Case Report: Disease progression of renal cell carcinoma containing a novel putative pathogenic KAT6A::NRG1 fusion on Ipilimumab- Nivolumab immunotherapy. A case study and review of the literature.

Renal cell carcinoma still carries a poor prognosis despite therapeutic advancements. Detection of genetic mutations is vital in improving our understanding of this disease as well as potential role in targeted therapy. Here we present a case of a 49 year old man with an aggressive renal cell carcinoma bearing a novel pathogenic KAT6A::NRG1 fusion. We will explore the clinical presentation, histological and molecular diagnostics, treatment and disease progression. We will discuss the relevance of this unique fusion and comparisons with cancer cases with similar genetic mutations. Further research is warranted for such cases, in order to facilitate better targeted treatments.

Rates and Outcomes of Breast Lesions of Uncertain Malignant Potential (B3) benchmarked against the National Breast Screening Pathology Audit; Improving Performance in a High Volume Screening Unit.

INTRODUCTION: Our breast screening unit was identified as high outlier for B3 lesions with a low positive predictive value (PPV) compared to the England average. This prompted a detailed internal audit and review of B3 lesions and their outcomes to identify causes and address any variation in practice. PATIENTS AND METHODS: The B3 rate was calculated in 4168 breast core biopsies from 2019, using the subsequent excision to determine the PPV. Atypical intraductal epithelial proliferation (AIDEP) cases were subject to microscopic review to reassess the presence of atypia against published criteria. The B3 rate was re-audited in 2021, and the results compared. RESULTS: Screening cases had a high B3 rate of 12.4% (30% above the national average), and a PPV of 7.7% (9.7% with atypia). AIDEP was identified as a possible cause of this outlier status. On review and by consensus, AIDEP was confirmed in only 66% of cases reported as such, 17% were downgraded, and 16% did not reach consensus, the latter highlighting the difficulty and subjectivity in diagnosis of these lesions. Repeat audit of B3 rates after this extended review revealed a reduction from 12.4% to 9.11%, which is more in line with national standards. CONCLUSION: Benchmarking against national reporting standards is critical for service improvement. Through a supportive environment, team working, rigorous internal review and adherence to guidelines, interobserver variation and outlier status in breast pathology screening outliers can both be addressed. This study can serve as a model to other outlier units to identify and tackle underlying causes.

Papillary urothelial neoplasm of low malignant potential (PUN-LMP): Still a meaningful histo-pathological grade category for Ta, noninvasive bladder tumors in 2019?

BACKGROUND: Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. OBJECTIVES: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. MATERIALS AND METHODS: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. RESULTS: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. CONCLUSIONS: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas.