Aims
In 2012, the International Society of Urological Pathology (ISUP) introduced a novel grading system for clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma. This system is ...incorporated into the latest World Health Organization renal tumour classification, being designated WHO/ISUP grading. This study was undertaken to compare WHO/ISUP and Fuhrman grading and to validate WHO/ISUP grading as a prognostic parameter in a series of clear cell RCC.
Methods and results
Analysis of 681 cases of ccRCC showed that 144 tumours could not be assigned a Fuhrman grade on the basis of ambiguous grading features. The application of WHO/ISUP grading resulted in a general down‐grading of cases when compared with Fuhrman grading. In a sub‐group of 374 cases, for which outcome data were available, 9.3% were WHO/ISUP grade 1, 50.3% were grade 2, 24.1% grade 3 and 16.3% grade 4, while the distribution of Fuhrman grades was 0.4% grade 1, 48.7% grade 2, 29.4% grade 3 and 21.5% grade 4. There were no recurrence/metastases amongst patients with WHO/ISUP grade 1 tumours and there was a significant difference in outcome for WHO/ISUP grades 2, 3 and 4. For Fuhrman grading the cancer‐free survival was not significantly different for grade 2 and grade 3 tumours. On multivariate analysis WHO/ISUP grade and pT staging category were found to retain prognostic significance.
Conclusions
The study demonstrates that FG cannot be applied in >20% of cases of ccRCC and the WHO/ISUP provides superior prognostic information.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Objectives
To investigate the role of cancer‐associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumour aggressiveness, metastasis development, and resistance to ...anti‐angiogenic therapy (vascular endothelial growth factor receptor‐tyrosine kinase inhibitors VEGFR‐TKI).
Patients and Methods
Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumour lymphangiogenesis was investigated, respectively, by transcriptional signatures and then correlated with tumour development and prognosis. The effect of these CAFs on tumour cell migration and VEGFR‐TKI resistance was analysed on co‐cultures of ccRCC cells with CAFs.
Results
Results from our cohorts and from in silico investigations showed that VEGFR‐TKI significantly increase the number of CAFs in tumours. In the same populations of patients with ccRCC, the proportion of intra‐tumoral CAFs correlated to shorter disease‐free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decreased the VEGFR‐TKI‐dependent cytotoxic effect of tumour cells.
Conclusions
Our results show that VEGFR‐TKI promote the development of CAFs, and CAFs favour tumour aggressiveness, metastatic dissemination, and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumours. Our results highlight their relevance in ccRCC.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Aims
The aims of this study were to evaluate the impact of tumour‐associated necrosis (TAN) on metastasis‐free survival for clear cell renal cell carcinoma (RCC), and to determine whether TAN ...provides survival information additional to World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading.
Methods and results
The study consisted of 376 cases of clear cell RCC treated by nephrectomy, for which follow‐up was available. WHO/ISUP grade was assigned, and sections were assessed for the presence of TAN. American Joint Committee on Cancer (AJCC) pT staging category and tumour size were also recorded. The development of metastatic disease was taken as the clinical endpoint, and survival analyses, utilising univariate and multivariate models, were performed. WHO/ISUP grades were: grade 1, 35 cases (9.3%); grade 2, 188 cases (50.0%); grade 3, 91 cases (24.2%); and grade 4, 62 cases (16.5%). Staging categories were pT1–pT2 234 tumours (62.2%) and pT3–pT4 139 tumours (37.0%). TAN was seen in 128 cases (34.0%). Neither TAN nor metastases were seen in grade 1 tumours. Among grade 2–4 tumours, those with TAN had a significantly worse prognosis than those without TAN (P = 0.017, P = 0.04, and P = 0.006, respectively). Multivariate analysis (WHO/ISUP grade, pT staging category, and TAN) showed all three variables to be independently associated with outcome (P = 0.009, P = 0.005, and P = 0.001, respectively). For all tumour grades and pT staging categories, it was found that the presence of TAN was associated with a 2.91‐fold greater risk of metastatic disease.
Conclusion
Tumour‐associated necrosis is an important prognostic factor for clear cell RCC, independently of WHO/ISUP grade. This supports the suggestion that TAN could be incorporated into tumour grading criteria.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Aims
First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain ...unclear.
Methods
We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data.
Results
TFEB‐amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high‐grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high‐level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases.
Conclusion
TFEB‐amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background
Prostate cancer (PCa) is more frequent and more aggressive in populations of African descent than in Caucasians. Since the fatty acid composition of peri‐prostatic adipose tissue (PPAT) ...has been shown to differ according to the ethno‐geographic origin and is involved in PCa aggressiveness, we aimed to analyze the cholesterol content of PPAT from Caucasian and African‐Caribbean patients, in correlation with markers of disease aggressiveness and cholesterol metabolism in cancer tissues.
Methods
The quantification of cholesterol in PPAT was analyzed in 52 Caucasian and 52 African‐Caribbean PCa patients, with in each group 26 indolent tumors (ISUP Group1 and pT2) and 26 potentially aggressive tumors (ISUP Group 3–5 and/or pT3). The expression of proteins involved in cholesterol metabolism was analyzed by immunohistochemistry on cancer tissue samples included in tissue microarrays.
Results
The amount of cholesterol esters was lower in PPAT from African‐Caribbean patients compared with Caucasians, without any correlation with markers of disease aggressiveness. In cancer tissues from African‐Caribbean patients, the expression of ABCA1 (involved in cholesterol efflux) was decreased, and that of SREBP‐2 (involved in cholesterol uptake) was increased. In both groups of patients, SREBP‐2 expression was strongly associated with that of Zeb1, a key player in the epithelial‐to‐mesenchymal transition (EMT) process.
