Prognostic value of programmed death ligand-1 and programmed death-1 expression in patients with upper tract urothelial carcinoma.

OBJECTIVE: To evaluate the prognostic value of programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) expression in patients with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: A retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm-core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut-off for positivity on tumour cells and tumour-infiltrating lymphocytes to evaluate PD-L1 and PD-1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). RESULTS: Overall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD-L1-positive and -negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD-1-positive and -negative disease, respectively. Patients who expressed PD-L1 or PD-1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high-grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD-L1 and PD-1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09-3.08, P = 0.023; and HR 1.59, 95% CI 1.01-2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48-5.04, P = 0.001; and HR 1.96, 95% CI 1.12-3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23-3.53, P = 0.006; and HR 1.71, 95% CI 1.05-2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four-tier combination of PD-L1 and PD-1 expression showed that only PD-L1/PD-1-positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70-5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62-10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13-6.85; P < 0.001) as compared to those with PD-L1/PD-1-negative disease (n = 167 [59.0%]). CONCLUSIONS: We observed that PD-L1 and PD-1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU.

Prognostic Impact of pT3 Subclassification in a Multicentre Cohort of Patients with Urothelial Carcinoma of the Renal Pelvicalyceal System Undergoing Radical Nephroureterectomy: A Propensity Score-weighted Analysis After Central Pathology Review.

BACKGROUND: The current pathological tumour-node-metastasis (pTNM) classification for upper tract urothelial carcinoma (UTUC) does not include any risk stratification of pT3 renal pelvicalyceal tumours. OBJECTIVE: To assess the prognostic impact of pT3 subclassification in a multicentre cohort of patients with UTUC of the renal pelvicalyceal system undergoing radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: Data from all consecutive patients treated with RNU for pT3 renal pelvicalyceal UTUC at 14 French centres from 1995 to 2013 were reviewed retrospectively. INTERVENTION: A central pathology review (CPR) was used to stratify pT3 patients into those with infiltration of the renal parenchyma on a microscopic level (pT3a) versus those with infiltration of the renal parenchyma visible on gross inspection of the resection specimen and/or invasion of peripelvic fat (pT3b). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability weighting (IPW)-adjusted Cox regression analyses were used to compare recurrence-free survival (RFS) and cancer-specific survival (CSS) between pT3a and pT3b patients. RESULTS AND LIMITATIONS: Overall, 202 patients were included and further stratified into pT3a (n = 98; 48.5%) and pT3b (n = 104; 51.5%) subgroups. Median time to follow-up in the weighted population was 68 (interquartile range, 50-95) mo. In IPW-adjusted Cox regression analyses, pT3b versus pT3a substage was associated with a significant adverse effect on RFS (hazard ratio [HR] = 2.02; 95% confidence interval [CI] = [1.36-3.01]; p < 0.001) and CSS (HR = 1.84; 95% CI = [1.20-2.82]; p = 0.005). The study is limited by its retrospective design. CONCLUSIONS: Using IPW-adjusted analyses after the CPR, we observed that RNU patients with pT3b renal pelvicalyceal UTUC had adverse prognosis as compared with those with pT3a disease. As such, this subclassification could help refine the current pTNM system for UTUC. PATIENT SUMMARY: In this report, we looked at the prognostic interest of stratifying patients with pT3 renal pelvicalyceal upper tract urothelial carcinoma based on the extent of local invasion. We found that those with extensive infiltration (pT3b) had adverse prognosis as compared with those with limited infiltration (pT3a). This information could be provided on pathology reports to further guide clinical decision making.

High rate of IIA/IIB neck groups involvement supports complete lateral neck dissection in thyroid carcinoma.

BACKGROUND: Although therapeutic lateral neck dissection (LND) may be indicated in thyroid carcinoma, the cervical lymph node groups IIA and IIB, according to Robbins classification, are often not removed. The aim of our study was to determine the relevance of complete comprehensive LND in thyroid carcinoma. METHODS: We conducted a retrospective study between January 2011 and August 2018 in a university teaching hospital. Histopathological analysis of LND performed during total thyroidectomy in thyroid carcinoma was reviewed according to lymph node level. To demonstrate that neck dissection of upper groups, IIA/IIB, is necessary when therapeutic LND is indicated in thyroid carcinoma, we compared histopathological involvement in complete comprehensive LND of the upper groups IIA/IIB to the lower groups III/IV/V. RESULTS: A total of 30 LND (24 patients) were suitable for analysis. Analysis by neck side revealed that comprehensive LND dissection samples were negative in 3 cases, and positive in 27. In those 27 positive LND, 15 demonstrated involvement of the groups IIA/IIB, and 12 were positive for involvement of the III/IV/V groups only. The combined presence of positive IIA/IIB and positive III/IV/V was observed in 15 of the 27 neck sides. There was no positive IIA/IIB without positive involvement of III/IV/V groups. CONCLUSIONS: The high rate of positive cervical lymph nodes in the upper groups IIA/IIB supports complete comprehensive LND rather than selective III/IV/V LND in thyroid carcinoma surgery. However, impact on survival and whether postoperative radioactive iodine treatment may be modulated remain to be studied.

[Comparison of UICC and AJCC 8th edition TNM classifications in uropathology]. / Comparaison des classifications TNM des 8es éditions de l'UICC et de l'AJCC en uropathologie.

The pTNM stage is one of the most important parameters in the handling of tumor patients. The pathologist plays a major role in the determination of the stage. The classifications undergo an evolution according to the state of art. The TNM system is used worldwide and allows to precise the tumor (T) and lymph node stage and the presence of distant metastasis. This system helps to stratify patient groups and determine their prognosis. In 2017, the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) published their 8th edition. Unluckily several differences exist between both classifications. The UICC neglected to make several recommendations according to the International Society of Urological Pathology (ISUP) decisions, which organises the consensus in uropathology.

[The role of biomarkers in the diagnosis, prognosis and therapy of patients with immuno-oncological treatments of genito-urinary carcinomas]. / Die Rolle von Biomarkern in Diagnose, Prognose und Therapie von Patienten unter immunonkologischer Therapie mit urologischen Malignomen.

In recent years, fundamental research has yielded new insights into tumour biology, and new treatments have been developed. This review highlights the role of the pathologist and how he can support clinicians to find the right treatment for each patient. We explain the problems of the molecular subgroups of bladder cancer, the role of neo-adjuvant chemotherapy in the context of these findings, and show the important role of checkpoint inhibitors. Furthermore we focus on kidney cancer, with the clear cell carcinoma as the most frequent tumour type. We briefly consider prostate cancer, which as a hormone-dependent tumour probably requires different therapies. We also try to show the feasibility and the limits of pathology with the emerging tumour markers.

Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.

Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10(-7)). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.