Low-grade Urothelial Neoplasia Research Articles

Low-Grade Urothelial Neoplasia

This chapter reviews the clinical, histopathologic, and cytologic features of low-grade urothelial neoplasia, including urothelial papilloma, papillary urothelial neoplasm of low malignant potential, and low-grade papillary urothelial carcinomas. An overview of various surgical pathology and cytology classification systems, diagnostic criteria, and common molecular alterations will be reviewed.

New edition of the Paris classification 2022: What is new?

As an internationally accepted diagnostic system, the Paris classification has achieved aglobal breakthrough in the standardization of diagnoses in urine cytology. Based on experience over the past few years since its first publication, the new edition of the Paris classification refines the diagnostic criteria and discusses diagnostic pitfalls. While the detection of high-grade urothelial carcinoma remains the main focus, other aspects of urine cytology, including cytology of the upper urinary tract and the associated challenges, have also been addressed. Low-grade urothelial neoplasia is no longer listed as aseparate category but is now included in the category "negative for high-grade urothelial carcinoma" (NGHUC). Essentially, the Paris classification provides an important basis for estimating the risk of malignancy and further clinical management.

Abstract B018: KDM6A and MTAP expression loss enable identification of a large fraction of low grade non-invasive urothelial neoplasia of the urinary bladder

Abstract The identification of low-grade urothelial neoplasia in cytologic samples or in biopsies with dysplastic lesions poses a particular problem for pathologists in routine diagnostics. Improved diagnosis of low-grade urothelial neoplasia could help to reduce the number of cystoscopic follow-up examinations. KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is an epigenetic regulator which is frequently mutated in urothelial carcinoma. Because KDM6A is localized on chromosome Xp11.3, and because of the male predominance in bladder cancer, many KDM6A mutations should result in a complete loss of KDM6A protein expression and become detectable by immunohistochemistry (IHC). Similarly, S-methyl-5′-thioadenosine phosphorylase (MTAP), a critical enzyme for DNA and RNA synthesis, is co-deleted with the CDKN2A tumor suppressor located on chromosome 9p21 in about 25% of bladder cancers, resulting in reduced or lost protein expression. To study the prevalence and diagnostic potential of immunohistochemical loss of KDM6A and MTAP expression, 928 tumors were analyzed by IHC in a tissue microarray format. The cohort included 628 non-invasive papillary tumors (pTa) and 300 tumors from patients who underwent radical cystectomy for muscle-invasive disease (pT2-4). A complete KDM6A expression loss occurred in 35% of 342 pTa G2 low-grade, 23% of 150 pTa G2 high-grade, 17.8% of 90 pTa G3 tumors, and 20.1% of 243 interpretable muscle invasive (pT2-4) cancers (p<0.0001). Within pTa tumors, there was a strong correlation between KDM6A loss and low tumor grade (p=0.0003), whereas no significant difference was found between pT3 G3 and muscle invasive cancers (p=0.8828). Complete absence of MTAP expression occurred in 11% of 297 pTa G2 low-grade, 29.6% of 125 pTa G2 high-grade, 18.4% of 76 pTa G3 tumors, and 26.3% of 217 muscle invasive (pT2-4) cancers (p<0.0001). A combined analysis of 702 cancers with interpretable data for KDM6A and MTAP showed that 6.6% of tumors had expression loss of both KDM6A and MTAP, 20% had KDM6A loss only, and 13% had MTAP loss only. The rate of expression loss of KDM6A and/or MTAP was markedly higher in pTa G2 low (41.2%) and in pTa G2 high (40.3%) than in pTa G3 tumors (29%). In summary, our data demonstrate that about 40% of low-grade non-invasive urothelial neoplasias – which are usually not detected by urine cytology – had a completed expression loss of either KDM6A or MTAP. In patients with these alterations, follow-up could be potentially facilitated by immunohistochemistry. Citation Format: Florian Viehweger, Neele Heckmann, Natalia Gorbokon, Henning Plage, Sebastian Hofbauer, Sarah Weinberger, Florian Roßner, Simon Schallenberg, Sefer Elezkurtaj, Maximilian Lennartz, Tim Mandelkow, Elena Bady, Margit Fisch, Thorsten Ecke, Stefan Koch, Nico Adamini, Ronald Simon, Guido Sauter, Tobias Klatte, Thorsten Schlomm, David Horst, Henrik Zecha, Martina Kluth, Sarah Minner. KDM6A and MTAP expression loss enable identification of a large fraction of low grade non-invasive urothelial neoplasia of the urinary bladder [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B018.

