Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.

High-resolution and highly accelerated MRI T2 mapping as a tool to characterise renal tumour subtypes and grades.

BACKGROUND: Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades. METHODS: Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades. RESULTS: High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037). CONCLUSIONS: Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03741426 . Registered on 13 November 2018. RELEVANCE STATEMENT: The newly developed T2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses.

A Novel Classification System of Renal Hilar Tumors for Surgical Guidance: Technique, Outcome, and Safety.

BACKGROUND: This study was designed to develop an innovative classification and guidance system for renal hilar tumors and to assess the safety and effectiveness of robot-assisted partial nephrectomy (RAPN) for managing such tumors. METHODS: A total of 179 patients undergoing RAPN for renal hilar tumors were retrospectively reviewed. A novel classification system with surgical techniques was introduced and the perioperative features, tumor characteristics, and the efficacy and safety of RAPN were compared within subgroups. RESULTS: We classified the tumors according to our novel system as follows: 131 Type I, 35 Type II, and 13 Type III. However, Type III had higher median R.E.N.A.L., PADUA, and ROADS scores compared with the others (all p < 0.001), indicating increased operative complexity and higher estimated blood loss [180.00 (115.00-215.00) ml]. Operative outcomes revealed significant disparities between Type III and the others, with longer operative times [165.00 (145.00-200.50) min], warm ischemia times [24.00 (21.50-30.50) min], tumor resection times [13.00 (12.00-15.50) min], and incision closure times [22.00 (20.00-23.50) min] (all p < 0.005). Postoperative outcomes also showed significant differences, with longer durations of drain removal (77.08 ± 18.16 h) and hospitalization for Type III [5.00 (5.00-6.00) d] (all p < 0.05). Additionally, Type I had a larger tumor diameter than the others (p = 0.009) and pT stage differed significantly between the subtypes (p = 0.020). CONCLUSIONS: The novel renal hilar tumor classification system is capable of differentiating the surgical difficulty of RAPN and further offers personalized surgical steps tailored to each specific classification. It provides a meaningful tool for clinical practice.

[2022 WHO classification of renal cell carcinomas: Focus on papillary renal cell carcinoma]. / Classification OMS 2022 des cancers du rein : focus sur le carcinome rénal papillaire.

Renal cell carcinomas (RCC) represent a group of heterogeneous tumors whose classification has greatly evolved since 1981. The latest update in 2022 classifies all renal cell carcinomas into six categories according to their morphology or the detection of specific molecular alterations. Molecular disassembly of renal cell carcinomas with papillary features has enabled the identification of new entities characterized by a specific molecular alteration, such as Fumarate Hydratase (FH) deficient RCC, TFE3-rearranged RCC or TFEB-altered RCC. This new classification allows for a more accurate diagnosis but requires a thorough knowledge of the genomic alterations to search for with immunohistochemical or molecular biology techniques. According to the new WHO 2022 classification, papillary renal cell carcinoma (PRC) type 1 or type 2 classification is no longer recommended. A classification based on nucleolar ISUP grade must be preferred: low-grade PRC (ISUP 1-2) or high-grade PRC (ISUP 3-4). The other prognostic factors remain the same: the pTNM stage, lymphovascular invasion, and the presence or absence of dedifferentiated areas referring to sarcomatoid or rhabdoid features. Of note, the presence of necrosis is not currently recognized as a poor prognostic element for this type of carcinoma. The diagnosis of high-grade PRC is from now on a diagnosis of exclusion. It can only be sustained after having ruled out TFE3-rearranged RCC, TFEB-altered RCC, and FH-deficient RCC. For clinicians, the diagnosis of PRC implies suggesting an oncogenetic consultation to screen for an associated genetic tumor syndrome regardless of the patient's age.

Differentiating mixed epithelial and stromal tumor family from predominantly cystic renal cell carcinoma using magnetic resonance imaging-based Bosniak classification system version 2019.

