Evaluation of the prognostic role of co-morbidities on disease outcome in renal cell carcinoma patients.

BACKGROUND: Co-morbidities may induce local and systemic tumor progression of renal cell carcinoma (RCC); however, the prognostic impact of co-morbidities has not yet been well characterized. PATIENTS AND METHODS: RCC patients (n = 2206) surgically treated at three academic institutions in the US and Europe were included in the analysis. Presence of diabetes mellitus, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, coronary heart disease, and hypothyroidism were investigated for their association with clinicopathological features and cancer-specific survival. RESULTS: Hypertension was associated with less advanced T stages (p = 0.025), a lower risk of lymph-node (p = 0.026) and distant metastases (p = 0.001), and improved cancer specific survival in univariable analysis (HR 0.81 95% CI 0.69-0.96, p = 0.013). However, hypertension was not an independent prognostic factor after adjustment for TNM stages, grading, and ECOG performance status (HR 0.95, 95% CI 0.80-1.12; p = 0.530). A correlation between the use of concomitant anti-hypertensive medications and improved survival outcome was not identified. All other investigated co-morbidities did not show significant associations with clinicopathological features or cancer-specific survival. CONCLUSION: Although the investigated co-morbidities are capable or inducing pathophysiological changes that are predisposing factors for tumor progression, none is an independent prognostic factor in patients with RCC.

Melanoma-associated antigen-A and programmed death-ligand 1 expression are associated with advanced urothelial carcinoma.

BACKGROUND: Melanoma-associated antigen-A (MAGE-A) and programmed-death ligand 1 (PD-L1) are present in urothelial carcinoma (UC). We assessed survival outcomes in patients with MAGE-A and PD-L1 expression. METHODS: MAGE-A and PD-L1 expression on neoplastic cells was analyzed using tissue microarrays from patients with UC. We compared differential expression between disease stage and grade. MAGE-A and PD-L1 co-expression was subcategorized. Fisher's exact test was done for categorical variables followed by univariable and multivariable analysis of recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: Co-expression of MAGE+/PD-L1+ was higher in advanced disease; however, only MAGE+/PD-L1- was associated with shorter RFS [hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.19-2.99; p = .006]. MAGE+/PD-L1+ was associated with the worst PFS (HR 17.1; 95% CI 5.96-49.4; p ≤ .001). MAGE-A expression was more prevalent with high-grade (p = .015), and higher-stage ≥ pT2 (p = .001) disease. The 5-year RFS was 44% for MAGE+ versus 58% for MAGE- patients. On multivariable analysis, MAGE+ was also associated with shorter RFS (HR 1.55; 95% CI 1.05-2.30; p = .03). Similarly, MAGE+ was associated with shorter PFS (HR 3.12; 95% CI 1.12-8.68; p = .03). CONCLUSION: MAGE-A and PD-L1 expression is increased in advanced disease and associated with shorter PFS. Furthermore, MAGE-A expression was significantly associated with higher-grade and -stage disease and associated with shorter RFS and PFS. The worse prognosis associated with MAGE-A+/PD-L1+ provides evidence that a combinatorial treatment strategy co-targeting MAGE/PD-L1 might be feasible. Further studies are needed to validate these findings.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

The contemporary role of ablative treatment approaches in the management of renal cell carcinoma (RCC): focus on radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), and cryoablation.

INTRODUCTION: Currently, most of renal tumors are small, low grade, with a slow growth rate, a low metastatic potential, and with up to 30 % of these tumors being benign on the final pathology. Moreover, they are often diagnosed in elderly patients with preexisting medical comorbidities in whom the underlying medical conditions may pose a greater risk of death than the small renal mass. Concerns regarding overdiagnosis and overtreatment of patients with indolent small renal tumors have led to an increasing interest in minimally invasive, ablative as an alternative to extirpative interventions for selected patients. OBJECTIVE: To provide an overview about the state of the art in radiofrequency ablation (RFA), high-intensity focused ultrasound, and cryoablation in the clinical management of renal cell carcinoma. METHODS: A PubMed wide the literature search of was conducted. RESULTS: International consensus panels recommend ablative techniques in patients who are unfit for surgery, who are not considered candidates for or elect against elective surveillance, and who have small renal masses. The most often used techniques are cryoablation and RFA. These ablative techniques offer potentially curative outcomes while conferring several advantages over extirpative surgery, including improved patient procedural tolerance, faster recovery, preservation of renal function, and reduction in the risk of intraoperative and postsurgical complications. While it is likely that outcomes associated with ablative modalities will improve with further advances in technology, their application will expand to more elective indications as longer-term efficacy data become available. CONCLUSION: Ablative techniques pose a valid treatment option in selected patients.

Deletions of chromosomes 3p and 14q molecularly subclassify clear cell renal cell carcinoma.

