Prognostic significance of circulating insulin growth-like factor 1 and insulin growth-like factor binding protein 3 in renal cell carcinoma patients.

Insulin growth-like factor-1 (IGF-1) and its main binding protein insulin growth-like factor binding protein 3 (IGFBP-3) play important roles in cancer development and progression. We hypothesize that circulating IGF-1 and IGFBP-3 may have significant prognostic values in renal cell carcinoma (RCC) patients. We used 1,010 histologically confirmed RCC patients in this case series study to test this hypothesis. We constructed a weighted genetic risk score (GRS) using a large panel of genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) to predict circulating IGF-1 and IGFBP-3 level, respectively. We analyzed the associations of the GRS with the prognosis of RCC patients using multivariate Cox proportional hazards model. We found significant associations between genetically predicted circulating IGF-1 level, but not IGFBP-3, and RCC prognosis. RCC patients with better prognosis had significantly higher baseline circulating IGF-1 level than those with worse prognosis. Dichotomized at the median value of GRS, patients with high IGF-1 exhibited significantly lower risks of recurrence (HR=0.81, 95% CI, 0.65-0.99, P=0.045) and death (HR=0.74, 95% CI, 0.60-0.91, P=0.004). If patients were dichotomized at the 75% value of GRS, those with the highest quarter of GRS had 27% lower risk of recurrence (OR=0.73, 95% CI, 0.55-0.96, P=0.025) and 34% lower risk of death (OR=0.66, 95% CI, 0.50-0.87, P=0.003) than the other three quarters of patients. High IGF-1/IGFBP-3 ratio was also associated with reduced risks of recurrence and survival. In conclusion, high circulating IGF-1 level and IGF-1/IGFBP-3 ratio at diagnosis is associated with better prognosis in RCC patients.

A generative adversarial approach to facilitate archival-quality histopathologic diagnoses from frozen tissue sections.

In clinical diagnostics and research involving histopathology, formalin-fixed paraffin-embedded (FFPE) tissue is almost universally favored for its superb image quality. However, tissue processing time (>24 h) can slow decision-making. In contrast, fresh frozen (FF) processing (<1 h) can yield rapid information but diagnostic accuracy is suboptimal due to lack of clearing, morphologic deformation and more frequent artifacts. Here, we bridge this gap using artificial intelligence. We synthesize FFPE-like images ("virtual FFPE") from FF images using a generative adversarial network (GAN) from 98 paired kidney samples derived from 40 patients. Five board-certified pathologists evaluated the results in a blinded test. Image quality of the virtual FFPE data was assessed to be high and showed a close resemblance to real FFPE images. Clinical assessments of disease on the virtual FFPE images showed a higher inter-observer agreement compared to FF images. The nearly instantaneously generated virtual FFPE images can not only reduce time to information but can facilitate more precise diagnosis from routine FF images without extraneous costs and effort.

Efficacy and safety of gemcitabine plus doxorubicin in patients with renal medullary carcinoma.

INTRODUCTION: Renal medullary carcinoma (RMC) is a rare and lethal renal cell carcinoma characterized by the loss of tumor suppressor SMARCB1. Molecular profiling studies have suggested that RMC cells may be vulnerable to therapies that generate DNA damage, such as the combination of the nucleoside analog gemcitabine, and topoisomerase inhibitor doxorubicin. PATIENTS AND METHODS: We retrospectively analyzed the records of patients with RMC treated with gemcitabine plus doxorubicin at our institution between January 2005 and September 2020. Best radiographic response and disease progression (RECIST v1.1) were assessed by a blinded radiologist. RESULTS: Sixteen patients were included in the study. All but 1 patient (93.8%) received prior platinum-based chemotherapy. Gemcitabine was given intravenously at 900-1200 mg/m2 and doxorubicin at 40-50 mg/m2 intravenously every 2 weeks. Three patients (18.8%) achieved partial response and 7 (43.8%) patients achieved stable disease. The median progression-free survival was 2.8 months (95% CI, 0-6.0). Median overall survival (OS) from gemcitabine plus doxorubicin initiation was 8.1 months (95% CI, 4.6-11.7) and OS from diagnosis was 15.5 months (95% CI, 4.2-26.8 months). There were no grade ≥ 4 AEs; grade 3 AEs were cytopenias (18.8%), nausea (12.5%), fatigue (12.5%), and cardiotoxicity (6.2%). No somatic alterations were detected in the 9 patients tested by targeted next generation sequencing assays. CONCLUSION: Gemcitabine plus doxorubicin was well tolerated and demonstrated clinical activity in patients with platinum-refractory RMC, with a subset of patients experiencing durable responses lasting longer than 6 months. Further investigation is warranted to determine biomarkers of sensitivity and target mechanisms of resistance.