PURPOSE: To differentiate mixed epithelial and stromal tumor family (MESTF) of the kidney from predominantly cystic renal cell carcinoma (RCC) using the magnetic resonance imaging (MRI)-based Bosniak classification system version 2019 (v2019). MATERIALS AND METHODS: The study included 36 consecutive patients with MESTF and 77 with predominantly cystic RCC who underwent preoperative renal MRI. One radiologist evaluated and documented the clinical and MRI characteristics (age, sex, laterality, R.E.N.A.L. Nephrometry Score [RNS], surgical approach, the signal intensity on T2-weighted imaging, restricted diffusion and enhancement features in corticomedullary phase). Blinded to clinical and pathological information, another two radiologists independently evaluated Bosniak category of all masses. Interobserver agreement based on Bosniak classification system v2019 was measured by the weighted Cohen/Conger's Kappa coefficient. Furthermore, predominantly cystic RCCs and MESTFs were divided into low (categories I, II, and IIF) and high-class (categories III, and IV) tumors. The independent sample t test (Mann-Whitney U test) or Pearson Chi-square test (Fisher's exact probability test) was utilized to compare clinical and imaging characteristics between MESTFs and predominantly cystic RCCs. The performance of the Bosniak classification system v2019 in distinguishing MESTF from predominantly cystic RCC was investigated via receiver operating characteristic curve analysis. RESULTS: MESTF and predominantly cystic RCC groups significantly differed in terms of age, lesion size, RNS, restricted diffusion, and obvious enhancement in corticomedullary phase, but not sex, laterality, surgical approach, and the signal intensity on T2WI. Interobserver agreement was substantially based on the Bosniak classification system v2019. There were 24 low-class tumors and 12 high-class tumors in the MESTF group. Meanwhile, 13 low-class tumors and 64 high-class tumors were observed in the predominantly cystic RCC group. The distribution of low- or high-class tumors significantly differed between the MESTF and predominantly cystic RCC groups. Bosniak classification system v2019 had excellent discrimination (cutoff value = category III), and an area under curve value was 0.81; accuracy, 80.5%; sensitivity, 87.0%; and specificity, 66.7%. CONCLUSION: The MRI-based Bosniak classification system v2019 can effectively distinguish MESTF from predominantly cystic RCC if category III was used as a cutoff reference.

An epidemiological and clinicopathological study of type 1 vs. type 2 morphological subtypes of papillary renal cell carcinoma- results from a nation-wide study covering 50 years in Iceland.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is the second most common histology of renal cell carcinoma (RCC), accounting for 10-15% of cases. Traditionally, pRCC is divided into type 1 and type 2, although this division is currently debated as a prognostic factor of survival. Our aim was to investigate the epidemiology and survival of the pRCC subtypes in a whole nation cohort of patients during a 50-year period. MATERIALS AND METHODS: A Population based retrospective study including consecutive cases of RCC in Iceland from 1971-2020. Comparisons were made between histological classifications of RCC, with emphasis on pRCC subtypes (type 1 vs. 2) for outcome estimation. Changes in RCC incidence were analyzed in 5-year intervals after age standardization. The Kaplan-Meier method and Cox regression were used for outcome analysis. RESULTS: A total of 1.725 cases were identified, with 74.4%, 2.1% and 9.2% having clear cell (ccRCC), chromophobe (chRCC), and pRCC, respectively. The age standardized incidence (ASI) of pRCC was 1.97/100.000 for males and 0.5/100.000 for females, and the proportion of pRCC increased from 3.7% to 11.5% between the first and last intervals of the study (p < 0.001). Age standardized cancer specific mortality (ASCSM) of pRCC was 0.6/100.000 and 0.19/100.000 for males and females, respectively. The annual average increase in ASI was 3.6% for type 1 pRCC, but the ASI for type 2 pRCC and ASCSM for both subtypes did not change significantly. Male to female ratio was 4.4 for type 1 pRCC and 2.3 for type 2. The average tumor size for type 1 and 2 was 58.8 and 73.7 mm, respectively. Metastasis at diagnosis was found in 8.7% in the type 1 pRCC, compared to 30.0% of patients with type 2 pRCC (p < 0.001). Estimated 5-year cancer-specific survival (CSS) were 94.4%, 80.7%, and 69.3% for chRCC, pRCC and ccRCC, respectively (p < 0.001). For the pRCC subtypes, type 1 was associated with better 5-year CSS than type 2 (86.3% vs. 66.0%, p < 0.001), although this difference was not significant after adjusting for cancer stage and grading. CONCLUSIONS: pRCC histology was slightly less common in Iceland than in other countries. Males are more than three times more likely to be diagnosed with pRCC, compared to other RCC histologies. The subtype of pRCC was not found to be an independent risk factor for worse survival, and as suggested by the most recent WHO Classification of Urinary Tumors, grade and TNM-stage seem to be the most important factors for estimation of survival for pRCC patients.

