The accurate diagnosis of Xp11‐translocation renal cell carcinoma (RCC) in adults is challenging. TFE3 (located on chromosome X) fuses with a partner gene generally located on another chromosome. In ...rare cases TFE3 may fuse with a neighboring gene: RBM10. Because TFE3 false‐positive immunostaining is a common pitfall in many laboratories, demonstration of the chromosomal rearrangement is required in order to ascertain the diagnosis. Fluorescence in situ hybridization (FISH)—that has been considered as the gold standard method—reaches its limits for detecting small Xp11 paracentric inversions. We performed a comprehensive clinical, histological and genomic study of six novel cases of RCC with RBM10‐TFE3 fusion. Using FISH, TFE3 rearrangement was equivocal in one case and negative in others. RBM10‐TFE3 fusion was discovered using targeted RNA sequencing (RNASeq). As all the previously reported cases (mean age: 50), the six patients were adults (mean age: 42), suggesting an epidemiologic difference between RBM10‐TFE3 RCC and tumors harboring some other partner genes, such as ASPSCR1 that rather occur in children. Array‐comparative genomic hybridization showed several alterations, notably a gain of 17q in four cases with papillary features and loss of 3p in one case with clear cells. Our study demonstrates that, though rare among adult cases of RCC, RBM10‐TFE3 fusion is not exceptional and warrants appropriate molecular detection. Notably, it would be worthy to systemically investigate by RNASeq challenging RCC with type‐2 papillary features and 17q gain.
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.
Background
Thyroid nodules with indeterminate cytology represent up to 30% of cases. Molecular testing is now highly recommended to improve management. This study aimed to evaluate the use of the ...Idylla™ NRAS/BRAF mutation test, a rapid and automated polymerase chain reaction (PCR) assay validated for fixed paraffin‐embedded use, on residual thyroid liquid‐based fine‐needle aspiration (LB‐FNA).
Methods
Concordance between mutations detected by the Idylla™ assay and the gold‐standard qPCR was assessed by splitting in two aliquots 31 BRAF or RAS mutated and 5 non‐mutated LB‐FNA samples. Samples were obtained either from simulated FNA after thyroidectomy or from FNA obtained during routine care. A third aliquot was used to assess the limit of detection of Idylla™ for five mutated samples.
Results
The Idylla™ assay showed a sensitivity of 97% and a specificity of 83% as results were concordant for 34 out of 36 samples. One discordant sample concerned a BRAF p.K601E‐mutation which is not detected by the Idylla™ cartridge. The other showed a false‐positive NRAS p.A146T detection and a weak BRAF p.V600E detection. The limit of detection of the Idylla™ assay was not reached by the dilution assay.
Conclusion
Idylla™ NRAS/BRAF mutation testing can be performed on residual thyroid LB‐FNA, using low DNA quantity input, thus not requiring a dedicated sample. The Idylla™ NRAS/BRAF assay offers a quick and easy first step for analyzing the main molecular alterations in indeterminate thyroid nodules, hence improving diagnostic management.
Programmed death ligand-1 (PD-L1) immunohistochemical (IHC) status is used to predict which patients with metastatic urothelial carcinoma (UC) will respond to immunotherapy. We aimed to compare ...QR1(Quartett), 22C3 (Dako), and SP263 (Ventana) detection of PD-L1 expression in muscle-invasive UCs and determine the best scoring algorithm for assessment of PD-L1 expression when using the QR1 clone. Our study included 69 UCs. For SP263 and 22C3, PD-L1-positive tumor cell (TC) and/or immune cell (IC) percentages (TC%/IC%) and the Combined Positive Score (CPS) were assessed, respectively (positivity cut-offs of ≥ 25% and ≥ 10). For QR1, both interpretation systems were evaluated. The concordances between assays were calculated. PD-L1 IHC staining characteristics were comparable between QR1, 22C3, and SP263 in both conventional and variant histology UCs. We demonstrated strong or very strong correlations between clones; the strongest correlation for TCs was between QR1 and SP263 (r = 0.92;
p
= 0.001) and for ICs was between QR1 and 22C3 (r = 0.85;
p
= 0.001). Our comparative analysis of the scoring algorithms revealed very good concordances among the three assays (range 0.791–0.878); the highest concordance was between QR1 and SP263 when CPS was used as the scoring algorithm for QR1 (0.878;
p
< 0.001). Our study is the first to demonstrate that the QR1 clone can be used to evaluate PD-L1 status in UCs, with a very good agreement rate with the reference clones. QR1 appeared to be more similar to the SP263 clone. With regard to the scoring algorithm, when evaluating PD-L1 expression using QR1 clone, CPS performed better compared with the TC%/IC% score.
