The results using the reporting criteria suggested by the manufacturer demonstrated a sensitivity of 68.3%, a specificity of 39.7%, a PPV of 56.8%, and a NPV of 51.9%. The results using the presence of any cytogenetic abnormality as a positive FISH test demonstrated a sensitivity of 82.9%, a specificity of 21.7%, a PPV of 54.8%, and an NPV of 51.7%.

CONCLUSIONS:

A negative UroVysion test did not rule out the presence of low‐grade or high‐grade urothelial carcinoma in urine specimens diagnosed as suspicious. The use of less strict criteria dramatically increased the sensitivity of UroVysion FISH; however, there was a marked decrease in specificity noted. The results in this current study appear to indicate that a more aggressive workup of patients with a suspicious cytology, positive UroVysion result, and negative cystoscopic evaluation is not currently justified. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Urine and bladder washing cytology for detection of urothelial carcinoma: standard test with new possibilities

Background

Light microscopic evaluation of cell morphology in preparations from urine or bladder washing containing exfoliated cells is a standard and primary method for the detection of bladder cancer and also malignancy from other parts of the urinary tract. The cytopathologic examination is a valuable method to detect an early recurrence of malignancy or new primary carcinoma during the follow-up of patients after the treatment of bladder cancer.

Conclusions

Characteristic cellular and nuclear signs of malignancy indicate invasive or in situ urothelial carcinoma or high-grade papillary urothelial carcinoma. However, low sensitivity of the method reflects the unreliable cytopathologic diagnosis of low-grade urothelial neoplasms as cellular and nuclear signs of malignancy in these neoplasms are poorly manifested. Many different markers were developed to improve the diagnosis of bladder carcinoma on urinary samples. UroVysion™ test is among the newest and most promising tests. By the method of in situ hybridization one can detect specific cytogenetic changes of urothelial carcinoma.     

The effect of tumor invasion patterns on pathologic stage of bladder urothelial carcinomas

The aim of this study was to investigate tumor invasion pattern, its heterogeneity and association with histopathological features and stage in invasive urothelial carcinoma of the bladder. We studied 62 cases of invasive urothelial carcinoma of the bladder. World Health Organization (WHO) 1973, WHO/ISUP1998 and WHO 1999 systems were used for tumor grading. Pathologic staging of each case was done according to 1997 TNM system. During evaluation of the slides three main tumor invasion patterns were detected: “nodular”, “trabecular” and “infiltrative”. In addition, homogeneity or heterogeneity of invasion patterns was also recorded for each case. Of sixty-two invasive cases, 17 (27%) had nodular, 36 (58%) trabecular, and 9 (15%) infiltrative invasion pattern. There was a statistically significant difference between invasion patterns in relation to pathologic stage (pT) (p=0.001), but not to grade. Of the 17 cases with nodular invasion pattern and 36 tumors with trabecular invasion pattern, 13 (77%) and 26 (72%) were pT1, respectively, whereas 8 of 9 infiltrative cases (89%) were advanced stage (pT2-3). According to heterogeneity, forty-two cases (68%) had homogeneous, while the remaining 20 (32%) had heterogeneous invasion pattern. Of the 42 homogeneous cases 34 (81%) were pT1, whereas 14 of 20 heterogeneous cases (70%) were advanced stage (p=0.000). The different invasion patterns seem to have a large impact on pathologic stage, especially the infiltrative pattern. In addition, invasion heterogeneity appears to be of value in determination of biologic aggressiveness in urothelial carcinoma.     

Diagnostic significance of ‘atypia’ in instrumented versus voided urine specimens

BACKGROUND.

Urine cytology plays an important role in monitoring patients with a history of urothelial carcinoma. Because it is difficult to reliably discriminate artifacts induced by instrumentation, inflammation, or therapy those of from malignant cells, many of these specimens are categorized as atypical. The objective of the current study was to study the prevalence and significance of atypical urine cytology with regard to the effect of instrumentation and prior biopsy.

METHODS.

