Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Abstract

Kidney cancer accounts for 5% and 3% of all adult malignancies in men and women, respectively, thus representing the 7th most common cancer in men, and the 10th most common cancer in women [1.Siegel R.L. Miller K.D. Jemal A. Cancer statistics.CA Cancer J Clin. 2016; 66: 7-30Crossref PubMed Scopus (21988) Google Scholar]. However, available statistics include not only renal parenchymal tumours, but also urothelial cancer of the renal pelvis; renal cell carcinoma (RCC) accounts for ∼80% of all kidney cancers. After over two decades of increasing rates, RCC incidence trends worldwide have shown signs of plateauing in recent years. Furthermore, kidney cancer mortality rates overall have levelled. These patterns are consistent with reports of incidental diagnosis and downward shift of tumour stage and size; indeed, the widespread use of non-invasive radiological techniques [e.g. ultrasonography (US), computed tomography (CT)], allows the frequent detection of early and small RCCs, which are potentially curable. Beyond well-known risk factors for RCC, such as cigarette smoking, obesity and hypertension, evidence is accumulating to suggest an aetiological or, on the contrary, a protective role, for additional factors [2.Chow W.H. Dong L.M. Devesa S.S. Epidemiology and risk factors for kidney cancer.Nat Rev Urol. 2010; 7: 245-257Crossref PubMed Scopus (983) Google Scholar], such as trichloroethylene. In a recently published case–control study of 699 RCC patients and 1001 frequency-matched controls, consumption of caffeinated coffee was found to be associated with reduced risk of RCC; interestingly, decaffeinated coffee was associated with an increased risk for aggressive clear cell RCC (ccRCC) [3.Antwi S.O. Eckel-Passow J.E. Diehl N.D. et al.Coffee consumption and risk of renal cell carcinoma.Cancer Causes Control. 2017; 28: 857-866Crossref PubMed Scopus (10) Google Scholar]. Furthermore, RCC also appears to be more common in patients with end-stage renal failure or acquired renal cystic disease, and in patients on dialysis, those who have had kidney transplantation or those with tuberous sclerosis syndrome. Approximately 2%–3% of all RCCs are hereditary and several autosomal dominant syndromes are described, each with a distinct genetic basis and phenotype, the most common one being von Hippel–Lindau (VHL) disease. Patients with multiple and bilateral lesions and/or other related disorders should be tested for these germline mutations since it is important that they are recognised. As stated above, >50% of RCCs are currently detected incidentally, making the classical triad of flank pain, gross haematuria and palpable abdominal mass less frequent than in the past. Despite this, RCC remains the ‘Internist’s cancer’ with paraneoplastic syndromes such as hypercalcaemia, unexplained fever, erythrocytosis and Stauffer’s syndrome (signs of cholestasis unrelated to tumour infiltration of the liver or intrinsic liver disease, which typically resolve after kidney tumour resection) still being relatively frequent. Suspicion of RCC should prompt laboratory examinations of serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio, lactate dehydrogenase, C-reactive protein (CRP) and serum-corrected calcium [IV, B]. Some of these tests are prognostic for survival and are used for risk assessment within different prognostic score systems (see Staging and risk assessment section). Most cases of RCC are strongly suspected by imaging. Diagnosis is usually suggested by US and further investigated by CT scan, which allows for assessment of local invasiveness, eventual lymph node involvement or distant metastases. Magnetic resonance imaging (MRI) may provide additional information in investigating local advancement and venous involvement by tumour thrombus. For accurate staging of RCC, contrast-enhanced chest, abdominal and pelvic CT is mandatory [III, A]; unless indicated by clinical or laboratory signs or symptoms, the use of bone scan or brain CT (or MRI) is not recommended for routine clinical practice [III, A]. In case of an allergy to CT contrast agent or renal insufficiency, adequate staging should include a high-resolution CT scan of the chest without contrast agent, together with an abdominal MRI. Fluorodeoxyglucose positron emission tomography (FDG-PET) is not a standard investigation in the diagnosis and staging of ccRCC and should not be used. The role of new tracers is under investigation. A renal tumour core biopsy provides histopathological confirmation of malignancy with high sensitivity and specificity; it is especially recommended before treatment with ablative therapies [III, B] as well as in patients with metastatic disease before starting systemic treatment [III, B]. Complications (e.g. bleeding or tumour seeding) are rare or even exceptional (as in the case of tumour seeding) [4.Volpe A. Kachura J.R. Geddie W.R. et al.Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy.J Urol. 2007; 178: 379-386Crossref PubMed Scopus (284) Google Scholar], while diagnostic accuracy remains high [5.Marconi L. Dabestani S. Lam T.B. et al.Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy.Eur Urol. 2016; 69: 660-673Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar]. The final histopathological diagnosis, classification, grading and evaluation of prognostic factors are based on the nephrectomy specimen when available. The last edition of the World Health Organization (WHO) histological classification of renal tumours has been reported in 2016 (Table 1), and was based on tumour histology, chromosomal alterations and molecular pathways [6.Moch H. Cubilla A.L. Humphrey P.A. et al.The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2016; 70: 93-105Abstract Full Text Full Text PDF PubMed Scopus (1573) Google Scholar].Table 1WHO 2016 classification of renal cell tumoursReprinted with permission from [6.Moch H. Cubilla A.L. Humphrey P.A. et al.The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2016; 70: 93-105Abstract Full Text Full Text PDF PubMed Scopus (1573) Google Scholar].Clear cell renal cell carcinomaMultilocular cystic renal neoplasm of low malignant potentialPapillary renal cell carcinomaHereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomaChromophobe renal cell carcinomaCollecting duct carcinomaRenal medullary carcinomaMiT family translocation renal cell carcinomasSuccinate dehydrogenase-deficient renal cell carcinomaMucinous tubular and spindle cell carcinomaTubulocystic renal cell carcinomaAcquired cystic disease-associated renal cell carcinomaClear cell papillary renal cell carcinomaRenal cell carcinoma, unclassifiedPapillary adenomaOncocytomaMiT, microphthalmia-associated transcription factor; WHO, World Health Organization. Open table in a new tab MiT, microphthalmia-associated transcription factor; WHO, World Health Organization. ccRCCs represent 80% of malignant renal tumours in adults, with the remaining 20% corresponding to several histological subtypes with different histological, molecular and cytogenetic profiles [7.Hsieh J.J. Purdue M.P. Signoretti S. et al.Renal cell carcinoma.Nat Rev Dis Primers. 2017; 3: 17009.Crossref PubMed Scopus (1204) Google Scholar]. Papillary and chromophobe RCCs account for 80% of non-ccRCCs. Papillary RCCs which represent a heterogeneous disease are characterised by:•type 1 RCCs more frequently associated to MET or epidermal growth factor receptor (EGFR) mutations and•type 2 RCCs often unique tumours with an aggressive phenotype that are associated with SETD2 mutations, CDKN2A mutations or TFE3 fusions [8.Linehan W.M. Spellman P.T. et al.Cancer Genome Atlas Research NetworkComprehensive molecular characterization of papillary renal-cell carcinomas.N Engl J Med. 2016; 374: 135-145Crossref PubMed Scopus (799) Google Scholar]. In papillary type 2 with familial history of papillary RCC, a fumarate hydratase (FH) mutation should also be investigated. The main goal in diagnosis of chromophobe RCC, especially in the eosinophilic histological subtype, is the differential diagnosis with oncocytoma. Chromophobe RCCs have diffuse positivity for cytokeratin 7 (CK7), whereas oncocytomas are negative or present focal positivity for CK7. Moreover, chromophobe RCCs display more frequent chromosome loss but fewer somatic mutations. The most frequently mutated gene is tumour suppressor protein 53 (TP53) (32%), and the most frequent oncogenic pathways involved in such tumours are mammalian target of rapamycin (mTOR) pathways (23%), including alterations of phosphatase and tensin homologue (PTEN) [9.Davis C.F. Ricketts C.J. Wang M. et al.The somatic genomic landscape of chromophobe renal cell carcinoma.Cancer Cell. 2014; 26: 319-330Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar]. Microphthalmia-associated transcription factor (MiT) family translocation RCCs (tRCCs) must be ruled out in young patients under the age of 40 years, if papillary architecture or complex