Application of the Paris Reporting System for Urine Cytology: The Three-Year Experience of a Single Tertiary Care Institute in Thailand

<b><i>Introduction:</i></b> Urothelial carcinoma is one of the most common human cancers, both in Thailand and worldwide. Urine cytology is a screening tool used to detect urothelial carcinoma. The Paris System for Reporting Urinary Cytology (TPSRUC) was first published in 2016 to standardize the procedures, reporting, and management of urothelial carcinoma. Diagnostic categories include negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUCs), suspicious for HGUC (SHGUC), HGUC, low-grade urothelial neoplasm, and other malignancies. <b><i>Material and Methods:</i></b> In a retrospective review, urine cytology specimens from 2016 to 2019 were reevaluated using the TPSRUC. The risk of high-grade malignant neoplasm (ROHM) for each diagnostic category was calculated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of prediction of high-grade malignant neoplasms were evaluated for cases with histological follow-up specimens. <b><i>Results:</i></b> In total, 2,178 urine cytology specimens were evaluated, of which 456 cases had follow-up histological specimens. The ROHM in each diagnostic category was as follows: NHGUC, 17.4%; AUC, 49.9%; SHGUC, 81.2%; HGUC, 91.3%; and other malignant neoplasms, 87.5%. The sensitivity, specificity, PPV, NPV, and accuracy for high-grade malignant neoplasm prediction were 63%, 92.8%, 89%, 73.1%, and 78.5% when AUC was included as malignant in the comparison and 82.6%, 74.7%, 75.1%, 82.3%, and 78.5% when AUC was not considered malignant. <b><i>Conclusions:</i></b> TPSRUC provides reliable results that are reproducible by different interpreters and is a helpful tool for the detection of HGUC.

Risk factor analysis of intravesical recurrence after retroperitoneoscopic nephroureterectomy for upper tract urothelial carcinoma

Background One of the major concerns of patients with upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy is intravesical recurrence (IVR). The purpose of the present study was to investigate the predictive risk factors for IVR after retroperitoneoscopic nephroureterectomy (RNU) for UTUC. Methods Clinicopathological and surgical information were collected from the medical records of 73 patients treated with RNU for non-metastatic UTUC, without a history of or concomitant bladder cancer. The association between IVR after RNU and clinicopathological and surgery-related factors, including preoperative urine cytology and pneumoretroperitoneum time, was analyzed using the Fisher exact test. Results During the median follow-up time of 39.1 months, 18 (24.7%) patients had subsequent IVR after RNU. The 1- and 3-year IVR-free survival rates were 85.9% and 76.5%, respectively. The Fisher exact test revealed that prolonged pneumoretroperitoneum time of ≥ 210 min was a risk factor for IVR in 1 year after RNU (p = 0.0358) and positive urine cytology was a risk factor for IVR in 3 years after RNU (p = 0.0352). Conclusions In UTUC, the occurrences of IVR in 1 and 3 years after RNU are highly probable when the pneumoretroperitoneum time is prolonged (≥ 210 min) and in patients with positive urine cytology, respectively. Strict follow-up after RNU is more probable recommended for these patients.

Risk Factors Leading to Radical Cystectomy in Patients Who Had Undergone Nephroureterectomy

Purpose: To identify the risk factors leading to radical cystectomy in patients who had undergone nephroureterectomy (NUx).Materials and Methods: We retrospectively reviewed the medical records of patients with upper tract urothelial carcinoma who underwent NUx during 2011–2019 and excluded patients with metastatic cancer. In total 646 patients were included in this study; of these, 532 had no previous bladder cancer history. Follow-up was performed every 3 months for 2 years after NUx was administered, and recurrence was confirmed using cystoscopy, urine cytology, computed tomography, and chest radiography. Bladder recurrence was confirmed through biopsy, urine cytology, or radiologic examination. Univariate and multivariate Cox regression analyzes were performed for statistical analysis of risk factors leading to radical cystectomy in patients undergoing NUx.Results: Lymphovascular invasion (LVI) (hazard ratio [HR], 4.728; 95% confidence interval [CI], 1.463–15.570; p=0.011), previous transurethral resection of bladder tumor history (HR, 3.825; 95% CI, 1.164–12.571; p=0.027), and intravesical recurrence (IVR) within 6 months (HR, 3.733; 95% CI, 1.091–12.778; p=0.036) in patients undergoing NUx are predictors of radical cystectomy implementation. In a multivariate analysis of patients without bladder cancer history, bladder recurrence was identified as a predictor of radical cystectomy implementation, if it occurred within 6 months of NUx (HR, 8.608; 95% CI, 1.545–47.976; p=0.014).Conclusions: LVI and IVR within 6 months and previous bladder cancer history are factors that can predict the need for radical cystectomy after NUx. Even in patients without bladder cancer history, early bladder recurrence within 6 months is a major predictor of radical cystectomy.