The New WHO Category of "Molecularly Defined Renal Carcinomas": Clinical and Diagnostic Features and Management Implications.

The evolution of classification of renal tumors has been impacted since the turn of the millennium by rapid progress in histopathology, immunohistochemistry, and molecular genetics. Together, these features have enabled firm recognition of specific, classic types of renal cell carcinomas, such as clear cell renal cell carcinoma, that in current practice trigger histologic-type specific management and treatment protocols. Now, the fifth Edition World Health Classification's new category of "Molecularly defined renal carcinomas" changes the paradigm, defining a total of seven entities based specifically on their fundamental molecular underpinnings. These tumors, which include TFE3-rearranged, TFEB-altered, ELOC-mutated, fumarate hydratase-deficient, succinate dehydrogenase-deficient, ALK-rearranged, and SMARCB1-deficient renal medullary carcinoma, encompass a wide clinical and histopathologic phenotypic spectrum of tumors. Already, important management aspects are apparent for several of these entities, while emerging therapeutic angles are coming into view. A brief, clinically-oriented introduction of the entities in this new category, focusing on relevant diagnostic, molecular, and management aspects, is the subject of this review.

World Health Organization 2022 Classification Update: Radiologic and Pathologic Features of Papillary Renal Cell Carcinomas.

RATIONALE AND OBJECTIVES: To describe imaging and pathology features of newly defined papillary renal cell carcinoma (pRCC) based on the WHO 2022 update. MATERIALS AND METHODS: This retrospective study included 87 patients with 93 pathologically proven papillary renal cell carcinomas who underwent pre-treatment renal mass protocol CT or MRI. Baseline and post-treatment follow-up imaging was evaluated by two radiologists systematically based on established lexicon. RESULTS: At pathology, 63 (68%) were grade 1-2, 29 (31%) were grade 3-4, and 1 (%) was unreported. At surgical pathology, 84 (90%) were localized (≤pT2b), 5 (5%) were pT3a, and none were ≥pT3b; 4 (4%) had unknown pT stage (core biopsies). 33 (35%) had necrosis and 39 (41%) had hemorrhage. None had sarcomatoid or rhabdoid differentiation. At imaging, 73 (83%) were solid and 16 (17%) were cystic. Of 16 cystic masses, four were Bosniak class IIF (three were heterogeneously T1 hyperintense) and 12 were class IV. All were well-circumscribed. 92 (99%) were hypovascular. Median follow-up for 74 patients was 30 months (IQR 12-56). One untreated patient had non-regional nodal metastasis at presentation, and one patient had metastasis to lymph nodes and bones after surgery, but the patient had unresected renal masses elsewhere without pathology. Otherwise, no recurrence or metastases were detected. CONCLUSION: Most pRCCs present as a hypovascular, circumscribed, solid renal mass. A few pRCCs present as the newly defined Bosniak class IIF subtype. Our results can form the basis of a non-invasive, likelihood score to identify this relatively indolent pathology in the era of virtual biopsy and active surveillance.