architecture with clear cells and/or epithelioid cells or psammoma bodies are present. The diagnosis is based on the use of both immunohistochemistry and fluorescent in situ hybridisation (FISH) analysis to demonstrate the presence of TFE3/TFEB rearrangement. Recently, Argani et al. reported cases of TFEB-amplified RCCs that occur in older patients. These tumours presented high-grade eosinophilic cells with necrosis and papillary or pseudopapillary architecture. The expression of melanocytic markers is variable and FISH analyses revealed high levels of TFEB gene amplification. The prognosis of such tumours is poor with usually advanced stage and metastatic outcome [10.Argani P. Reuter V.E. Zhang L. et al.TFEB-amplified renal cell carcinomas: an aggressive molecular subset demonstrating variable melanocytic marker expression and morphologic heterogeneity.Am J Surg Pathol. 2016; 40: 1484-1495Crossref PubMed Scopus (82) Google Scholar]. Collecting duct carcinoma (CDC) or Bellini duct carcinoma remains a highly aggressive RCC arising from the renal collecting tubules. A recent specific gene expression signature showed that CDC appears to be a unique entity among kidney cancers [11.Becker F. Junker K. Parr M. et al.Collecting duct carcinomas represent a unique tumor entity based on genetic alterations.PLoS One. 2013; 8: e78137Crossref PubMed Scopus (27) Google Scholar]. Moreover, these tumours are characterised by an immune profile with an average of 22% of tumour-infiltrating lymphocytes [12.Malouf G.G. Compérat E. Yao H. et al.Unique transcriptomic profile of collecting duct carcinomas relative to upper tract urothelial carcinomas and other kidney carcinomas.Sci Rep. 2016; 6: 30988Crossref PubMed Scopus (32) Google Scholar]. The prognostic factors validated by the International Society of Urological Pathology (ISUP) consensus and the WHO 2016 classification of RCC to be reported in routine practice are [13.Delahunt B. Cheville J.C. Martignoni G. et al.The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters.Am J Surg Pathol. 2013; 37: 1490-1504Crossref PubMed Scopus (511) Google Scholar]:•the tumour histological subtype;•the ISUP nucleolar grade (instead of the previous Fuhrman grade) that is only applicable to ccRCC and papillary RCC;•a sarcomatoid and/or rhabdoid differentiation that defines a grade 4 tumour;•the presence of necrosis;•the presence of microscopic vascular invasion;•the pathological tumour, node and metastasis (pTNM) staging anddescription of the non-neoplastic renal tissue. Beyond the classical one gene–one histology paradigm, a more complex biological classification of RCC (and especially of its clear cell histotype) is emerging [14.Brugarolas J. Molecular genetics of clear-cell renal cell carcinoma.J Clin Oncol. 2014; 32: 1968-1976Crossref PubMed Scopus (210) Google Scholar]. First, RCC proved to be an extremely heterogeneous disease [15.Gerlinger M. Rowan A.J. Horswell S. et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med. 2012; 366: 883-892Crossref PubMed Scopus (5730) Google Scholar]; beyond the seminal genetic alteration (mutation, deletion or hypermethylation) of the VHL tumour suppressor gene, which is present in the vast majority of sporadic RCCs, other genetic alterations may occur, especially over time [16.Gerlinger M. Horswell S. Larkin J. et al.Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.Nat Genet. 2014; 46: 225-233Crossref PubMed Scopus (893) Google Scholar], contributing to worsen the prognosis of patients harbouring these tumours. Notably, three of these other genes (PBRM1, BAP1 and SETD2) are located on the same short arm of chromosome 3 where the VHL gene is also located. On the contrary, some RCCs are characterised by mutations in the mTOR pathway, and especially in the highly conserved FAT (FRAP, ATM, TTRAP) and kinase domains of the MTOR gene; these cancers have been defined as metabolic RCCs [17.Hakimi A.A. Pham C.G. Hsieh J.J. A clear picture of renal cell carcinoma.Nat Genet. 2013; 45: 849-850Crossref PubMed Scopus (84) Google Scholar]. Finally, according to another comprehensive molecular characterisation of papillary RCCs, type 1 and type 2 papillary RCCs were shown to be clinically and biologically distinct. Alterations in the MET pathway were indeed associated with type 1 and activation of the NRF2-ARE pathway was associated with type 2, while CDKN2A loss and a CpG island methylator phenotype in type 2 contributed to convey a poor prognosis [8.Linehan W.M. Spellman P.T. et al.Cancer Genome Atlas Research NetworkComprehensive molecular characterization of papillary renal-cell carcinomas.N Engl J Med. 2016; 374: 135-145Crossref PubMed Scopus (799) Google Scholar]. The Union for International Cancer Control (UICC) tumour, node and metastasis (TNM) 8 staging system should be used [18.Brierley J.D. Gospodarowicz M.K. Wittekind C. IUCC TNM Classification of Malignant Tumours. 