French ccAFU guidelines – update 2020-2022: management of kidney cancer

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*Corresponding author.

E-mail address: karim.bensalah@chu-rennes.fr (K. Bensalah).

Disponible en ligne sur www.sciencedirect.com Progrès en urologie (2020) 30, S2-S51

French ccAFU guidelines – update 2020-2022:

management of kidney cancer

Recommandations françaises du Comité de cancérologie de l’AFU

− actualisation 2020‑2022 : prise en charge du cancer du rein

K. Bensalah

^a

, P. Bigot

^a

, L. Albiges

^a

, J.-C. Bernhard

^a

, T. Bodin

^a

, R. Boissier

^a

, J.-M. Correas

^a

, P. Gimel

^a

, J.-F. Hetet

^a

, J.-A. Long

^a

, F.-X. Nouhaud

^a

, I. Ouzaïd

^a

, N. Rioux-Leclercq

^a

, A. Méjean

^a

aComité de cancérologie de l’Association française d’urologie, groupe vessie, Maison de l’urologie, 11, rue Viète, 75017 Paris, France

Summary

Objective. − To update the French guidelines on kidney cancer.

Methods. − A systematic review of the literature between 2015 and 2020 was performed.

The most relevant articles regarding the diagnosis, the classification, surgical treatment, medical treatment and follow‑up of kidney cancer were retrieved and included in the new guidelines. The guidelines were updated with corresponding levels of evidence.

Results. − Thoraco‑abdominal CT scan with injection is the best radiological exam for the diagnosis of kidney cancer. MRI and contrast ultra‑sound can be useful in some cases. Percutaneous biopsy is recommended when histological results will affect clinical decision. Renal tumours must be classified according to pTNM 2017 classification and ISUP grade. Metastatic kidney cancers must be classified according to IMDC criteria. Partial nephrectomy is the recommended treatment for T1a tumours and can be done through an open, laparoscopic or robotic access. T1b tumours can be treated by partial or total nephrectomy according to tumour complexity. Radical nephrectomy is the recommended treatment of advanced localized tumours. There is no recommended adjuvant treatment.

In metastatic patients: cyto‑reductive nephrectomy can be offered in case of good prognosis; medical treatment must be counseled first in case of intermediate or bad prognosis. Surgical or local treatment of metastases should be considered in case of solitary lesion or oligo‑metastases. First line recommended drugs in metastatic patients KeywORdS

Kidney cancer;

Recommendations;

2020

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english version epidemiology

Kidney cancer is the 6^th most common cancer. In France, there were 15,323 new cases of kidney cancer in 2018 with an increase in incidence of 1.7% per year in men and 1.4% in women between 1990 and 2018. In 2018, kidney cancer was responsible for 5,589 deaths in France, i.e. a mortality rate of 5 and 1.5 deaths per 100,000 inhabitants in men and women respectively [1]. Age and gender are two non‑modifiable risk factors, with a male to female gender

ratio of 1.5 and peak incidence between 60 and 70 years of age [1]. The two main modifiable risk factors for kidney cancer are smoking and obesity [1,2]. High blood pressure has also been identified as a potential risk factor for kidney cancer and control of blood pressure in hypertensive patients could be beneficial [3]. Physical activity could reduce the risk of kidney cancer, notably by reducing obesity and high blood pressure [4]. Patients with chronic renal failure have an increased risk of developing kidney cancer (up to ten times higher than the general population), with frequent bilateral and/or multiple site involvement [5,6].

The CCAFU recommendations for prevention are shown in Table recommendation 1.

include the associations axitinib/pembrolizumab and nivolumab/ipilimumab. Cystic tumours must be classified according to Bosniak Classification. Surgical excision should be offered to patients with Bosniak III and IV lesions. It is recommended to follow patients clinically and with imaging according to tumour aggressiveness.

Conclusion. − These updated recommendations should assist French speaking urologists for their management of kidney cancers.