HER2-dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand-independent mechanisms. From ...41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors ARSI), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.
Urothelial bladder cancer (UBC) is characterised by a high risk of recurrence. Patient monitoring is currently based on iterative cystoscopy and on urine cytology with low sensitivity in ...non-muscle-invasive bladder cancer (NMIBC). Telomerase reverse transcriptase (TERT) is frequently reactivated in UBC by promoter mutations.
We studied whether detection of TERT mutation in urine could be a predictor of UBC recurrence and compared this to cytology/cystoscopy for patient follow-up. A total of 348 patients treated by transurethral bladder resection for UBC were included together with 167 control patients.
Overall sensitivity was 80.5% and specificity 89.8%, and was not greatly impacted by inflammation or infection. TERT remaining positive after initial surgery was associated with residual carcinoma in situ. TERT in urine was a reliable and dynamic predictor of recurrence in NMIBC (P<0.0001). In univariate analysis, TERT positive-status after initial surgery increased risk of recurrence by 5.34-fold (P=0.0004). TERT positive-status was still associated with recurrence in the subset of patients with negative cystoscopy (P=0.034).
TERT mutations in urine might be helpful for early detection of recurrence in UBC, especially in NMIBC.
Summary
Objective
To investigate the impact of the volume of thyroid surgery and pathologic detection on the risk of thyroid cancer.
Methods
We investigated the influence of the volume of thyroid ...surgery in a first study that included 23 384 thyroid surgeries and 5302 thyroid cancers collected between 2008 and 2013. Standardized incidence ratios (SIRs) and thyroid intervention rates (STIRs) were used as indicators of cancer risk and surgery volume, respectively. The influence of pathologic detection, using the number of cuts per gram of tissue as the indicator, was studied in a second study that included 1257 thyroid specimens, collected in 2014.
Results
We found departmental variations in SIRs and a significant effect of the STIR on the SIR (men, P = 0.0008; women, P < 0.0001). A 1/100 000 increase in the STIR resulted in a 3% and 1.3% increase in the SIR in men and women, respectively. This effect was greatest for microcancers and absent for tumours >4 cm. The risk of cancer diagnosis was significantly associated with the number of cuts per gram of tissue (OR 6.1, P < 0.001), and was greater for total thyroidectomy than for lobectomy (P = 0.014) and when FNA cytology had been preoperatively performed (P < 0.001). The prevalence of incidental microcancers was highest in the centres performing the highest number of cuts per gram.
Conclusions
The risk of thyroid cancer, particularly microcancer, is related to the volume of surgery and to the level of pathologist scrutiny. Both factors contribute to the increase in overdiagnosis. This further advocates for appropriate selection of patients for thyroid surgery.
Struma ovarii (SO) are rare, accounting for 0.3-1% of ovarian tumours, and include benign and malignant lesions. In most cases, histology is not predictive of clinical outcome and prognosis. The ...prognosis of histologically malignant thyroid-type carcinomas can indeed be excellent, while SO, composed of normal thyroid tissue, can recur and are designated highly differentiated follicular carcinoma of the ovary. Clearer diagnostic criteria are therefore required.
We retrospectively studied 31 SO using DNA and RNA sequencing with pan-cancer gene panels, including eight biologically malignant SO (BMSO) defined based on ovarian serosal or extra-ovarian dissemination at presentation or during follow-up, 10 stage IA histologically malignant SO (HMSO) with thyroid-type carcinoma morphology and 13 biologically and histologically benign SO (BSO), with none of the above-mentioned characteristics. Molecular alterations were observed in 87.5% of BMSO, 70% of HMSO and 7.7% of BSO (P < 0.001). All patients with a peritoneal dissemination at presentation or during follow-up had at least one gene alteration. BRAF mutations (44.5%) were only observed in malignant forms (HMSO and BMSO) and TERT promoter alterations (25%) only in cases of BMSO. The BRAF p.G469A mutation, which is extremely rare in thyroid carcinomas, was the molecular alteration most frequently associated with malignant SO (28.5%).
Our results highlight the clinical utility of molecular sequencing in SO, based on this limited number of cases. However, as malignant SO evolve slowly, more extensive molecular studies in SO with more than 10 years' follow-up are required to draw any conclusions on the prognostic value of the associated gene alterations.
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