426 A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)

BackgroundCG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG.1 2 This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC.Methods110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x10e12 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response. The primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. Study enrollment globally is ongoing.Trial RegistrationNCT04452591ReferencePackiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, Clark W, Kroeger M, Dumbadze I, Chamie K, Kader AK, Curran D, Gutheil J, Kuan A, Yeung AW, Steinberg GD. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol 2018;36:440–447.Ethics ApprovalCASTLE IRB: BOND-003 (CG3002S)

The Dynamics of Pathology Dataset Creation Using Urine Cytology as an Example

<b><i>Introduction:</i></b> Dataset creation is one of the first tasks required for training AI algorithms but is underestimated in pathology. High-quality data are essential for training algorithms and data should be labelled accurately and include sufficient morphological diversity. The dynamics and challenges of labelling a urine cytology dataset using The Paris System (TPS) criteria are presented. <b><i>Methods:</i></b> 2,454 images were labelled by pathologist consensus via video conferencing over a 14-day period. During the labelling sessions, the dynamics of the labelling process were recorded. Quality assurance images were randomly selected from images labelled in previous sessions within this study and randomly distributed throughout new labelling sessions. To assess the effect of time on the labelling process, the labelled set of images was split into 2 groups according to the median relative label time and the time taken to label images and intersession agreement were assessed. <b><i>Results:</i></b> Labelling sessions ranged from 24 m 11 s to 41 m 06 s in length, with a median of 33 m 47 s. The majority of the 2,454 images were labelled as benign urothelial cells, with atypical and malignant urothelial cells more sparsely represented. The time taken to label individual images ranged from 1 s to 42 s with a median of 2.9 s. Labelling times differed significantly among categories, with the median label time for the atypical urothelial category being 7.2 s, followed by the malignant urothelial category at 3.8 s and the benign urothelial category at 2.9 s. The overall intersession agreement for quality assurance images was substantial. The level of agreement differed among classes of urothelial cells – benign and malignant urothelial cell classes showed almost perfect agreement and the atypical urothelial cell class showed moderate agreement. Image labelling times seemed to speed up, and there was no evidence of worsening of intersession agreement with session time. <b><i>Discussion/Conclusion:</i></b> Important aspects of pathology dataset creation are presented, illustrating the significant resources required for labelling a large dataset. We present evidence that the time taken to categorise urine cytology images varies by diagnosis/class. The known challenges relating to the reproducibility of the AUC (atypical) category in TPS when compared to the NHGUC (benign) or HGUC (malignant) categories is also confirmed.

Should National Institute for Clinical Excellence (NICE) Guidelines Remove Urine Cytology as a Suggested Adjunct in Suspected Bladder Cancer (haematuria) Investigations?

BackgroundDespite National Institute for Clinical Excellence (NICE) guidelines suggesting the use of urine cytology (UC) for the diagnosis of bladder cancer, its use is variable. Reasons for this include sub-optimal sensitivity, financial cost, availability of alternative tests, and uncertainty over interpretation of results. Anecdotally, however, suspicious or malignant UC when other investigations are normal, occasionally leads to a cancer diagnosis. Therefore, we retrospectively assessed a cohort of our haematuria patients to determine the value of UC in cancer diagnosis and the clinical significance of atypical UC (graded as C3). Patients and methodsWe identified 3018 patients with haematuria referred on the suspected cancer pathway (“two-week wait”) in 2015. We retrospectively analysed clinical, demographic, and follow-up/outcome data in a random cohort of 500 cases. ResultsMedian follow up was 58 months. Urological malignancy was diagnosed in 61/500 patients; all were identified by cystoscopy or imaging, i.e., irrespective of UC result. No cases of atypical UC re-presented with a ‘missed’ cancer diagnosis within the five-year follow-up period. However, suspicious and malignant cytology was associated with high-grade/aggressive tumours and subsequent tumour recurrence. ConclusionUrine cytology did not identify any cancers that were not already found by imaging or cystoscopy. Atypical UC in the presence of negative haematuria investigations does not appear to be associated with malignancy, and therefore should not alter patient management nor prompt further investigation. Suspicious and malignant UC was associated with higher risk cancers and could therefore be used to prioritise waiting lists for transurethral resection of bladder tumour (TURBT), however, it is unclear whether this might benefit patient outcomes. We conclude therefore that UC has no role in haematuria investigations.