BACKGROUND: The short arm of chromosome 3 (3p) harbors the von Hippel-Lindau (VHL) tumor suppressor gene, and the long arm of chromosome 14 (14q) harbors the hypoxia-inducible factor 1α (HIF-1α) gene. The objective of this study was to evaluate the significance of 3p loss (loss VHL gene) and 14q loss (loss HIF-1α gene) in clear cell renal cell carcinoma (ccRCC). METHODS: In total, 288 ccRCC tumors underwent a prospective cytogenetic analysis for alterations in chromosomes 3p and 14q. Tumors were assigned to 1 of 4 possible chromosomal alterations: VHL +3p/+14q (VHL wild type [VHL-WT]), VHL +3p/-14q (VHL-WT plus HIF2α [WT/H2]), -3p/+14q (HIF1α and HIF2α [H1H2]), and -3p/-14q (HIF2α [H2]). RESULTS: Among patients who had loss of 3p, tumors with -3p/-14q (H2) alterations were larger (P = .002), had higher grade (P = .002) and stage (P = .001), and more often were metastatic (P = .029) than tumors that retained 14q (H1H2). All patients who had tumors with -3p/-14q (H2) had worse cancer-specific survival (P = .014), and patients who had localized disease (P = .012) and primary T1 (pT1) tumors (P = .008) had worse recurrence-free survival. In patients who had pT1 tumors, combined 3p/14q loss was an independent predictor of recurrence-free survival (hazard ratio, 11.19; 95% confidence interval, 1.91-65.63) and cancer-specific survival (hazard ratio, 15.93; 95% confidence interval, 3.09-82.16). The current investigation was limited by its retrospective design, single-center experience, and a lack of confirmatory protein analyses. CONCLUSIONS: Loss of chromosome 3p (the VHL gene) was associated with improved survival in patients with ccRCC, whereas loss of chromosome 14q (the HIF-1α gene) was associated with worse outcomes. The results of the current study support the hypothesis that HIF-1α functions as an important tumor suppressor gene in ccRCC.

Prognostic impact of preoperative neutrophil-to-lymphocyte ratio in localized nonclear cell renal cell carcinoma.

PURPOSE: The preoperative neutrophil-to-lymphocyte ratio was proposed as a prognostic factor for localized clear cell renal cell carcinoma. We evaluated its role in nonclear cell renal cell carcinoma. MATERIALS AND METHODS: We queried 2 prospective kidney cancer databases. Patients who underwent full resection of localized (T1-3 N0/+ M0) nonclear cell renal cell carcinoma by radical or partial nephrectomy were included in analysis. Associations of the continuously coded neutrophil-to-lymphocyte ratio with disease-free survival were assessed with univariable and multivariable Cox regression models. Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: Our final cohort included 281 patients. The 5-year disease-free survival rate was 88.1%. The neutrophil-to-lymphocyte ratio was significantly associated with disease-free survival. With each 1.0 increase in the ratio the risk of recurrence increased by 15% (HR 1.15, p=0.028). On multivariable analysis TNM group (HR 2.84, p=0.025), Fuhrman grade (HR 3.40, p<0.001) and the neutrophil-to-lymphocyte ratio (HR 1.17, p=0.022) were independently associated with disease-free survival. Adding the neutrophil-to-lymphocyte ratio improved the accuracy of a base model to predict disease-free survival from 78.8% to 80.8%. CONCLUSIONS: The neutrophil-to-lymphocyte ratio is an independent prognostic factor for disease-free survival after surgery with curative intent for localized nonclear cell renal cell carcinoma. It significantly increases the accuracy of established prognostic factors. The neutrophil-to-lymphocyte ratio may provide a meaningful adjunct for patient counseling and clinical trial design.

Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma.

BACKGROUND: The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease-specific survival (DSS). METHODS: The tumor karyotypes of 336 consecutive patients with CCRCC were prospectively evaluated with classical cytogenetic analysis. Chromosome 8q status was correlated with clinicopathological variables, and its impact on DSS was evaluated. RESULTS: Gain of 8q occurred in 28 tumors (8.3%). Gain of 8q was associated with a higher risk of regional lymph node (21.4% vs 6.2%, P = .011) and distant metastases (50.0% vs 24.4%, P = .006), and greater tumor sizes (P = .030). Patients with gain of 8q had a 3.22-fold increased risk of death from CCRCC (P < .001). In multivariable analysis, gain of 8q was identified as an independent prognostic factor (hazard ratio, 2.37; P = .006). The concordance index of a multivariable base model increased significantly following inclusion of 8q gain (P = .0015). CONCLUSIONS: Gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto-oncogene c-MYC is among the list of candidate genes located on 8q, our data suggest that these tumors may have unique pathways activated, which are associated with an aggressive tumor phenotype. If confirmed, defining tumors with gain of 8q may assist in identifying patients who would benefit for specific c-MYC inhibitors or agents that target the MAPK/ERK (mitogen-activated protein kinase) pathway.

Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival.