Reclassifying Papillary, Oncocytic and Chromophobe Renal Tumours Based on the 5 < sup > th < /sup > Who Classification 2022.

OBJECTIVE: The classification of renal tumors is expanding with the addition of new molecular entities in the 5th World Health Organization classification. Apart from this, the major updates in the definition of papillary renal cell carcinoma are that these tumors are no longer subtyped into type 1 and type 2. In oncocytic tumors, the new molecularly defined renal tumors, emerging and novel entities need to be considered in the diagnosis of oncocytic and chromophobe renal tumors. MATERIAL AND METHODS: This is a retrospective study to review and reclassify papillary, oncocytic, and chromophobe renal tumors based on the new WHO classification and correlate with clinical data, gross, microscopic features, and immunohistochemistry markers. RESULTS: A total of thirteen cases were reviewed and the tumor grade was changed for three out of four cases of papillary renal cell carcinoma and a single case was recategorized and graded. In nine cases of oncocytic and chromophobe renal tumors, the diagnoses were modified in 3 cases. CONCLUSION: Newly defined molecular renal tumors require advanced immunohistochemistry markers and molecular tests. This poses diagnostic challenges to pathologists practicing in low resource settings where molecular tests are not available.

Clinical, pathological and long-term oncologic outcomes of papillary type I vs. type II renal cell carcinoma.

BACKGROUND: Despite papillary renal cell carcinoma (pRCC) subtype represents the second most common histological renal tumor, controversial findings have been shown regarding its prognosis. Thus, we investigated the natural history of patients harbouring pRCC, focusing on its clinicopathological characteristics and long-term oncologic outcomes among pRCC subtypes. MATERIALS AND METHODS: We identified 447 patients treated with either partial (PN) or radical nephrectomy (RN) for pRCC at a single tertiary centre, between 1994 and 2019. First, we explored differences in baseline and clinicopathological characteristics. Second, Kaplan-Meier plots investigated progression-free survival (PFS) and cancer-specific survival (CSS) differences among pRCC subtypes. Third, multivariable Cox-regression analyses (MVA) were used to assess predictors of clinical progression (CP) and cancer-specific mortality (CSM). RESULTS: Overall, 120 (27%) patients had symptoms at time of diagnosis. 263 (58.8%) vs. 184 (41.2%) patients underwent PN vs. RN. At histopathological evaluation, 243 (54.4%) harboured pRCC type I vs. 204 (45.6%) type II. pRCC type II more frequently showed higher tumor grade, tumor necrosis or lymphovascular invasion (all P<0.001). After a median follow-up of 51 months, 2.5% and 11% of patients had local relapse and CP, respectively. Kaplan-Meier plots revealed 93 vs. 83% 5-year PFS (P<0.001) and 96 vs. 89% 5-year CSS (P=0.01) for non-metastatic pRCC type I vs. II, respectively. At MVA, pRCC type II predicted higher risk of CP (Hazard ratio [HR]: 3.03, 95%CI 1.42-6.44; P=0.01), as well as of CSM (HR: 2.60, 95%CI 1.05-6.29; P=0.02), relative to pRCC type I. CONCLUSIONS: PRCC type II harbour more unfavorable tumor characteristics, such as higher tumor grade, more frequent tumor necrosis or lymphvascular invasion, which translates into worse long-term oncologic outcomes, compared with pRCC type I. Thus, patients harbouring pRCC type II may benefit from stricter follow-up, as well as earlier risk-based adjuvant therapies, based on potential worse oncologic outcomes in this patient population.