Oncologic outcomes and subsequent treatment following organ sparing surgery for penile carcinoma: The University of Texas M.D. Anderson Cancer Center Experience.

OBJECTIVES: To determine the oncologic outcomes of organ sparing surgery (OSS) for penile cancer and to determine the management of and risk factors for local recurrence at a tertiary referral center in the United States. METHODS AND MATERIALS: Patients undergoing OSS from 1996 to 2018 at The University of Texas, MD Anderson Cancer Center were identified using a prospective database. Organ sparing procedures included: wide local excision (WLE; including circumcision and glans resurfacing), partial or total glansectomy, laser therapy, or OSS combined with laser ablation (i.e., laser combination). Clinical and pathologic data were collected for descriptive analysis. Recurrences (local and regional) were identified, and the association between overall and local recurrences was determined using Cox proportional hazards regression. Overall and recurrence free survival analyses were performed using Kaplan-Meier estimates. RESULTS: A total of 129 patients undergoing OSS were identified with a median follow up interval of 28.0 months. The most common OSS was laser combination (38.8%), and 65.1% of patients presented with pTis or ≤pT1a disease. Twenty (15.5%) recurrences were identified, of which 17 (13.2%) were local and 3 (2.3%) were regional. There were no distant recurrences as the initial site of recurrence. The median time to local recurrence was 20.9 months, and 88.2% were identified within 5 years of surgery. Most (76.5%) local recurrences were successfully treated with further penile preservation without a detrimental impact on overall survival. Patients with pathologic Ta or T1a disease treated with laser or laser combination surgery were more likely to present with local recurrence. CONCLUSION: OSS using a variety of techniques to achieve negative surgical margins provides long-term effective local control for localized penile cancer. Most local recurrences can be successfully treated with further penile preserving strategies and long follow-up is essential. Laser therapy or laser combination with OSS should be used with caution in patients with invasive penile cancer.

Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel-Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. EXPERIMENTAL DESIGN: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. RESULTS: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. CONCLUSIONS: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.

Effective combinatorial immunotherapy for penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.

Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.

Hybrid oncocytic/chromophobe tumor (HOCT) of the kidney represents a poorly understood clinicopathologic entity with pathologic features that overlap between benign renal oncocytoma (RO) and malignant chromophobe renal cell carcinoma (ChRCC). Consequently, characterization of HOCT and its separation from the foregoing entities are clinically important. The aim of this study was to describe the pathologic and molecular features of HOCT and to compare them with those of RO and ChRCC. We retrospectively identified a cohort of 73 cases with renal oncocytic tumors (19 RO, 27 HOCT, and 27 ChRCC) for whom clinical follow-up data were available by 2 tertiary care hospitals. All cases were sporadic except for 2 HOCTs that were associated with Birt-Hogg-Dubé syndrome. Lesional tissues were retrieved for molecular analysis. We performed targeted gene sequencing of all exons of 261 cancer related genes on a subset of HOCT samples (n = 16). Gene expression profiling of a customized codeset was conducted on 19 RO, 24 HOCT, and 27 ChRCC samples. Clinicopathologic characteristics as well as DNA copy number alterations, mutational and transcriptional features of HOCT derived from sequencing and expression profiling data are described and compared to those in RO and ChRCC. HOCTs were more frequently multifocal and did not exhibit mutations in genes that are recurrently mutated in RO or ChRCC but showed copy number alterations primarily involving losses in chromosomes 1 and X/Y. The mRNA transcript data show that HOCT can be separated from RO and ChRCC. Hence, HOCT appears to represent a distinct renal tumor entity with genomic features that are intermediate between those of RO and ChRCC.

Renal cell carcinoma and pathologic nodal disease: Implications for American Joint Committee on Cancer staging.