Evaluation of the Implementation and Diagnostic Accuracy of the Paris Classification for Reporting Urinary Cytology in Voided Urine Specimens: A Cyto-Histological Correlation Study in a Cancer Center

Introduction: The Paris classification highlights the need to focus on accurately identifying high-grade urothelial carcinoma (HGUC). Herein, we aimed to assess the overall implementation and diagnostic performance of the Paris classification for reporting urinary cytology in a cancer center. Methods: All urinary cytology reports from July 2018 to December 2019 were collected (n = 1,240). Only voided urine samples were included (n = 1,180). Risk of high-grade malignancy (ROHM) was calculated for each Paris category. The diagnostic performance of urinary cytology was assessed, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Results: The distribution of categories was: 0.3% unsatisfactory, 90.5% negative for HGUC, 5.6% atypical urothelial cells (AUC), 1.6% suspicious for HGUC, 1.9% HGUC, and 0.1% other malignancies. No diagnosis of low-grade urothelial neoplasia was given. The ROHM was 21.4% for negative for HGUC, 66.7% for AUC, 91.7% for suspicious for HGUC, and 100% for HGUC. When using suspicious for HGUC as a cutoff, the diagnostic performance of urinary cytology in identifying HGUC histology was 46% sensitivity, 98% specificity, 96% PPV, 68% NPV, and 74% accuracy. Conclusion: Specificity of urinary cytology was very high (with only 1 false-positive result), which is important since this will trigger a clinical intervention. The ROHM for each category was in accordance with literature, except for AUC where ROHM was slightly higher (66.7%). This may be explained by the study population characteristics (cancer center; many patients treated with intravesical therapies; lack of clinical annotation for patients referred from outside institutions).

Cytomorphology of Low-Grade Urothelial Neoplasia (LGUN) in Urine Cytology

Cytomorphology of Low-Grade Urothelial Neoplasia (LGUN) in Urine Cytology

Applicability of the Paris System for veterans: high rates of undiagnosed low-grade urothelial neoplasia

The Paris System for Reporting Urinary Cytology (TPS) is a recently developed standardized terminology system. It is well-established that urine cytology has low sensitivity for detecting low-grade urothelial neoplasia (LGUN). Though the majority of tumors are low-grade, surveillance of these lesions is important to monitor for possible progression. Herein, we compared TPS to our veteran integrated system network (VISN) to assess its applicability. We also introduced semi-quantitative scoring to further evaluate cytomorphologic features of high-grade urothelial carcinoma (HGUC). Voided and instrumented urine cytology specimens and concurrent biopsies were reviewed from Sept 2018 - Jan 2020. Cytologic diagnoses reported using the VISN institutional system were reevaluated by staff cytopathologists and categorized according to TPS. A semi-quantitative scoring system to evaluate cytomorphologic features was devised. Cytology and surgical specimens from 105 patients were reviewed. The VISN and TPS reporting systems were compared and showed similar sensitivities and specificities for the detection of HGUC. Rates of biopsy-proven LGUN were high for the negative for high-grade urothelial carcinoma category (NHGUC; 27/53, 50.9%) and atypical urothelial cells (AUC; 14/30; 46.7%) compared to suspicious/positive (0/22, 0%) categories. Major and minor criteria as outlined in TPS were evaluated semi-quantitatively. Urine cytology has limited sensitivity for LGUN regardless of the cytologic reporting system used. There was a high rate of LGUN following NHGUC/AUC diagnoses in the Veteran population. Coarse chromatin was determined to be the least sensitive criterion for the detection of high-grade lesions and irregular chromatin rim was most specific.

Applicability of the Paris System for Veterans: High Rates of Low-grade Urothelial Neoplasia in Negative and Atypical Urines and its Impact on Cytologic Reporting

Applicability of the Paris System for Veterans: High Rates of Low-grade Urothelial Neoplasia in Negative and Atypical Urines and its Impact on Cytologic Reporting

Cell blocks in urine cytopathology: do they add value to the diagnosis? A pilot study