Predictive Value of Preoperative Positive Urine Cytology for Development of Bladder Cancer After Nephroureterectomy in Patients With Upper Urinary Tract Urothelial Carcinoma: A Prognostic Nomogram Based on a Retrospective Multicenter Cohort Study and Systematic Meta-Analysis

BackgroundUpper urinary tract urothelial carcinoma (UUT-UC) is a rare and severe urinary malignancy. Several studies have explored the relationship between preoperative urine cytology and intravesical recurrence (IVR) in patients with UUT-UC. However, the results of these studies are controversial or even contradictory, and investigations with UUT-UC patients in northeast China are rare.MethodsWe first estimated the prognostic significance of preoperative urine cytology in the outcomes of intravesical recurrence in 231 UUT-UC patients (training cohort = 142, validation cohort = 89) after radical nephroureterectomy (RNU) by the nomogram model. Subsequently, we quantitatively combined our results with the published data after searching several databases to assess whether preoperative positive urine cytology was associated with poor intravesical recurrence-free survival and a high risk of tumor malignant biological behavior.ResultsFirstly, the multicenter retrospective cohort study demonstrated that preoperative positive urine cytology correlated with poor intravesical recurrence-free survival and can serve as significant independent predictors of IVR by Kaplan–Meier curves and Cox regression analysis. The construction of the nomogram demonstrated that predictive efficacy and accuracy were significantly improved when preoperative urine cytology was combined. Meanwhile, meta-analysis showed that preoperative positive urine cytology was associated with a 49% increased risk of IVR. In the subgroup analysis by region, study type, and sample size, the pooled hazard ratios (HRs) were statistically significant for the Japan subgroup (HR 1.32), China subgroup (HR 1.88), cohort study subgroup (HR 1.45), and the single-arm study subgroup (HR 1.63).ConclusionsPreoperative urine cytology was validated as a potential predictor of intravesical recurrence in patients with UUT-UC after RNU, although these results need to be generalized with caution. Large, prospective trials are required to further confirm its significance in prognosis and tumor malignant biological behavior.

The MicroRNA Prediction Models as Ancillary Diagnosis Biomarkers for Urothelial Carcinoma in Patients With Chronic Kidney Disease

Urothelial carcinoma is a common urological cancer in chronic kidney disease patients. Cystoscopy and urine cytology are the clinical diagnostic tools for UC. However, cystoscopy is an invasive procedure, while urine cytology showed low sensitivity for low-grade urothelial tumors. High accuracy with non-invasive tools for UC is needed for CKD patients. Our study collected a total of 272 urine and 138 plasma samples to detect the miRNA expression levels for establishing UC signatures from CKD patients. Seventeen candidate miRNAs of biofluids were selected and confirmed by qRT-PCR. Our results showed that urinary miR-1274a and miR-30a-5p expression levels were significantly lower but miR-19a-5p expression levels were higher in UC when compared with CKD. In plasma samples, miR-155-5p, miR-19b-1-5p, miR-378, and miR-636 showed significantly lower expression in UC compared to those with CKD. The Kaplan-Meier curve showed that lower expression of miR-19a, miR-19b, miR-636 and miR-378, and higher expression of miR-708-5p were associated with poor prognosis in patients with bladder cancer. In addition, we produced classifiers for predicting UC by multiple logistic regression. The urine signature was developed with four miRNAs, and the AUC was 0.8211. Eight miRNA expression levels from both urine and plasma samples were examined, and the AUC was 0.8595. Two miRNA classifiers and the nomograms could improve the drawbacks of current UC biomarker screenings for patients with CKD.