Conclusion
These results suggest that cholesterol metabolism differs according to the ethno‐geographic origin, in both PPAT and cancer tissues. In African‐Caribbeans, the orientation towards accumulation of cholesterol in cancer cells is associated with a more frequent state of EMT, which may promote PCa aggressiveness in this population.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign ...from malignant variants but lacked prognostic value.
Methods
This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event‐free survival (EFS). They built the PEComa prognostic score (PEC‐PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2).
Results
Analyzing 87 patients who had a median 46‐month follow‐up (interquartile range, 20–74 months), the median EFS was 96.5 months (95% confidence interval CI, 47.1 months to not applicable), with 2‐year and 5‐year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2‐year and 5‐year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio HR, 5.17; 95% CI, 1.65–16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16–13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19–8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low‐risk PEC‐PRO scores had a 2‐year EFS rate of 93.7% (95% CI, 83.8%–100.0%), those with intermediate‐risk PEC‐PRO scores had a 2‐year EFS rate of 67.4% (95% CI, 53.9%–80.9%), and those with high‐risk PEC‐PRO scores had a 2‐year EFS rate of 2.3% (95% CI, 0.0%–18.3%).
Conclusions
The PEC‐PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow‐up strategies but requires validation in a prospective trial.
By using a weighted combination of clinicopathologic features, the perivascular epithelioid cell neoplasm prognostic (PEC‐PRO) score identified three different prognostic groups, including a low risk (score = 0), an intermediate risk (score = 1), and a high risk (score ≥2) of recurrence. The PEC‐PRO score reliably predicts the recurrence risk in patients with localized perivascular epithelioid cell neoplasms and has the potential to improve follow‐up strategies and personalize adjuvant treatments.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and ...offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer‐related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV‐positive tumors, while HPV‐negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV‐positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = 1.25,5.17, P value = .010; HRPIK3CA = 2.43, 95%CI = 1.3,4.56, P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV‐positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.
What's new?
To develop personalized therapies for anal squamous cell carcinoma (ASCC), researchers need to learn more about the genomics of the disease. Here, the authors examined pathogenic variants in 571 cancer‐related genes identified in surgical samples collected form patients with ASCC. They found that more than 40% of patients carried mutations known to be targetable in other cancers. In patients with HPV‐positive tumors, pathogenic variants in KMT2C and PIK3CA were associated with worse overall survival. These results support genomic profiling to identify patients for clinical trials of targeted therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims
To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC.
Methods and results
We identified 28 tumours from multiple institutions. They ...typically showed two cell populations—larger cells with eosinophilic cytoplasm and higher‐grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5–100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39–86 years). The median tumour size was 20 mm (range 9–65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low‐grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt–Hogg–Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α‐methylacyl‐CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA‐3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow‐up was available for 23 patients (median 24 months, range 1–244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes).
Conclusions
Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Aims
Renal cell carcinomas (RCCs) represent 2–5% of kidney malignancies in children and adolescents. Appropriate diagnostic and classification are crucial for the correct management of the patients ...and in order to avoid inappropriate pre‐operative chemotherapy, which is usually recommended if a Wilms' tumour is suspected.
Methods and results
A French–Italian series of 93 renal cell carcinomas collected from 1990 to 2019 in patients aged less than 18 years was reclassified according to the 2016 World Health Organization (WHO) classification and the latest literature. TFE3 and TFEB fluorescence in‐situ hybridisation (FISH) analyses and a panel of immunohistochemical stains were applied. The median age at diagnosis was 11 years (range = 9 months–17 years). MiT family (MiTF) translocation RCCs accounted for 52% of the tumours, followed by papillary (20%) and unclassified RCCs (13%). Other subtypes, such as SDHB‐deficient and fumarate hydratase‐deficient RCCs, represented 1–3% of the cases. We also described a case of ALK‐rearranged RCC with a metanephric adenoma‐like morphology.
Conclusion
A precise histological diagnosis is mandatory, as targeted therapy could be applied for some RCC subtypes, i.e. MiTF‐translocation and ALK‐translocation RCC. Moreover, some RCC subtypes may be associated with a predisposition syndrome that will impact patients' and family's management and genetic counselling. A precise RCC subtype is also mandatory for the clinical management of the patients and inclusion in new prospective clinical trials.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Engaging in exercise while undergoing radiotherapy (RT) has been reported to be safe and achievable. The impact of exercise training (ET) on RT efficiency is however largely unknown. Our study aims ...to investigate the interactions between ET and RT on prostate cancer growth. Athymic mice received a subcutaneous injection of PPC‐1 cells and were randomly assigned to either cancer control, cancer ET, cancer RT, or cancer RT combined with ET (CaRT‐ET). Mice were sacrificed 24 days post‐injection. All three intervention groups had reduced tumor size, the most important decrease being observed in CaRT‐ET mice. Apoptotic marker cleaved caspase‐3 was not modified by ET, but enhanced with RT. Importantly, this increase was the highest when the two strategies were combined. Furthermore, NK1.1 staining and gene expression of natural killer (NK) cell receptors Klrk1 and Il2rβ were not affected by ET alone but were increased with RT, this effect being potentiated when combined with ET. Overall, our study shows that (a) ET enhances RT efficiency by potentiating NK cell infiltration, and (b) while ET alone and ET combined with RT both reduce tumor growth, the mechanisms mediating these effects are different.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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