The utility of cell block (CB) preparation is well established in cytopathology. Despite 23.3% of College of American Pathologists-accredited laboratories using CB with liquid-based preparations on urine cytology (UC) cases, there are very few studies on their performance. To determine their usefulness, we conducted a retrospective review of UC cases that received CB. We identified 27 UC cases with ThinPrep (TP) and CB preparation between 2016 and 2020 at our institution. Clinical history and follow-up data were compiled. A blinded review of TP alone, and TP together with CB, was performed by 2 pathologists and 2 cytotechnologists. Diagnoses were rendered in accordance with The Paris System for Reporting Urine Cytology. Blood and acute inflammation were common background elements in cases that received CB preparation. In total, CB upgraded the diagnosis in 7 of 27 cases (26%). The maximum utility of CB preparation was seen in indeterminate cases where 60% (6 of 10) were upgraded, including 71% (5 of 7) of atypical urothelial cells (AUC) and 30% (1 of 3) of suspicious for high-grade urothelial carcinoma (HGUC). One case (1 of 12, 8%) diagnosed as negative for HGUC on TP was diagnosed as low-grade urothelial neoplasia on CB. Our results demonstrate that adjunct use of CB preparation aids in a definitive diagnosis on AUC category and may be helpful in cases with cell clusters or tissue fragments, or cases suspicious for HGUC. Further correlation studies are warranted in this area to expand our knowledge about the utility of CBs in urine cytology.

The Paris system of Reporting Urinary Cytology: Strengths and opportunities.

The Paris system for reporting urinary cytopathology (TPS) was created to address inherent weaknesses inherent in the practice of urinary cytopathology. While urothelial cytology has always performed well at finding high grade, genetically unstable urothelial carcinoma, it performs poorly when it comes to detecting low-grade urothelial neoplasia. TPS intends to improve the utility of urothelial cytology by focusing on what is important, high-grade urothelial carcinoma. This article is a snapshot of the current state of TPS as it heads into its second edition. Successes are described and further developments are considered.

Comparison of urine cytology diagnostic reports before and after the implementation of the Paris System classification system in China.

In 2013, The Paris System for Reporting Urinary Cytology (TPS) was developed as a uniform practical urine cytology system that could be applied worldwide. Here, we investigated the effectiveness of TPS diagnostic approach compared with that of the traditional urine cytological diagnosis method used in China. Based on the diagnostic criteria of TPS, 412 urine samples from 143 patients with histological follow-up data were retrospectively analysed, and the diagnoses were compared with the original cytological diagnoses. In total, 110 patients were histologically diagnosed with high-grade urothelial carcinoma (HGUC), and 33 patients were diagnosed with low-grade urothelial neoplasia. Based on the traditional urine cytological analysis method, 50 patients (34.9%) were diagnosed as negative, 48 patients (33.6%) were diagnosed as having atypical urothelial cells, and 45 patients (31.5%) were diagnosed as positive. After reclassification using TPS, urine samples from 11 cases (7.7%) were categorised as unsatisfactory, 34 cases (23.8%) were negative, 21 cases (14.7%) were categorised as having atypical urothelial cells, 12 cases (8.4%) were diagnosed as suspicious for HGUC, 59 cases (41.2%) were diagnosed with HGUC, and six cases (4.2%) were reclassified as having low-grade urothelial neoplasia. Thus, after implementing TPS criteria, the sensitivity for positive malignancy diagnoses (HGUC alone) increased from 38.2% to 50.9%, while the specificity of the diagnosis was barely changed. The Paris System for Reporting Urinary Cytology greatly contributes to the standardisation of urine cytology reports and significantly improves the diagnostic sensitivity for HGUC.

The Paris System for reporting urinary cytology in daily practice with emphasis on ancillary testing by multiprobe FISH

AimsThe Paris System (TPS) was introduced in the diagnostic routine with the goal to simplify and standardise diagnostic reporting of urinary cytology. The diagnostic categories of TPS are based on...

Urinary tract washing specimens containing atypical urothelial tissue fragments are significantly associated with urothelial neoplasia.

We previously found that the presence of atypical urothelial tissue fragments (AUTF) was associated with an increased risk of high-grade urothelial carcinoma (HGUC) but not low-grade urothelial neoplasia (LGUN) in voided urine (VU) specimens. However, we subsequently found that patients with LGUN were more likely to have cytologic atypia in urinary washing (UW) specimens, suggesting that cytologic atypia found in UW specimens might be associated with both LGUN and HGUC. In this study, we retrospectively examined UW specimens containing AUTF to determine whether they were associated with HGUC, LGUN, or both HGUC and LGUN. 1173 UW specimens and any follow up biopsies were identified over a 10-year period and the presence of AUTF was recorded based on the original clinical diagnosis. The presence of AUTF in UW specimens was significantly associated with high-risk indeterminate diagnosis or definitive diagnosis of HGUC (P < .001). In addition, AUTF specimens were significantly associated with a neoplastic diagnosis of low-grade urothelial carcinoma (LGUC) or HGUC on subsequent biopsies when compared to specimens lacking AUTF (P = .047). The overall rate of CIS/HGUC in specimens with AUTF was 33.0 vs. 13.5% for specimens without AUTF (P = .051). Urothelial tissue fragments (UTF) found in UW specimens should be examined for the presence of cytomorphological atypia, as the presence of AUTF almost triples the risk of HGUC. As opposed to what has been found in VU specimens, AUTF in UW specimens is also associated with an increased risk of LGUN.