Résumé

Objectif. − Mettre à jour les recommandations sur la prise en charge des cancers du rein.

Méthodes. − Une revue systématique de la littérature a été faite sur la période allant de 2015 à 2020. Les articles jugés les plus pertinents concernant le diagnostic, la classification, le traitement chirurgical, le traitement médical et le suivi du cancer du rein ont été sélectionnés et incorporés aux recommandations. Les recommandations ont ainsi été actualisées en spécifiant le niveau de preuve (fort ou faible).

Résultats. − L’examen de référence pour faire le diagnostic et le bilan d’extension des cancers du rein est le scanner thoraco‑abdominal injecté. L’imagerie par résonance magnétique (IRM) et l’échographie de contraste sont indiquées dans certains cas particuliers. La biopsie percutanée est recommandée dans les situations où ses résultats influenceront la décision thérapeutique. Les tumeurs du rein doivent être classées selon la classification pTNM 2017 et le grade nucléolaire de l’ISUP. Les cancers du rein métastatiques doivent être classés selon les critères de l’IMDC. La néphrectomie partielle est le traitement de référence des tumeurs T1a et peut être faite par voie ouverte, laparoscopique ou robotique. Les thérapies ablatives et la surveillance active sont des options chez les patients âgés avec des comorbidités. Les tumeurs T1b doivent être traitées par néphrectomie partielle ou totale en fonction de la complexité tumorale. La néphrectomie totale est le traitement de première intention des cancers localement avancés localisés. Aucun traitement adjuvant n’est recommandé. Chez les patients métastatiques : la néphrectomie cytoréductrice peut être proposée et recommandée en cas de bon pronostic ; le traitement médical doit être proposé en première intention en cas de pronostic mauvais ou intermédiaire.

Le traitement chirurgical ou local des métastases peut être proposé en cas de lésion unique ou d’oligo‑métastases. Les molécules recommandées en première ligne chez les patients métastatiques sont les associations axitinib/pembrolizumab et nivolumab/

ipilimumab. Les tumeurs kystiques doivent être classées selon la classification de Bosniak. L’exérèse chirurgicale doit être proposée en priorité aux lésions Bosniak III et IV. Il est recommandé de suivre les patients en adaptant les modalités à l’agressivité tumorale.

Conclusion. − Ces recommandations actualisées sont un référentiel qui permettra aux praticiens français et francophones d’encadrer au mieux leur prise en charge des cancers du rein.

MOTS-CLéS Cancer du rein ; Recommandations ; 2020

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S4 K. Bensalah et al.

Table recommendation 1

Recommendation Level

Recommendations for primary prevention are smoking cessation, physical activity and weight loss in obese patients to reduce the risk of kidney cancer

Strong

diagnostic evaluation of renal tumours Imaging techniques: technique and results

Diagnosis and characterization of renal masses are based on three complementary imaging techniques, Doppler ultrasound, CT scan and MRI, which can be performed with or without the injection of contrast medium.

doppler ultrasound

Renal tumours are often often diagnosed by this imaging modality. It provides the basic information concerning characteristics of the tumour: cystic or solid tumour, typical or atypical, markedly hyperechoic in nature and suggestive of angiomyolipoma (AML). Along with the Doppler, it evaluates tumour vascularisation and can be useful in vascular staging (renal vein, inferior vena cava). It can be usedin active surveillance to measure renal tumour diameter. Finally, it enables effective guidance of biopsy when applicable through a real time image of the needle path.

Intravenous injection of a contrast medium (Sonovue^®) improves the characterisation of poorly vascularised solid tumours, atypical cystic tumours and venous thrombus (tumour vs. cruor), and guidance of the biopsy to non‑necrotic areas in case of large tumours [7‑9]. In clinical practice, tolerance to this contrast medium is excellent, and there are no contraindications related to renal function [7].