BACKGROUND: Lymph node (LN) metastases are associated with poor outcomes for patients with renal cell carcinoma (RCC). This study compared the survival outcomes of patients with stage III, node-positive disease (pT123 N1 M0 ) and patients with stage III, node-negative disease (pT3 N0 M0 ). METHODS: A database of 4652 patients with RCC of any histological subtype treated with surgery at The University of Texas MD Anderson Cancer Center from 1993 to 2012 was retrospectively assessed. A total of 115 patients with pT123 N1 M0 disease, 274 patients with pT3 N0 M0 disease, and 523 patients with pT123 N0/x M1 disease were included. Overall survival (OS) and cancer-specific survival (CSS) were estimated and compared between each cohort. RESULTS: Median OS and CSS times were significantly better for pT3 N0 M0 patients than pT123 N1 M0 patients (OS, 10.2 vs 2.4 years, P < .0001; CSS, not reached vs 2.8 years, P < .0001). Similar median OS and CSS times were noted for pT123 N1 M0 and pT123 N0/x M1 patients (OS, 2.4 vs 2.4 years; P = .62; CSS, 2.8 vs 2.4 years; P = .10). In a multivariate analysis, tumor grade (hazard ratio [HR] for OS, 2.47; P < .0001; HR for CSS, 2.99; P < .0001) and pathologic LN involvement (HR for OS, 2.44; P < .0001; HR for CSS, 2.85; P < .0001) were associated with worse OS and CSS. CONCLUSIONS: Among RCC patients classified with stage III disease, those with pT123 N1 M0 disease had significantly worse survival than those with pT3 N0 M0 disease. OS and CSS were similar for patients with pT123 N1 M0 disease and patients with pT123 N0/x M1 disease (stage IV). If validated, these findings suggest that RCC patients with nodal disease should be reclassified as having stage IV disease.

Challenges in Pathologic Staging of Renal Cell Carcinoma: A Study of Interobserver Variability Among Urologic Pathologists.

Staging criteria for renal cell carcinoma differ from many other cancers, in that renal tumors are often spherical with subtle, finger-like extensions into veins, renal sinus, or perinephric tissue. We sought to study interobserver agreement in pathologic stage categories for challenging cases. An online survey was circulated to urologic pathologists interested in kidney tumors, yielding 89% response (31/35). Most questions included 1 to 4 images, focusing on: vascular and renal sinus invasion (n=24), perinephric invasion (n=9), and gross pathology/specimen handling (n=17). Responses were collapsed for analysis into positive and negative/equivocal for upstaging. Consensus was regarded as an agreement of 67% (2/3) of participants, which was reached in 20/33 (61%) evaluable scenarios regarding renal sinus, perinephric, or vein invasion, of which 13/33 (39%) had ≥80% consensus. Lack of agreement was especially encountered regarding small tumor protrusions into a possible vascular lumen, close to the tumor leading edge. For gross photographs, most were interpreted as suspicious but requiring histologic confirmation. Most participants (61%) rarely used special stains to evaluate vascular invasion, usually endothelial markers (81%). Most agreed that a spherical mass bulging well beyond the kidney parenchyma into the renal sinus (71%) or perinephric fat (90%) did not necessarily indicate invasion. Interobserver agreement in pathologic staging of renal cancer is relatively good among urologic pathologists interested in kidney tumors, even when selecting cases that test the earliest and borderline thresholds for extrarenal extension. Disagreements remain, however, particularly for tumors with small, finger-like protrusions, closely juxtaposed to the main mass.

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

Oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25-year single institution experience.

PURPOSE: To evaluate oncologic outcomes and management of patients with microscopic positive surgical margin (PSM) after partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: We reviewed our database to identify patients who underwent PN between 1990 and 2015 for RCC and had PSM on final pathology. A 1:3 matching was performed to a negative surgical margin (NSM) cohort. Kaplan-Meier method and log-rank test were used to estimate survival and differences in outcomes, respectively. Cox proportional hazards models were conducted to estimate the Hazards ratio. RESULTS: A total of 2297 patients underwent PN at our institution, of which 1863 (81%) had RCC. Microscopic PSM was found in 34 (1.8%) RCC patients who were matched to 100 patients with NSM. Of these 34 patients, local recurrence (n = 4), distant kidney recurrences (n = 4), and metastases (n = 5) developed during a median follow-up of 62 months. Bilateral tumors/tumors in a solitary kidney (n = 12/13, 92%), and multifocal tumors (n = 7/13, 54%) were found in patients who developed recurrence/metastasis. PSM patients were at a higher risk of shorter overall survival (p = 0.001), local recurrence-free survival (p = 0.003), distant recurrence-free survival (p = 0.032) and metastasis-free survival (p = 0.018). There was statistically significant association between PSM and bilateral tumors, prior treated RCC at presentation and higher nephrometry score in multivariable model. CONCLUSIONS: There was a low rate of microscopic PSM in our large cohort of patients undergoing PN despite tumor complexity. Higher nephrometry score, bilateral tumors, and prior treated RCC independently predicted PSM which showed worse survival, recurrence and metastasis compared to patients with NSM.