Redox Metabolism-Associated Molecular Classification of Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. Redox metabolism has been recognized as the hallmark of cancer. But the concrete role of redox-related genes in patient stratification of ccRCC remains unknown. Herein, we aimed to characterize the molecular features of ccRCC based on the redox gene expression profiles from The Cancer Genome Atlas. Differentially expressed redox genes (DERGs) and vital genes in metabolism regulation were identified and analyzed in the ccRCC. Consensus clustering was performed to divide patients into three clusters (C1, C2, and C3) based on 139 redox genes with median FPKM value > 1. We analyzed the correlation of clusters with clinicopathological characteristics, immune infiltration, gene mutation, and response to immunotherapy. Subclass C1 was metabolic active with moderate prognosis and associated with glucose, lipid, and protein metabolism. C2 had intermediate metabolic activity with worse prognosis and correlated with more tumor mutation burden, neoantigen, and aneuploidy, indicating possible drug sensitivities towards immune checkpoint inhibitors. Metabolic exhausted subtype C3 showed high cytolytic activity score, suggesting better prognosis than C1 and C2. Moreover, the qRT-PCR was performed to verify the expression of downregulated DERGs including ALDH6A1, ALDH1L1, GLRX5, ALDH1A3, and GSTM3, and upregulated SHMT1 in ccRCC. Overall, our study provides an insight into the characteristics of molecular classification of ccRCC patients based on redox genes, thereby deepening the understanding of heterogeneity of ccRCC and allowing prediction of prognosis of ccRCC patients.

Modified cancer TNM classification for localized renal cell carcinoma based on the prognostic analysis of 3748 cases from a single center.

The optimal cutoff point for evaluating the prognosis of localized renal cell carcinoma (LRCC) remains unclear. This study aimed to verify the efficacy of tumor diameter in the 2010 American Joint Committee on Cancer (AJCC) TNM staging system and contribute to the modification of TNM staging on the prognosis of this disease. A total of 3748 patients with LRCC were enrolled and grouped according to the 2010 AJCC TNM staging system. COX analysis was used to stratify the prognosis. The optimal cutoff point of the tumor diameter in the T1 and T2 prognosis was explored. There were 3330 (88.9%) patients in stage T1 and 418 (11.1%) in stage T2. The cancer-specific mortality rate was 2.7% (100/3748). The mean follow-up was 49.8 months. A tumor diameter of 7 cm can determine the prognosis of patients at stages T1 and T2; however, 4.5 cm and 11 cm as the cutoff points for T1 and T2 sub-classification of patients with LRCC might show better recognition ability than 4 cm and 10 cm, respectively. The 2010 AJCC TNM stage can predict the prognosis of LRCC in stages T1 and T2. In addition, a tumor diameter of 4.5 cm and 11 cm might be the optimal cutoff points for the sub-classification of stages T1 and T2.

Analysis of CT, MRI imaging features of renal cell carcinoma with different histopathological types.

PURPOSE: This study aimed to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of different histological types of renal cell carcinoma (RCC) (clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC). METHODS: The clinical data of 67 patients (including 38 patients with ccRCC, 20 patients with pRCC and 9 patients with chRCC) with RCC confirmed pathologically in the Affiliated Hospital of Jining Medical University were retrospectively analyzed. All patients underwent CT, MRI plain scan and three-phase enhanced scan, and their CT and MRI imaging features were analyzed. RESULTS: Most of the enhancement was non-uniform. Most of the lesions presented as "fast-in, fast-out", with obvious enhancement in the early stage and enhancement decline in the later stage. Non-uniform and slightly higher signals were mostly present in DWI. The CT scan of pRCC patients showed equal density and homogeneous enhancement. Some of the larger lesions showed cystic necrosis and hemorrhage. MRI showed a lower signal on T1WI and a slightly higher signal on T2WI. The CT of patients with chRCC showed equal density and more uniform enhancement. DWI showed high signal, and central radial scar showed low signal. There was a significant difference in the percentage of cystic necrosis in ccRCC, pRCC and chRCC among groups (p<0.05). The incidence of cystic necrosis in ccRCC and pRCC was significantly higher than that in chRCC (p<0.05). The CT values in ccRCC patients were significantly higher than those in pRCC and chRCC patients in the parenchymal phase, corticomedullary phase and excretory phase (p<0.05). The CT value of chRCC patients in the parenchymal phase was significantly higher than that of pRCC (p<0.05). CONCLUSION: The CT and MRI of ccRCC, pRCC and chRCC have their own imaging characteristics, which has important reference value for the preoperative differential diagnosis of RCC.

Undifferentiated and dedifferentiated urological carcinomas: lessons learned from the recent developments.

Loss of the morphological and immunophenotypic characteristics of a neoplasm is a well-known phenomenon in surgical pathology and occurs across different tumor types in almost all organs. This process may be either partial, characterized by transition from well differentiated to undifferentiated tumor component (=dedifferentiated carcinomas) or complete (=undifferentiated carcinomas). Diagnosis of undifferentiated carcinoma is significantly influenced by the extent of sampling. Although the concept of undifferentiated and dedifferentiated carcinoma has been well established for other organs (e.g. endometrium), it still has not been fully defined for urological carcinomas. Accordingly, undifferentiated/ dedifferentiated genitourinary carcinomas are typically lumped into the spectrum of poorly differentiated, sarcomatoid, or unclassified (NOS) carcinomas. In the kidney, dedifferentiation occurs across all subtypes of renal cell carcinoma (RCC), but certain genetically defined RCC types (SDH-, FH- and PBRM1- deficient RCC) seem to have inherent tendency to dedifferentiate. Histologically, the undifferentiated component displays variable combination of four patterns: spindle cells, pleomorphic giant cells, rhabdoid cells, and undifferentiated monomorphic cells with/without prominent osteoclastic giant cells. Any of these may occasionally be associated with heterologous mesenchymal component/s. Their immunophenotype is often simple with expression of vimentin and variably pankeratin or EMA. Precise subtyping of undifferentiated (urothelial versus RCC and the exact underlying RCC subtype) is best done by thorough sampling supplemented as necessary by immunohistochemistry (e.g. FH, SDHB, ALK) and/ or molecular studies. This review discusses the morphological and molecular genetic spectrum and the recent develoments on the topic of dedifferentiated and undifferentiated genitourinary carcinomas.

Renal cell carcinoma, part 2.

ABSTRACT: Renal cell carcinoma (RCC) accounts for most renal malignancies. This article, the second in a three-part series, addresses how renal masses are classified, signs and symptoms of RCC, medical treatments for RCC, and priority nursing interventions for patients with RCC.

[Criteria for an improved prognostic stratification in category pT renal carcinoma]. / La Categoría Tumor en el carcinoma renal. Criterios morfológicos para una mejor estratificación pronóstica.

Asymptomatic renal carcinomas are usually small and localized and thus, for the assessment of pT, precise criteria are required, able to identify the initial phases of a local extension and correlate them with current prognostic prospects. Various studies and consensus meetings have defined precisely how to measure tumoral nodules (solid, cystic and multiple). Furthermore, they have distinguished tumoral extension to the renal sinus, which has a worse prognosis, from that to the perirenal adipose tissue. They have also analyzed the clinical significance of invasion of the sinus vessels, the hilar veins and parenchymal vascular retroinvasion. Our aim is to revise and update the criteria of the different pT subcategories and consider those morphological aspects which could be clinically significant and that are not currently included in the TNM classification.

Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male (case-only odds ratio [OR] 2.68, 95% confidence interval [CI] 1.43-5.03). In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs <25 kg/m2 ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs 10th percentile). In a meta-analysis of case-only results including three patient cohorts, we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors.

Non-clear cell renal carcinomas: Review of new molecular insights and recent clinical data.