All urine cytology cases seen during a 4‐year period (2001‐2004) with a diagnosis of atypical urothelial cells (AU) were obtained from the cytopathology computer database. In all cases with available surgical follow‐up, the following data were extracted: total number and type of urine specimen, the primary histologic diagnosis, and follow‐up histologic diagnosis.

RESULTS.

In all, 1653 voided and 3502 instrumented urine specimens were examined. A diagnosis of AU was rendered in 115 (6.9%) of the voided urine specimens and in 277 (7.9%) of the instrumented specimens. Follow‐up histology was available in 70 cases, including 55 instrumented and 15 voided urine specimens. A nonbenign follow‐up diagnosis was observed in 18 of 55 (32.7%) cases in the instrumented group and in 7 of 15 (46.6%) cases in the voided group. Voided urine was marginally associated with a worse subsequent biopsy diagnosis (Pexact Monte Carlo = .09)

CONCLUSIONS.

An AU diagnosis is more predictive of a subsequent adverse biopsy diagnosis in voided urine specimens compared with instrumented urines. In the absence of a benchmark for the atypia rate, it is prudent to keep the atypia rate low to keep it more meaningful. This important category should be used by the pathologist to convey concern and recognize the difficulty in interpretation of specimens that may require close follow‐up. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

p53 immunodetection of liquid-based processed urinary samples helps to identify bladder tumours with a higher risk of progression

p53 could help identify bladder tumour cases with a risk of progression from superficial to invasive disease. Semiautomatic, liquid-based cytology (LBC) techniques offer an opportunity to standardise molecular techniques. The aim of our study was to investigate whether LBC could improve p53 immunolabelling, and to assess whether urinary p53 could have a prognostic value. Immunoreactivity for p53 was studied in 198 urine samples after treatment with the Cytyc Thinprep processor. After antigen retrieval, cells were labelled with a monoclonal antibody that recognises both wild-type and mutant form of the p53 protein (Clone DO-7, Dako), 1/1000. Positivity for p53 was assessed in 17.2% of the cases. High-grade (G3) tumours were positive in 74.1% of the cases. Comparatively, low-grade (G1-2) urothelial carcinomas were positive in 23.5% of the cases. During a median follow-up period of 26 months, recurrence was observed in 52.9% of the cases with p53 overexpression, and in only 10.9% of negative cases (P < 0.001). The progression rate was 35.3% of p53-positive cases vs 5.5% of p53-negative cases (P < 0.001). Progression-free survival was significantly shorter in patients with p53 accumulation (P = 0.007). In a multivariate analysis stratified on grade and stage, p53 was an independent predictor of overall survival (P = 0.042). The results show that using Thinprep LBC, p53 immunolabelling of voided urothelial cells allows most high-grade tumours to be detected and may help identify cases with a higher risk of recurrence and progression.     

Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study

Background:

Controversy exists on whether urinary tract infection (UTI) is a risk factor for urinary bladder cancer (UBC). Here, the association is investigated using data from one of the largest bladder cancer case–control studies worldwide.

Methods:

Information on (i) history and age at onset of regular cystitis (‘regular low-UTI'') and (ii) number and age at onset of UTI treated with antibiotics (‘UTI-ab'') from 1809 UBC patients and 4370 controls was analysed. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, education, smoking, and use of aspirin/ibuprofen were generated, for men and women separately.

Results:

Regular low-UTI was associated with an increased UBC risk (men: OR (95% CI) 6.6 (4.2–11); women: 2.7 (2.0–3.5)), with stronger effects in muscle-invasive UBC. Statistically significant decreased risks (ORs ∼0.65) were observed for up to five UTI-ab, specifically in those who (had) smoked and experienced UTI-ab at a younger age. In women, UTI experienced after menopause was associated with a higher UBC risk, irrespective of the number of episodes.

Conclusions:

Regular cystitis is positively associated with UBC risk. In contrast, a limited number of episodes of UTI treated with antibiotics is associated with decreased UBC risk, but not in never-smokers and postmenopausal women.