P16/Ki‐67 dual labeling and urinary cytology results according to the New Paris System for Reporting Urinary Cytology: Impact of extended follow‐up

Overexpression of p16INK4a has been identified in urothelial malignancies both cytologically and histologically. In addition, p16/Ki-67 dual labeling has been shown to identify high-grade urothelial cancer cells and some progression cases within a 12-month delay. The Paris System for Reporting Urinary Cytology (TPS) was published in late 2015. Its aim is to clarify the criteria for diagnosing or, conversely, excluding high-grade urothelial carcinoma (HGUC). Dual labeling was performed on archived ThinPrep-based Papanicolaou slides. A total of 208 samples (negative for high-grade urothelial carcinoma [NHGUC], 59; consistent with low-grade urothelial neoplasia [LGUN], 24; atypical urothelial cells [AUC], 15; and suspicious for or showing HGUC, 110) were analyzed for p16/Ki-67 after reclassification according to TPS. We assessed the oncologic status of the patients with cystoscopy, urinary cytology, histology, and prolonged 36-month follow-up data. The sensitivity of p16/Ki-67 for life-threatening lesions was not different from that of urinary cytology (82.8% vs 83.6%; P = 1). However, among patients with samples classified as NHGUC and AUC, disease-free survival was significantly shorter for dual-labeled cases versus cases with negative dual labeling (P < .0001). The same tendency was observed in patients with histologically proven LGUN (P < .0001). As for specificity in patients with negative cystoscopy and cytology combined, prolonged follow-up showed 90% overall survival at 24 months. A long-term evaluation of p16/Ki-67 dual labeling may identify HGUC and progression in cases with negative/low-grade urinary cytology results, and there are potential implications for the clinical management of patients after the conservative treatment of non-muscle-invasive urothelial carcinoma. Cancer Cytopathol 2017;125:552-62. © 2017 American Cancer Society.

Voided urine cytology and low-grade urothelial neoplasia of the bladder: factors that influence the sensitivity

The aims of this study were to show the 10-year results of voided urine cytology (VUC) performed using liquid-based cytology (LBC) with CytoRich Red and to discuss the factors that influence the sensitivity of low-grade urothelial neoplasia (LGUN) of the urinary bladder. We calculated the sensitivity of VUC in 421 histologically confirmed cases included in the pathology database of Hokkaido Cancer Center in Japan and studied various factors influencing sensitivity. The cumulative sensitivity of VUC was 95.8% in 143 cases of primary high-grade urothelial carcinomas, compared with 59.5% in 74 cases of LGUN. These findings were only slightly different from the previous results of Koss etal. The sensitivity in LGUN, however, showed lower values in some conditions, including in secondary cases, with a lower frequency of examinations and smaller tumor volumes. LBC preparations allowed us to observe a greater number of tumor cells and cell clusters than conventional methods in LGUN cases. The sensitivity of VUC can be improved by increasing the frequency of examinations and adopting a valid preparation method in order to augment the number of cells and cell clusters on individual glass slides. LBC preparations may allow cytopathologists to obtain a better sense for and understanding of the cytologic findings of LGUN.

Atypical urothelial tissue fragments in noninstrumented voided urine specimens are associated with low but significantly higher rates of urothelial neoplasia than benign-appearing urothelial tissue fragments.