8. John Wiley & Sons, Inc, Oxford2016: 114-115Google Scholar] (Table 2).Table 2UICC TNM 8 staging of RCC [18.Brierley J.D. Gospodarowicz M.K. Wittekind C. IUCC TNM Classification of Malignant Tumours. 8. John Wiley & Sons, Inc, Oxford2016: 114-115Google Scholar]Reprinted from [18.Brierley J.D. Gospodarowicz M.K. Wittekind C. IUCC TNM Classification of Malignant Tumours. 8. John Wiley & Sons, Inc, Oxford2016: 114-115Google Scholar] with permission from John Wiley & Sons, Inc.T—primary tumourTX Primary tumour cannot be assessedT0 No evidence of primary tumourT1 Tumour 7 cm or less in greatest dimension, limited to the kidney T1a Tumour 4 cm or less T1b Tumour more than 4 cm but not more than 7 cmT2 Tumour more than 7 cm in greatest dimension, limited to the kidney T2a Tumour more than 7 cm but not more than 10 cm T2b Tumour more than 10 cm, limited to the kidneyT3 Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia T3a Tumour extends into the renal vein or its segmental branches, or tumour invades the pelvicalyceal system or tumour invades perirenal and/or renal sinus fat (peripelvic) fat but not beyond Gerota fascia T3b Tumour extends into vena cava below diaphragm T3c Tumour extends into vena cava above the diaphragm or invades the wall of the vena cavaT4 Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)N—regional lymph nodesNX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in regional lymph node(s)M—distant metastasisM0 No distant metastasisM1 Distant metastasispTNM pathological classificationaThe pT and pN categories correspond to the T and N categories.StageStage I T1 N0 M0Stage II T2 N0 M0Stage III T3 N0 M0 T1, T2, T3 N1 M0Stage IV T4 Any N M0 Any T Any N M1pTNM, pathological tumour, node, metastasis; RCC, renal cell carcinoma; TNM, tumour, node, metastasis; UICC, Union for International Cancer Control.a The pT and pN categories correspond to the T and N categories. Open table in a new tab pTNM, pathological tumour, node, metastasis; RCC, renal cell carcinoma; TNM, tumour, node, metastasis; UICC, Union for International Cancer Control. The natural clinical course varies in RCC, which has led to the development of different prognostic models for the assessment of the patient’s individual risk. Extent of disease, histology, grading and clinical factors have been recognised as having prognostic value in RCC and may be used in localised or in metastatic disease [6.Moch H. Cubilla A.L. Humphrey P.A. et al.The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2016; 70: 93-105Abstract Full Text Full Text PDF PubMed Scopus (1573) Google Scholar]. Different pre- or post-operative scores have been developed to assess prognosis in RCC, and are used for risk-adapted follow-up strategies. Integrated prognostic scores offer some predictive advantages over single tumour characteristics and are used preferentially. These models are composed of histological and clinical factors. The most recent modifications of the stage, size, grade and necrosis (SSIGN) score [19.Leibovich B.C. Blute M.L. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (587) Google Scholar] (Table 3) and the University of California Los Angeles Integrated Staging System (UISS) (Table 4) [20.Patard J.J. Kim H.L. Lam J.S. et al.Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.J Clin Oncol. 2004; 22: 3316-3322Crossref PubMed Scopus (302) Google Scholar] score are frequently used.Table 3SSIGN score for localised RCC [19.Leibovich B.C. Blute M.L. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (587) Google Scholar]Adapted from [19.Leibovich B.C. Blute M.L. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (587) Google Scholar], with permission from John Wiley & Sons, Inc.FeatureScorePathological T category of primary tumour (as per 2002 TNM staging)pT1a0pT1b2pT23pT3a-pT3c4pT44Regional lymph node status (as per 2002 TNM staging)pNx or pN00pN1 or pN22Tumour size<10 cm010 cm or more1Nuclear grade1 or 203143Histological tumour necrosisNo0Yes1ScoresGroup5-year metastasis- free survival rate (%)0–2Low risk97.13–5Intermediate risk73.86 or moreHigh risk31.2RCC, renal cell carcinoma; SSIGN, size, stage, grade and necrosis; TNM, tumour, node, metastasis. Open table in a new tab Table 4UISS risk groups and 5-year disease-specific survival [20.Patard J.J. Kim H.L. Lam J.S. et al.Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.J Clin Oncol. 2004; 22: 3316-3322Crossref PubMed Scopus (302) Google Scholar]Reprinted from [20.Patard J.J. Kim H.L. Lam J.S. et al.Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.J Clin Oncol. 2004; 22: 3316-3322Crossref PubMed Scopus (302) Google Scholar] with permission. © 2004 American Society of Clinical Oncology. All rights reserved.Patient groupPrognostic groupT stageFuhrman gradeECOG status5-year disease-specific survival (%)Localised disease (N0, M0)Low risk11–2091.1Intermediate risk11–21 or more80.413–4Any2AnyAny31Any32–4AnyHigh32–41 or more54.74AnyAnyMetastatic diseaseLow riskN1M0AnyAny32N2M0/M11–20Intermediate riskN2M0/M11–21 or more19.530, 1 or more40HighN2M0/M141 or more0ECOG, Eastern Cooperative Oncology Group; UISS, University of California Los Angeles Integrated Staging System. Open table in a new tab RCC, renal cell carcinoma; SSIGN, size, stage, grade and necrosis; TNM, tumour, node, metastasis. ECOG, Eastern Cooperative Oncology Group; UISS, University of California Los Angeles Integrated Staging System. However, among different prognostic scores, a concordance of 0.68–0.89 for cancer-specific survival (CSS) and 0.74–0.82 for recurrence-free survival (RFS) was reported [21.Sun M. Shariat S.F. Cheng C. et al.Prognostic factors and predictive models in renal cell carcinoma: a contemporary review.Eur Urol. 2011; 60: 644-661Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar], indicating that a plateau has been reached for prognostication with available models. Hence, no clear preference for a specific prognostic model may be given. The Memorial Sloan Kettering Cancer Center (MSKCC) system was the gold standard for the risk assessment during cytokine treatment in metastatic RCC (mRCC) [22.Motzer R.J. Mazumdar M. Bacik J. et al.Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.J Clin Oncol. 1999; 17: 2530-2540Crossref PubMed Google Scholar], and it is still commonly used. Further refinement was introduced with the International Metastatic RCC Database Consortium (IMDC) score, which extended the previous factors to a total number of six in order to increase concordance [23.Ko J.J. Xie W. Kroeger N. et al.The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.Lancet Oncol. 2015; 16: 293-300Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar]:•Karnofsky performance status (PS) <80%;•haemoglobin level below the lower limit of normal;•time from diagnosis to treatment <1 year;•corrected calcium above the upper limit of normal;•platelets greater than the upper limit of normal and•neutrophils greater than the upper limit of normal. A recent evaluation of this model in second-line treatment underscored its predictive value in previously treated mRCC [24.Heng D.Y. Xie W. Regan M.M. et al.Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.J Clin Oncol. 2009; 27: 5794-5799Crossref PubMed Scopus (1532) Google Scholar] (Table 5). Interestingly, this model is also applicable in further lines of therapy as well as in non-clear cell histology.Table 5Median OS estimates in first- and second-line RCC according to IMDC risk groupsNumber of risk factorsRisk categoryMedian OS (months)First line [24.Heng D.Y. Xie W. Regan M.M. et al.Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.J Clin Oncol. 2009; 27: 5794-5799Crossref PubMed Scopus (1532) Google Scholar]Second line [23.Ko J.J. Xie W. Kroeger N. et al.The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.Lancet Oncol. 2015; 16: 293-300Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar]0Favourable43.235.31–2Intermediate22.516.63–6Unfavourable7.85.4IMDC, International Metastatic RCC Database Consortium; OS, overall survival; RCC, renal cell carcinoma. Open table in a new tab IMDC, International Metastatic RCC Database Consortium; OS, overall survival; RCC, renal cell carcinoma. Gene signatures can be used to detect different risk groups in RCC. ClearCode34 is a 34-gene expression panel that proved able to classify ccRCC into two subtypes, clear cell A (ccA) and clear cell B (ccB), significantly associated with relapse-free survival and CSS, as well as overall survival (OS) [25.Brooks S.A. Brannon A.R. Parker J.S. et al.ClearCode34: a prognostic risk predictor for localized clear cell renal cell carcinoma.Eur Urol. 2014; 66: 77-84Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar]. Another gene signature, based on a 16-gene assay, was shown to improve prediction of RFS in localised RCC when compared with the SSIGN score according to the Leibovich score (concordance: 0.81 versus 0.74) [26.Rini B. Goddard A. Knezevic D. et al.A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies.Lancet Oncol. 