Intraoperative Conversion From Partial to Radical Nephrectomy: Incidence, Predictive Factors, and Outcomes.

OBJECTIVE: To evaluate preoperative and intraoperative predictors of conversion to radical nephrectomy (RN) in a cohort of patients undergoing a planned partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: A single-center, retrospective review was conducted using our PN database that includes patients who were scheduled to undergo PN (regardless of the approach) but were converted to RN between August 1990 and December 2016. Reasons for conversion were collected from the operative report. Patient demographics and perioperative variables were compared with the successful PN group. Univariate and multivariate logistic regression analyses were conducted to assess predictors of conversion. RESULTS: A total of 1857 patients were scheduled to undergo PN. Of these patients, 90 (5%) were converted to RN. The multivariate model showed that larger tumor size (odds ratio [OR] = 1.20, P = .040), higher RENAL nephrometry score (OR = 1.41, P = .001), hilar tumor or renal sinus invasion (OR = 2.80, P = .004), laparoscopic PN (OR = 7.34, P <.001), intraoperative bleeding (OR = 19.62, P <.001), positive surgical margin (OR = 31.85, P <.001), and advanced pathologic tumor-stage (T3 or T4) (OR = 7.29, P <.001) were associated with increased odds of intraoperative conversion to RN. CONCLUSION: The rate of conversion to RN was low in patients who were scheduled to undergo PN in this series. Larger tumor size with increasing complexity, hilar tumor location or renal sinus invasion, locally advanced tumors, laparoscopic PN but not robotic PN, bleeding complication, and positive surgical margin were associated with intraoperative conversion from scheduled PN to RN.

Local Tumor Bed Recurrence Following Partial Nephrectomy in Patients with Small Renal Masses.

PURPOSE: We examined the incidence, characteristics and treatment of patients with tumor bed recurrence after partial nephrectomy. MATERIALS AND METHODS: We retrospectively reviewed the charts of 2,256 patients with sporadic small renal masses treated with partial nephrectomy between 2000 and 2014. Local tumor bed recurrence was strictly defined as detection of a new enhancing lesion 1) specifically in the surgical defect or 2) in the same region (eg lower pole) as the partial nephrectomy site. To determine differences in multiple characteristics 44 patients (1.9%) with local recurrence were compared to 163 randomly selected patients who underwent partial nephrectomy with no recurrence. RESULTS: Patients with local tumor bed recurrence were more likely to have a solitary kidney (27% vs 4%, p <0.01) and bilateral disease at presentation (23% vs 10.4%, p = 0.02) compared to the group with no recurrence. Positive margins were found in 15.9% of local tumor bed recurrences compared to 3% of the control group (p <0.01). Median time between partial nephrectomy and the detection of local tumor bed recurrence was 23 months (range 2 to 107). Male gender, a solitary kidney at partial nephrectomy, positive surgical margins, multiple tumors, and higher nephrometry score and pathological stage were associated with local tumor bed recurrence. CONCLUSIONS: Local tumor bed recurrence after partial nephrectomy is associated with several preoperative factors, including multiple tumors and a solitary kidney, as well as intraoperative and postoperative factors such as a positive surgical margin and higher pathological stage.

Carcinoma of the urethra.

Primary carcinomas of the urethra are rare and poorly understood lesions; hence, their clinical and pathologic spectrum is not completely defined. We analyzed a series of 130 primary urethral tumors and classified 106 of them as primary urethral carcinomas. The age at diagnosis of patients with primary urethral carcinomas ranged from 42 to 97 years (mean, 69.4 years; median, 70 years). There were 73 male and 33 female patients with a ratio of 2.2:1. In male patients, the tumors most frequently developed in the bulbous-membranous segment of the urethra. In female patients, the entire length of the urethra was typically involved. Microscopically, they were poorly differentiated carcinomas with hybrid squamous and urothelial features and developed from precursor intraepithelial conditions such as dysplasia and carcinoma in situ, which were frequently present in the adjacent urethral mucosa. High-risk human papilloma virus infection could be documented in 31.6% of these tumors. Follow-up information was available for 95 patients. Twenty-three patients died of the disease with a mean and median survival of 39 and 21 months, respectively. Urethral carcinomas are aggressive tumors with a high propensity for regional and distant metastases with mean and median survival of 39 and 21 months, respectively. Our observations have important implications for the management of patients with primary carcinoma of the urethra by defining them as a unique entity linked to human papilloma virus infection.