In practice, the place of Doppler ultrasound is limited to preoperative evaluation of renal tumours.

Computed tomography (CT scan) Iodinated contrast media (ICM)

ICM are the least tolerated contrast media, and the incidence of hypersensitivity reactions is up to 3%, including 0.04% of severe anaphylactic reactions, and a risk of decline in renal function ranging from 2 to 6% depending on the route of administration for low osmolality contrast media [10‑12].

Patients at risk for induced nephropathy are those with 1) acute renal failure, 2) a glomerular filtration rate (GFR) of less than 45 ml/min/1.73 m² for suprarenal intra‑arterial injection or being hospitalised in intensive care, 3) or GFR of less than 30 ml/min/1.73 m² for subrenal intra‑arterial injection or intravenous injection (e.g. CT scan). In patients at risk, either an alternative imaging modality (MRI/ultrasound with injection) should be offered or hyperhydration should be ensured, with ICM injections spaced at least 3 days apart, the injected dose limited to the minimum that is necessary, and creatinine levels monitored 48 to 72 hours after injection.

Haemodialysis after contrast injection does not reduce the renal toxicity of ICM [12]. However, in patients on dialysis, it is preferable to perform a CT scan with injection rather than an MRI with injection if the diagnostic benefit is equivalent. In diabetic patients treated with metformin, there is no need to discontinue therapy due to the risk of lactic acidosis if the GFR is above 30 ml/min/1.73 m². When the GFR is less than 30 ml/min/1.73 m², metformin should be discontinued on the day of the injection until creatinine levels are checked in 48 hours. It can only be restarted if there is no significant change in renal function.

Finally, depending on renal function, myeloma is no longer an absolute contraindication for ICM injection, even secretory and light chain types [13].

Technique

CT scan is the gold standard for the evaluation of renal tumours in the absence of ICM contraindications. The dose of ICM should be sufficient to enable detection of the enhancement of hypovascular tumours and Bosniak III and IV cystic masses (0.2 ml/kg of a medium containing iodine 350 mg/ml).

CT scan should include the following four phases:

• An acquisition without injection which is essential to define the contrast (> + 20 HU between the tubular phase and the acquisition without injection).

• An acquisition at the cortical nephrography phase, 30 to 40 seconds after injection.

• An acquisition at the tubular nephrography phase 80 to 100 seconds after injection (different from the portal phase acquired 60 seconds after injection on which the medulla is not yet enhanced).

• A late excretory acquisition.

These phases can be combined, according to the indications, in order to limit irradiation. The acquisition at the excretory phase depends on the indication (identification of late enhancement, examination of the relationship of the tumour with the urinary tract) [14‑16]. For renal imaging, patients should not be fasting and the gastrointestinal tract should not be opacified.

Dual‑energy spectral CT is a new technology with promi- sing results for the evaluation of renal pthologies [17]. With the introduction of new multilayer sensors and high‑speed reconstructors, it could provide access to mono‑energetic images and iodine mapping in standard practice. These examinations, which are less irradiating, could be performed with an ICM volume of less than 50 ml. It limits the artefacts related to the pseudoenhancement of central renal masses and metal artefacts and could improve the characterization of renal tumours, as, among other things, it is more sensitive to the enhancement of poorly vascularised masses (papillary carcinomas) [18‑20].

Results and indications

CT scan is the method of choice to identify AML because it can detect macroscopic fat islets (density < –20 HU).

Uncommonly, there might be fat metaplasia associated with calcifications in clear cell carcinomas. Macroscopic fat‑free AMLs may have moderate spontaneous hyperdensity (density

> 45 HU) and homogeneous enhancement [21].

Cystic lesions should be analysed according to the Bosniak classification, which distinguishes five categories according to the risk of malignancy. This classification applies to cystic

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masses excluding any infectious context or autosomal domi- nant polycystic disease. Nevertheless, there is significant variability in malignancy rates related to diagnostic criteria, study biases, acquisition technique and imaging method (CT scan vs. MRI vs. contrast ultrasound).

CT scan also provides elements of tumour characterization for renal carcinoma types, according to whether the enhancement is hypervascular or homogeneous. Nevertheless, these elements are only indicative and should prompt the performance of a renal biopsy if the results can impact further management.

CT scan with contrast injection is the key examination in the preoperative evaluation of renal tumours. Whenever possible, it should include a pre‑injection examination and three post‑injection phases, with multiplanar and MIP reconstructions. It allows precise evaluation of the tumour (size, location, relationship to the upper urinary tract and vessels) and perirenal fat. Classification according to RENAL or PADUA scores may be useful in predicting the complexity of partial nephrectomy [22]. It helps in locoregional (veins, lymph nodes, adrenal glands) and metastatic (lung, liver, pancreas) staging and in case of vena cava thrombosis should specify the level of the upper portion of the thrombus in relation to the diaphragm and the ostium of the suprahepatic veins. It identifies synchronous tumours in the contralateral kidney.

MRI

MRI has become more than a substitute modality for CT scan in case of contraindications to ICM injection (renal failure with GFR < 30 ml/min, history of anaphylactic reaction to ICM injection). It is indicated for the characterization of cystic and atypical solid masses that have remained unde- termined on CT scan, for staging (particularly vascular), and to monitor patients with hereditary cancer. However, the pre‑therapeutic evaluation of renal tumours is still primarily based on a CT scan.

Gadolinium-based contrast agents (GBCA) [11,12]

They are very well tolerated in clinical practice and nephrogenic systemic fibrosis is now a very exceptional side effect, if not non‑existent. It used to occur in patients with acute renal failure (GFR < 15 ml/min/1,73 m²) or who were on dialysis, and the incidence was related to the stability of the chelate complex Gadolinium. In at‑risk patients, injection is currently not contraindicated if the clinical benefit outweighs the risk, which is the case with kidney cancer, but only products with high stability should be used (Gadobutrol, Gadoterate meglumine and Gadoteridol). GBCAs can lead to an accumulation of Gadolinium in the basal ganglia but, to date, there is no specific neurological symptomatology related to these deposits. There are also deposits in bone, liver (asymptomatic) and skin, which cause erythematous plaques similar to those in nephrogenic systemic fibrosis (but in the absence of renal failure).

MRI technique

The multiparametric examination comprises axial and coronal T2‑weighted sequences with and without fat signal saturation, T1‑weighted gradient echo in‑phase and

opposed‑phase sequences (detection of intra‑tumour fat on the opposed‑phase sequence), high b‑value diffusion (800 to 1,000), and finally a dynamic sequence after contrast injection with late acquisition (tumour washout study, contrast acquisition of the stellate central fibrotic scar of oncocytoma).

Results and indications

The T2‑weighted sequences (with or without fat signal saturation) make it possible to distinguish solid tumours from typical (even infracentimetric) or atypical cystic lesions, and to a lesser extent AML (even low‑fat) in T2 hyposignal (haemorrhagic suffusions, papillary formations or muscle cells) [23,24]. Clear cell carcinomas and oncocytic tumours often have a hypersignal [25,26]. The dynamic T1‑weighted sequence before and after injection of GBCA distinguishes hypervascular and heterogeneous tumours (corresponding to clear cell carcinomas and AMLs) from homogeneous less enhanced (chromophobe carcinomas) or poorly enhanced (papillary carcinomas) tumours. The presence of a signal drop in the opposed‑phase and on fat saturation sequences is not specific for a low fat component AML, as it is pre- sent for many carcinomas [27]. MRI can also be used to identify microcystic territories or necrotic haemorrhagic changes. A hypovascular stellar central area is consistent with the diagnosis of oncocytoma but can also be found in renal carcinomas [28]. Diffusion imaging is very sensitive to detect small infracentimetric tumours that are difficult to characterize by other sequences and during staging or surveillance to identify lymph node, adrenal, pancreatic or liver metastases.

While MRI provides guidance for identifying the different types of solid tumours, itdoes not allow a histological diag‑

nosis to be made with certainty due to the lack of specificity of the different signs combined. Biopsy remains essential when the subsequent therapeutic course can be modified by the histological results [29].

PeT CT scan

Fluorine‑18‑fluorodeoxyglucose (F‑FDG) PET CT is used to stage many cancers. It is not useful in the characterization of renal tumours. On the other hand, it could be useful at the time of staging or after surgery to detect recurrences.

A recent meta‑analysis evaluated its sensitivity at 0.86 (95% CI, 0.88‑0.93) and specificity at 0.88 (95% CI, 0.84‑

0.91) in detecting metastases. However, further prospective studies are needed to define its place and the additional information it could provide compared to the conventional CT scan [30].

Staging

Standard staging is based on thoracic and abdominal CT scan with and without injection, and the thoraco‑abdomino‑

pelvic scan should be performed at the time of arterial nephrography. If there is a strict contraindication to the injection of an ICM, a thoraco‑abdominal CT scan without injection can be combined with an abdominal MRI with and without injection.

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Anatomical classifications

Different morphometric classifications have been reported with the aim of assisting the clinician with surgical planning and informing the patient in preparation for conservative surgery [31]. The oldest are the RENAL [22] and PADUA [32]

scores but over the past 10 years, 16 other classifications have been presented [33]. The vast majority of available studies are retrospective. The predictive values of the RENAL and PADUA scores are higher when they are used as categorical variables and in particular for estimating the risk of global or major perioperative complications and the duration of renal ischaemia. Their major interest is to provide objective categorisation of tumour characteristics allowing comparability with the scientific literature.

The modalities and indications for imaging examinations are summarized in Table recommendation 2.

Summary of the recommendations for renal

tumour imaging Level

Ultrasound should include a precise examination

in B‑mode and colour Doppler mode Strong Injection of contrast media during ultrasound

is being evaluated weak

CT scan is the standard imaging modailty in the absence of contraindications to iodinated contrast media. It should consist of at least three phases.

Strong

Abdominal and thoracic CT scan are

recommended to assess locoregional, venous, lymph node and metastatic invasion

of the tumour

Strong

Tumours with a cystic component should be analysed according to the Bosniak classification

Strong

MRI has a particular interest in patients with renal failure and the exploration of cystic tumours and tumours poorly characterized by other imaging examinations.

Strong

Morphometric scores have not demonstrated

usefulness in clinical practice weak

Biological tests

Standard biological examination

The standard biology examination for renal tumour should include:

• Serum creatinine test,

• Blood count.

In case of metastatic cancer, the following should be added:

• LFTs,

• Alkaline phosphatases,

• LDH,

• Serum calcium with corrected serum calcium,

• Coagulation assessment.

The aim is to evaluate renal function, determine prog‑

nostic factors (for metastatic tumour) and to screen for a possible paraneoplastic syndrome: anaemia, polycythaemia, hypercalcaemia, cholestasis [34,35].

Kidney function assessment

The reference technique for estimating glomerular filtration rate is the calculation of creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration 2009 (CKD EPI) equation. The CKD EPI equation is considered to be more effective than the Cockroft/Gault and MDRD (Modification of Diet in Renal Disease) methods [36].

However, there are situations in which the calculation of creatinine clearance does not provide a reliable assessment of renal function: extreme situations concerning muscle mass (obesity, cachexia), inhibition of renal tubular secretion (trimethoprim and fenofibrate) and extra‑renal creatinine elimination by microbiota (broad‑spectrum antibiotic therapy) [36]. It is advisable to evaluate renal function separated by scintigraphy in case of renal failure or bilateral tumours [37].

Histological diagnosis

what elements should be displayed in a standard pathology report?

The pathology report is a key element in the prognostic assessment and management of patients. The French Pathology Society and the French Cancer Institute have developed standardised reports with items that must appear in each conclusion for kidney cancer (French Pathology Society http://www.sfpathol.org/; French Cancer Institute www.e‑cancer.fr.).

A typical conclusion for kidney cancer should include a number of items that are listed in Table 1 [1,2].

Main histological subtypes

There has been no change in histological subtypes since the last WHO 2016 classification of urological and male genital tract tumours [3‑4]. However, many entities are still in the process of being categorised, particularly oncocytic renal tumours and renal carcinomas with a leiomyomatous stroma (Table 2).

Unclassified renal cell carcinomas (approximately 6% of renal malignancies), with a metastatic risk, are defined as follows: 1) tumour does not meet the diagnostic criteria for the classic histological subtypes of renal cell carcinomas or 2) unclassified low‑grade oncocytic carcinoma or 3) tumour with a pure sarcomatoid component [5].

Other renal tumours are much rarer and are of hae- matopoietic, mesenchymal, metanephric, nephroblastic, endocrine, germinal or metastatic origin.

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2017 pTNM classification

It is recommended to use the 2017 classification reviewed in 2019 by the American Joint Committee on Cancer /AJCC which is identical to the Union for International Cancer Control/

UICC 2017 pTNM classification (table 3) [6‑8]. Compared to the previous 2010 pTNM classification, infiltration of pyelocalicial cavities has been added in the pT3a stage.

Special cases

Several emerging entities are still in the process of being categorised, including oncocytic tumours. Among these tumours, oncocytomas and chromophobe oncocytic carcinomas are well known to uropathologists and have a common feature of membrane positivity in CD117 immunohistochemistry. CK7 Table 2. Histological subtypes of tubular renal tumours.

Histological subtypes

Clear cell renal cell carcinoma

Multilocular cystic renal neoplasia of low malignant potential

Papillary renal cell carcinoma subtype 1 or 2 Chromophobe renal cell carcinoma

Collecting duct carcinoma Renal medullary carcinoma

MiT family translocation renal cell carcinoma (TFE3/

TFEB)

Mucinous, tubular and spindle cell renal carcinoma Tubulocystic renal cell carcinoma

Acquired cystic disease‑associated renal cell carcinoma Clear cell papillary renal cell carcinoma

Hereditary leiomyomatosis and renal cell carcinoma‑

associated renal cell carcinoma (HLRCC‑RCC) Succinate dehydrogenase (SDH) deficient renal carcinoma

Unclassified renal cell carcinoma Papillary adenoma

Oncocytoma

Table 3. AJCC/UICC pTNM Malignant Tumour Classification 2017, 8th Edition.

AJCC/UICC

(2017) Status

Tumour (T) Tx Tumour cannot be assessed T1a Tumour ≤ 4 cm, limited

to the kidney

T1b Tumour > 4 cm but ≤ 7 cm, limited to the kidney T2a Tumour > 7 cm but ≤ 10 cm,

limited to the kidney T2b Tumour > 10 cm, limited

to the kidney

T3a Tumour invades the perirenal adipose tissue and/or hilar adipose tissue but not Gerota’s fascia and/or macroscopic thrombus in the renal vein or one of its branches and/or infiltration of the pyelocaliceal cavities

T3b Thrombus extends into the vena cava below the diaphragm T3c Tumour extends into the vena

cava above the diaphragm or invades the wall of the vena cava T4 Tumour invades beyond

Gerota’s fascia and/or contiguous extension into the adrenal gland

Lymph node

metastasis (N) Nx LN cannot be assessed N0 No lymph node metastases N1 Metastasis in 1 regional LN only N2 Metastasis in more than

1 regional LNs Distant

metastases (M) Mx No assessment of metastasis M0 No metastasis

M1 Distant metastasis Table 1. Items that should be reported routinely in a renal

tumour analysis report.