2015; 16: 676-685Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar]. Some gene mutations have also been reported as prognostic. The University of Texas Southwestern group identified distinct clinical outcomes in mutation-defined subtypes of ccRCC: a high-risk BAP1-mutant group and a favourable PBRM1-mutant group [27.Kapur P. Peña-Llopis S. Christie A. et al.Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.Lancet Oncol. 2013; 14: 159-167Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar]. Notably, 80% of patients from both the development and the validation cohorts had localised (or locoregional) disease. In the metastatic setting, the immunohistochemical expression of programmed death ligand 1 (PD-L1) is presently under the spotlight, although the results available so far are still controversial. In 2016, a systematic review and meta-analysis of 6 studies and 1323 cases clearly demonstrated a negative prognostic role of elevated level of PD-L1 tumour expression in RCC [28.Iacovelli R. Nolè F. Verri E. et al.Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis.Target Oncol. 2016; 11: 143-148Crossref PubMed Scopus (136) Google Scholar], although discrepancies between PD-L1 expression between the primary tumour and the metastases have been reported. A possible predictive value of PD-L1 expression remains controversial, although recently, PD-L1 tumour expression was shown to be able to identify patients benefiting from a combination of two immune-checkpoint inhibitors [29.Motzer R.J. Tannir N.M. McDermott D.F. et al.Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Engl J Med. 2018; 378: 1277-1290Crossref PubMed Scopus (2494) Google Scholar]. In addition, angiogenesis, T-effector/interferon (IFN)-γ response and myeloid inflammatory gene expression signatures have been suggested to predict response to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) and immunotherapy [30.McDermott D.F. Huseni M.A. Atkins M.B. et al.Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.Nat Med. 2018; 24: 749-757Crossref PubMed Scopus (690) Google Scholar]. As a whole, PD-L1 expression should not be routinely used but is a putative biomarker for future treatment selection because of remaining unanswered issues related to the different tests and cut-offs used, to the cells where PD-L1 expression should be checked and to the role of PD-L1 expression heterogeneity (e.g. between different primary tumour sites, or between primary tumour and its metastases). Other putative markers such as circulating DNA, microRNA or DNA methylation status were shown to have prognostic relevance in RCC and warrant future investigation. Overall, these data indicate that molecular analysis may provide additional benefit to already established clinical and histo-anatomical parameters, which may lead to an individual risk assessment in the future. Currently, no specific molecular marker can be recommended for clinical use. Partial nephrectomy (PN) is recommended as the preferred option in organ-confined tumours measuring up to 7 cm (elective indication). This is based on a systematic review including multiple retrospective studies and a prospective, randomised controlled trial (RCT) which compared radical nephrectomy (RN) with PN in solitary T1a-b N0M0 renal tumours <5 cm with normal contralateral kidney function [I, A] [31.MacLennan S. Imamura M. Lapitan M.C. et al.Systematic review of oncological outcomes following surgical management of localised renal cancer.Eur Urol. 2012; 61: 972-993Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar]. PN can be carried out via open, laparoscopic or robot-assisted laparoscopic approaches. Laparoscopic RN is recommended if PN is not technically feasible. In patients with compromised renal function, solitary kidney or bilateral tumours, PN is also the standard of care, with no tumour size limitation (imperative indication). Systematic reviews comparing surgical management of localised RCC (T1-2N0M0) were unable to identify prospective comparative studies reporting on oncological outcomes for minimally invasiv