The interpretation of urothelial tissue fragments (UTF) in voided urine (VU) specimens is controversial. If UTF contain cytomorphologically atypical cells, the diagnosis often becomes more challenging. The authors previously analyzed the outcome of patients with benign-appearing UTF in 274 noninstrumented VU specimens. In this retrospective study, noninstrumented VU specimens containing UTF with atypical cytomorphological features (AUTF) were evaluated and compared with the previous results. The Johns Hopkins Hospital electronic pathology database was searched for VU cases containing UTF over a 5-year period. A total of 170 noninstrumented VU specimens containing AUTF were identified. Twenty-four specimens had subsequent or coincidental surgical pathology specimens with the following overall rates of neoplasia: high-grade urothelial carcinoma: 8.8% (15 specimens), low-grade urothelial neoplasia: 1.2% (2 specimens), and prostate carcinoma invading the bladder: 0.6% (1 specimen). A total of 49 specimens (28.8%) were diagnosed with urolithiasis on follow-up. Twenty-five cases had follow-up cytology specimens, all of which were negative for malignancy. Of 72 cases without histopathologic, radiologic, or cytopathologic follow-up, 62 (86.1%) had a mean clinical follow-up of 22.5 months and 10 cases did not have clinical follow-up. The presence of AUTF in noninstrumented VU is associated with low rates of urothelial neoplasia but a statistically higher risk of urothelial neoplasia than the presence of BUTF (10.0% vs 4.4%; P<.05). In particular, the rate of high-grade urothelial carcinoma is significantly higher in noninstrumented VU specimens containing AUTF than those containing BUTF (8.8% vs 0.7%; P<.0001). In addition, urolithiasis is associated with AUTF in a substantial percentage of noninstrumented VU specimens.

Benign-appearing urothelial tissue fragments in noninstrumented voided urine specimens are associated with low rates of urothelial neoplasia.

The presence of urothelial tissue fragments (UTF) in voided urine (VU) is often considered an abnormal finding that may be associated with the presence of urothelial papillary neoplasms. In the current study, the authors reviewed VU specimens containing benign-appearing UTF (BUTF) to determine the associated rate of urothelial neoplasia at the study institution. A retrospective search of the electronic pathology database system over a 5-year period (2009-2013) revealed 1131 VU specimens containing UTF. Of these, 459 cases (40.6%) did not have a recent history of instrumentation. Fifteen cases were excluded because the slides were not available for review. In the remaining 444 cases, 274 cases (61.7%) had BUTF. A total of 170 cases (38.3%) had UTF with atypical cytologic features and were therefore excluded. Of the 274 cases, 29 (10.6%) had follow-up surgical pathology specimens available. The overall rate of urothelial neoplasia on follow-up was 3.6% for low-grade urothelial neoplasia (10 cases) and 0.7% for high-grade urothelial carcinoma (2 cases). Forty-five cases (16.4%) were determined to have urinary tract stones on follow-up. The presence of BUTF in VU specimens requires careful examination of the medical history because their presence may be explained by recent instrumentation. If recent instrumentation is not identified, the etiology of BUTF is not usually determined; in the current study, BUTF were found to be associated with urinary tract stones in 16.4% of cases. They also present a low risk of low-grade urothelial neoplasia (3.6%) and high-grade urothelial carcinoma (0.7%) when compared with the overall benign category at the study institution (2.3% [P =.15] and 0.7%, respectively).

UroVysion® multiprobe FISH in the triage of equivocal urinary cytology cases

The search for biological and clinical significance of equivocal urinary cytology has emerged as the most promising application of fluorescence in situ hybridization (FISH). Using the multiprobe UroVysion(®) assay, a negative FISH result in the presence of atypical urothelial cells favors the presence of reactive, benign alterations and helps to avoid unnecessary invasive procedures. However, a negative FISH result in case of a negative or equivocal cytology does not exclude low-grade urothelial neoplasia. Equivocal findings are a notorious problem after conservative treatment, particularly after BCG immunotherapy of carcinoma in situ, where even benign reactive changes can appear worrisome. In this situation, a positive FISH result in spite of non-high grade cytology independently indicates persistent or recurrent urothelial carcinoma. However, chromosomal abnormalities are not restricted to malignancy but may also occur in benign cells. Tetraploidy with a balanced duplication of the whole genome, or polyploidy can occur in non-neoplastic conditions of the bladder such as Decoy cells, radiotherapy-induced changes and urolithiasis. Thus, a positive FISH result in a patient with a history of pelvic irradiation does not prove cancer unless there is unequivocal 9p21 deletion. Recent studies show that an aggressive workup of patients with a suspicious cytology+positive UroVysion(®) result and negative cystoscopy is not currently justified. However, multi-target UroVysion(®) FISH remains an excellent tool to improve diagnosis in urinary cytopathology, provided that FISH results are interpreted in the light of the clinical situation, and that one reminds that FISH adds no diagnostic value in case of clearly positive, high-grade cytology.