Primary Ewing Sarcoma / Primitive Neuroectodermal Tumor of the Kidney: A Clinicopathologic Study of 23 Cases.

Primary Ewing sarcoma / primitive neuroectodermal tumor (ES) of the kidney is a rare neoplasm with limited clinicopathologic data. We report 23 such cases with no history of ES elsewhere in the body. The patients included 13 male and 10 female, aged 8-70 years (mean, 31 years). The average tumor size was 11.7 cm (range, 5-20 cm). Microscopic analysis showed predominantly lobular growth (n = 14), with focal papillary (n = 3), alveolar (n = 1), and hemangiopericytoma-like (n = 1) patterns. Several tumors (n = 11) exhibited robust mitotic activity (>10 mitoses/10 high-power fields). Necrosis (n = 13) and lymphovascular invasion (n = 14) were common. Homer Wright rosettes (n = 6) and perivascular pseudorosettes (n = 1) were also identified. The tumors invaded the renal sinus or perinephric fat (n = 11), renal vein (n = 13), and adrenal gland (n = 2). Molecular and fluorescence in situ hybridization analysis showed rearrangement of EWSR1 gene (10/10), associated with EWSR1-FLI1 gene fusion (7/10). All patients with follow-up information (n = 18) had metastasis, commonly in the lungs (n = 12) and bone (n = 6). Twelve patients died of disease in a mean of 21 months; 6 patients were alive at a mean of 49 months after diagnosis. Primary kidney ES usually present at an advanced stage with extrarenal spread and metastasis. Although renal ES share histologic, immunohistochemical, and molecular features with their bone and soft tissue counterparts, they appear to be more aggressive tumors with poorer clinical outcome.

Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation.

BACKGROUND: The immune profile of sarcomatoid renal cell carcinoma (sRCC), including the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) status, has not been well characterized. METHODS: An immunohistochemical digital analysis of PD-L1, PD-1, CD4, and CD8 was performed on nephrectomy specimens from 118 sRCC patients and 92 nonsarcomatoid clear cell renal cell carcinoma (ccRCC) patients. The clinical characteristics of the population were compared between sRCC and ccRCC. Overall survival was estimated, and comparisons were made between PD-L1-positive and PD-L1-negative groups as well as tumor-infiltrating lymphocyte (TIL)-high and TIL-low groups. RESULTS: The PD-L1 H-score of sRCC (mean, 3.7; range, 0-192.1) was significantly higher than the score of grade 4 ccRCC (P = .001), and 41.3% of sRCC cases showed a PD-L1 H-score ≥ 10. The PD-1-positive cell density was significantly higher in sRCC versus ccRCC within the tumor and at the invasive front. The intratumoral CD8-positive cell density was significantly higher in sRCC versus ccRCC. Forty-one percent in the sarcomatoid component of sRCC and 8% in the epithelioid component of sRCC had an adaptive immune resistance phenotype (PD-L1-positive and TIL-positive), whereas only 1% in ccRCC had the type I phenotype. CONCLUSIONS: sRCC showed higher PD-L1 expression and higher PD-1- and CD8-positive cell density than grade 4 ccRCC. The results indicate a notable immunosuppressive environment in sRCC. Despite advances in the treatment of advanced-stage renal cell carcinoma, sRCC still has a poor prognosis. This work describes highly immunosuppressive characteristics of sRCC in comparison with an appropriate ccRCC control. The results suggest PD-1/PD-L1 blockade therapy as a potential therapeutic approach for sRCC. Cancer 2017;123:4823-31. © 2017 American Cancer Society.

Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape.

Purpose: Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of nonsarcomatoid RCC (RCC). We evaluated whole-exome sequencing, single-nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n = 65) and RCC (n = 598) across different parent RCC subtypes, including clear-cell RCC, papillary RCC, and chromophobe RCC subtypes.Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFß signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer-related genes despite a higher mutational burden in S-. Notably, sarcomatoid clear-cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared with ccRCC. A two-hit loss involving VHL predicted for ccRCC and a better prognosis, whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.Conclusions: SRCC segregates by parent subtype, and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC, with diagnostic, prognostic, and therapeutic implications. Clin Cancer Res; 23(21); 6686-96. ©2017 AACRSee related commentary by Bergerot et al., p. 6381.