Non-clear cell renal cell carcinomas (nccRCC) represent a highly heterogeneous group of kidney tumors, consisting of the following subtypes: papillary carcinomas, chromophobe renal cell carcinoma, so-called unclassified carcinomas or aggressive uncommon carcinomas such as Bellini carcinoma, renal cell carcinoma (RCC) with ALK rearrangement or fumarate hydratase-deficient RCC. Although non-clear cell cancers account for only 15 to 30% of renal tumors, they are often misclassified and accurate diagnosis continues to be an issue in clinical practice. Current therapeutic strategy of metastatic nccRCC is based primarily on guidelines established for clear cell tumors, the most common subtype, however this approach remains poorly defined. To date, published clinical trials for all histological nccRCC subtypes have been collectively characterized into one group, in contrast to clear cell RCC, and given the small numbers of cases, the interpretation of study results continues to be challenging. This review summarizes the available literature for each nccRCC subtype and highlights the lack of supportive evidence from prospective clinical trials and retrospective studies. Future trials should evaluate treatment approaches which focus on a specific histological subtype and progress in treating nccRCC will be contingent on understanding the unique biology of their individual histologies.

Comprehensive characterization of alternative splicing in renal cell carcinoma.

Irregular splicing was associated with tumor formation and progression in renal cell carcinoma (RCC) and many other cancers. By using splicing data in the TCGA SpliceSeq database, RCC subtype classification was performed and splicing features and their correlations with clinical course, genetic variants, splicing factors, pathways activation and immune heterogeneity were systemically analyzed. In this research, alternative splicing was found useful for classifying RCC subtypes. Splicing inefficiency with upregulated intron retention and cassette exon was associated with advanced conditions and unfavorable overall survival of patients with RCC. Splicing characteristics like splice site strength, guanine and cytosine content and exon length may be important factors disrupting splicing balance in RCC. Other than cis-acting and trans-acting regulation, alternative splicing also differed in races and tissue types and is also affected by mutation conditions, pathway settings and the response to environmental changes. Severe irregular splicing in tumor not only indicated terrible intra-cellular homeostasis, but also changed the activity of cancer-associated pathways by different splicing effects including isoforms switching and expression regulation. Moreover, irregular splicing and splicing-associated antigens were involved in immune reprograming and formation of immunosuppressive tumor microenvironment. Overall, we have described several clinical and molecular features in RCC splicing subtypes, which may be important for patient management and targeting treatment.

Single-cell analysis reveals metastatic cell heterogeneity in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the leading causes of cancer-related death worldwide. Tumour metastasis and heterogeneity lead to poor survival outcomes and drug resistance in patients with metastatic RCC (mRCC). In this study, we aimed to assess intratumoural heterogeneity (ITH) in mRCC cells by performing a combined analysis of bulk data and single-cell RNA-sequencing data, and develop novel biomarkers for prognosis prediction on the basis of the potential molecular mechanisms underlying tumorigenesis. Eligible single-cell cohorts related to mRCC were acquired using the Gene Expression Omnibus (GEO) dataset to identify potential mRCC subpopulations. We then performed gene set variation analysis to understand the differential function in primary RCC and mRCC samples. Subsequently, we applied weighted correlation network analysis to identify coexpressing gene modules that were related to the external trait of metastasis. Protein-protein interactions were used to screen hub subpopulation-difference (sub-dif) markers (ACTG1, IL6, CASP3, ACTB and RAP1B) that might be involved in the regulation of RCC metastasis and progression. Cox regression analysis revealed that ACTG1 was a protective factor (HR < 1), whereas the other four genes (IL6, CASP3, ACTB and RAP1B) were risk factors (HR > 1). Kaplan-Meier survival analysis suggested the potential prognostic value of these sub-dif markers. The expression of sub-dif markers in mRCC was further evaluated in clinical samples by immunohistochemistry (IHC). Additionally, the genetic features of sub-dif marker expression patterns, such as genetic variation profiles, correlations with tumour-infiltrating lymphocytes (TILs), and targeted signalling pathway activities, were assessed in bulk RNA-seq datasets. In conclusion, we established novel subpopulation markers as key prognostic factors affecting EMT-related signalling pathway activation in mRCC, which could facilitate the implementation of a treatment for mRCC patients.