Mitotic activity in noninvasive papillary urothelial carcinoma: its value in predicting tumor recurrence and comparison with the contemporary 2-tier grading system

Zaleski, Michael; Gogoj, Augustyna; Walter, Vonn; Raman, Jay D.; Kaag, Matthew; Merrill, Suzanne; Joshi, Monika; Holder, Sheldon L.; DeGraff, David J.; Warrick, Joshua I.

doi:10.1016/j.humpath.2018.10.008

Cited by 12 publications

(15 citation statements)

References 21 publications

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“…S1 and “ Materials and methods ”). Measures of cell cycle activity were mitotic index 4 , defined as the number of mitotic figures seen histologically in 10 high-powered microscopic fields 4 , and expression of late versus early cell cycle genes, with expression of the former considered to indicate greater cell cycle activity 11 . Activity of each TF regulon was quantified in each tumor as “enrichment score”.…”

Section: Resultsmentioning

confidence: 99%

“…S1 ). To winnow this list to the TF regulons most strongly associated with cell cycle dysregulation, we utilized Cohort 1 to investigate the association between activity of these 413 TF regulons and two measures of cell cycle activity: cell cycle group and mitotic index (the number of mitotic figures per 10 high-powered microscopic fields, which served as an orthogonal measure of cell cycle dysregulation) 4 . Cell cycle group was assigned by consensus clustering, using the approach described above.…”

Section: Methodsmentioning

confidence: 99%

“…Patients may be treated conservatively, with transurethral resection of the tumor, often followed by intravesical instillation of Bacillus Calmette–Guérin (BCG) 3 . However, the majority recur 4 , and a subset progresses to advanced-stage disease 2 , which is often fatal. BCG also confers considerable morbidity, including bladder pain, voiding dysfunction, and occasional sepsis 5 .…”

Section: Introductionmentioning

confidence: 99%

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A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma

Warrick

Knowles

Hurst

et al. 2022

Sci Rep

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Human cancers display a restricted set of expression profiles, despite diverse mutational drivers. This has led to the hypothesis that select sets of transcription factors act on similar target genes as an integrated network, buffering a tumor’s transcriptional state. Noninvasive papillary urothelial carcinoma (NIPUC) with higher cell cycle activity has higher risk of recurrence and progression. In this paper, we describe a transcriptional network of cell cycle dysregulation in NIPUC, which was delineated using the ARACNe algorithm applied to expression data from a new cohort (n = 81, RNA sequencing), and two previously published cohorts. The transcriptional network comprised 121 transcription factors, including the pluripotency factors SOX2 and SALL4, the sex hormone binding receptors ESR1 and PGR, and multiple homeobox factors. Of these 121 transcription factors, 65 and 56 were more active in tumors with greater and less cell cycle activity, respectively. When clustered by activity of these transcription factors, tumors divided into High Cell Cycle versus Low Cell Cycle groups. Tumors in the High Cell Cycle group demonstrated greater mutational burden and copy number instability. A putative mutational driver of cell cycle dysregulation, such as homozygous loss of CDKN2A, was found in only 50% of High Cell Cycle NIPUC, suggesting a prominent role of transcription factor activity in driving cell cycle dysregulation. Activity of the 121 transcription factors strongly associated with expression of EZH2 and other members of the PRC2 complex, suggesting regulation by this complex influences expression of the transcription factors in this network. Activity of transcription factors in this network also associated with signatures of pluripotency and epithelial-to-mesenchymal transition (EMT), suggesting they play a role in driving evolution to invasive carcinoma. Consistent with this, these transcription factors differed in activity between NIPUC and invasive urothelial carcinoma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma

Warrick

Knowles

Hurst

et al. 2022

Sci Rep

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“…Tumors with greater activation of the cell cycle have higher rates of recurrence and progression to muscleinvasion (29). This has been shown with various methods, including complex expression signatures( 29), immunohistochemistry for cell cycle genes such as cyclin D1 (30,31), Ki-67 labelling index (31), and mitotic index (32). Non-invasive papillary carcinomas are also somewhat diverse in expression of luminal markers, with some tumors being more "luminal" than others, but this does not appear to affect clinical behavior (29,33).…”

Section: Molecular Classification Of Early Stage Bladder Cancermentioning

confidence: 98%

Report From the International Society of Urological Pathology (ISUP) Consultation Conference On Molecular Pathology Of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer

Warrick

Knowles

Allory

et al. 2020

American Journal of Surgical Pathology

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During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into “molecular subtypes,” based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended. Mutations in the TERT promoter are present in the majority of bladder cancers, including the noninvasive stage of tumor evolution, but not in reactive conditions. Mutational analysis of the TERT promoter thus distinguishes histologically deceptive cancers from their benign mimics in some cases. A minority of pathologists employ this test. FGFR3 mutations are common in bladder cancer, and metastatic urothelial carcinoma (UC) with such mutations frequently responds to erdafitinib, an FGFR inhibitor. Testing for FGFR3 alterations is required before using this drug. Metastatic UC responds to immune-oncology (IO) agents in 20% of cases. These are approved as first and second-line treatments in metastatic UC. Several biological parameters associate with response to IO agents, including tumor mutational burden, molecular subtype, and infiltration by programmed death-ligand 1–positive lymphocytes, detected by immunohistochemistry. Programmed death-ligand 1 immunohistochemistry is mandatory before administering IO agents in the first-line setting. In conclusion, much has been learned about the biology of bladder cancer, and this understanding has improved the care of patients with the disease.

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“…63 Others have suggested the possibility of adding additional morphologic information for grade stratification, such as mitotic activity. 64,65 For example, a recent study demonstrated that mitotic activity was superior to grade alone in predicting recurrence on multivariate analysis. Though other authors have also investigated the clinical utility of incorporating additional immunohistochemical and molecular markers to better predict clinical outcome, 64,66 to date none of these markers have been independently validated or uniformly adopted.…”

Section: Perspectives On Current Classificationmentioning

confidence: 99%

The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia

Amin

Compérat

Epstein

et al. 2021

Advances in Anatomic Pathology

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The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the From the

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Mitotic activity in noninvasive papillary urothelial carcinoma: its value in predicting tumor recurrence and comparison with the contemporary 2-tier grading system

Cited by 12 publications

References 21 publications

A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma

A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma

Report From the International Society of Urological Pathology (ISUP) Consultation Conference On Molecular Pathology Of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer

The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia

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