BACKGROUND: Tobacco use is a leading cause of premature death, yet few studies have investigated the effect of tobacco exposure on the outcome of patients with renal cell carcinoma (RCC). The authors of this report retrospectively studied the impact of smoking on clinicopathologic factors, survival outcomes, and p53 expression status in a large cohort of patients with RCC. METHODS: Eight hundred-two patients (457 nonsmokers and 345 smokers) who had up to 232 months of follow-up were compared for differences in their clinicopathologic features and survival outcomes. Immunohistochemical differences in p53 expression were correlated with smoking status. RESULTS: Smokers presented more commonly with pulmonary comorbidities (P < .0001) and cardiac comorbidities (P = .014) and with a worse performance status (P = .031) than nonsmokers. Smoking was associated significantly with tumor multifocality (P = .022), higher pathologic tumor classification (P = .037), an increased risk of bulky lymph node metastases (P = .031), and the presence of distant metastases (P < .0001), especially lung metastases (P < .0001). Both overall survival (OS) (62.37 months vs 43.64 months; P = .001) and cancer-specific survival (CSS) (87.43 months vs 56.57 months; P = .005) were significantly worse in patients who smoked. The number of pack-years was retained as an independent predictor of CSS and OS in patients with nonmetastatic disease. Mean expression levels of p53 were significantly higher in current smokers compared with former smokers and nonsmokers (P = .012). CONCLUSIONS: In patients with RCC, a history of smoking was associated with worse pathologic features and survival outcomes and with an increased risk of having mutated p53. Further investigation of the genetic and molecular mechanisms associated with decreased CSS in patients with RCC who have a history of smoking is indicated.

Prognostic value of microvascular invasion in predicting the cancer specific survival and risk of metastatic disease in renal cell carcinoma: a multicenter investigation.

PURPOSE: While microvascular invasion is an accepted risk factor in various cancers, its prognostic role in renal cell carcinoma is still unclear. Therefore, a large multicenter study examining the experience of 5 international institutions was performed to evaluate the prognostic value of microvascular invasion in the occurrence of metastases and cancer specific survival. MATERIALS AND METHODS: A total of 2,596 patients (475 with microvascular invasion and 2,121 without microvascular invasion) having up to 212 (median 22.4) months of followup were compared for differences in clinicopathological features, occurrence of metastases and cancer specific survival. RESULTS: Patients with microvascular invasion presented with higher age (p = 0.001) and a worse Eastern Cooperative Oncology Group performance status (p <0.0001). Microvascular invasion was associated with larger tumor diameter (p <0.0001), higher Fuhrman grade (p <0.0001), more advanced pT stage (p <0.0001), and the presence of lymph node and distant metastases (p <0.0001). In particular, in nonmetastatic cases worse survival was associated with microvascular invasion (p <0.0001, HR 2.38). Univariate analysis demonstrated a strong correlation between microvascular invasion and cancer specific survival (p <0.0001). However, after controlling for gender, Eastern Cooperative Oncology Group performance status, Fuhrman grade and TNM stage statistical significance was lost. Of interest, low stage tumors with microvascular invasion were strongly correlated with the occurrence of metastases (p <0.0001). CONCLUSIONS: Microvascular invasion occurs in nearly 1 of 5 patients with renal cell carcinoma, is tightly correlated with adverse clinicopathological features and is an independent predictor of metastatic spread including in those presenting with low stage tumors.

Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma.

UNLABELLED: Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sarcomatoid renal cell carcinoma can occur in the setting of all histological subtypes of kidney cancer. These tumours are very aggressive and many patients present with disseminated disease. Long-term survival is poor and the durable responses to systemic therapy are infrequent. Our large cohort analyses the influence of pathological tumour characteristics in determining prognosis for patients with sarcomatoid renal cell carcinoma undergoing surgical resection. This series helps define the prognostic influence of histological subtype, type of sarcomatoid morphology, the percentage necrosis and sarcomatoid features, and the presence of microvascular invasion. OBJECTIVES: To examine the influence of pathological tumour characteristics on survival to aid prognostication and clinical trial design. Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have poor prognosis and response to systemic therapy. PATIENTS AND METHODS: A single-centre database was reviewed to identify all patients with sRCC. Clinical variables and pathological information, including histology, necrosis, percentage of sarcomatoid features (PSF) and microvascular invasion (MVI), were recorded and correlated to outcome. RESULTS: Analyses of 104 patients with sRCC found that the median (range) size of tumours was 9.5 cm (2.5-30), 65% of patients had areas of clear cell histology, and 69.2% had metastatic disease at presentation. The PSF did not influence tumour size, stage, necrosis, MVI, nodes or metastasis. A total of 85 patients (81.7%) died during the follow-up period with a median (95% confidence interval [CI]) survival of 5.9 months (4.7-8.9). In the overall cohort, Eastern Cooperative Group performance status (ECOGPS), tumour size and metastatic disease were independent predictors of poor survival. MVI, PSF and percentage necrosis were strongly associated with outcome but were not independent predictors of outcome. A multivariate risk model was established that incorporated six covariates (tumour size, MVI, ECOGPS, PSF, necrosis, and metastatic disease) to produce a predictive tool. CONCLUSIONS: Both patients with localized and metastatic sRCC have very poor survival outcomes. Pathological features MVI, PSF and necrosis are important predictors of survival and could be used in a prognostic model while grade and histology do not influence prognosis. A prognostic model, if validated, could aid in patient counselling and/or clinical trial design.