Histological evaluation of renal tumours

The type of surgery (partial or simple nephrectomy) Laterality (right/left)

Histological subtype according to the WHO 2016 classification

Size of the tumour in terms of the largest diameter in cm. In case of multiple tumours, indicate the size of the largest tumour

Nucleolar grade from 1 to 4

The presence or absence of a sarcomatoid component and evaluate the %

The presence or absence of a rhabdoid component and evaluate the %

The presence or absence of necrosis

The presence or absence of microscopic vascular emboli The locoregional stage of the tumour according to the pTNM UICC/ AJCC 2017 classification The presence or absence of lymph node metastases The quality of the surgical margins in case of

tumorectomy/partial nephrectomy and in the renal vein in case of tumour thrombus

Aspect of non tumoural kidney and other associated lesions

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is negative or sparse in oncocytomas, whereas it is strong and diffused in chromophobe carcinomas, although it may be negative in 30% of the cases [9].

Recently, the following emerging entities have been reported [10‑12]:

• Low‑grade oncocytic tumours (LOT): this is a renal tumour with oncocytic cells that often have a solid architecture, but which has the particularity of being CD117‑negative and CK7‑strongly positive. Few cases have been described but progression seems to be benign.

• High‑grade oncocytic tumours (HOT) are renal tumours that also have oncocytic cells, often with a solid architecture and the same immunohistochemical profile as oncocytoma with CD117 positivity, and CK‑negative or focally positive. This tumour has the particularity of presenting very prominent nucleoli, hence the use of the term high‑grade, whereas in principle, they are non‑

aggressive small tumours.

Oncogenetics: in which cases?

Hereditary predispositions to renal tumours occur in approximately 5% of the adult cases. There are 11 syndromes with 17 identified genes: VHL, MET, FH, SDHA, SDHB, SDHC, SDHD, PTEN, BAP1, PBRM1, TSC1, TSC2, FLCN, MITF, CDC73, CDKN2B and HNF1β. The incidence of these hereditary predispositions is higher in non‑clear cell carcinomas (12% versus 3% for clear cell carcinomas).

The renal tumours most frequently encountered in these predispositions are clear cell, papillary, chromophobe cell carcinomas and angiomyolipomas.

The most common hereditary syndromes are listed in Table 4.

The criteria for suggesting oncogenetic consultation are listed in Table 5.

The place of biopsy Technique

Biopsy can be performed under local anaesthesia as an outpatient procedure with ultrasound or CT guidance. The

CCAFU recommends the use of a 16‑18 G coaxial needle to prevent the risk of tumour dissemination, to avoid targeting necrotic areas and to harvest at least two samples.

The diagnostic performance of the biopsy is best when:

• The tumour is solid rather than cystic.

• A biopsy needle is used rather than fine needle aspiration [38].

Cytoponction is not effective and is no longer recommended [38].

Biopsies should be fixed in 4% buffered formaldehyde which allows histological analysis, FISH and genetic sequen- cing. Unfixed conditioning for freezing is recommended for paediatric renal tumours, but freezing is optional for adult renal tumours.

diagnostic performance and complications

In centres with a high level of expertise, biopsy performs well in establishing the diagnosis of malignancy, but there are frequent cases of non‑contributive biopsies (absence of tumour tissue or histological material not sufficient for a proper histologic evaluation).

In 2016 two systematic reviews of the literature evaluated the performance of renal biopsy [38,39]:

• For the diagnosis of malignancy, sensitivity and specificity were > 95%.

• For the determination of the histological subtype, the biopsy/surgical specimen concordance was 90%.

• The diagnosis of oncocytoma is difficult on biopsy: it can be challenging to distinguish from chromophobe

Table 4. The various hereditary syndromes that predispose to renal tumours.

Syndrome Type of kidney cancer Chromosomal abnormality Risk of kidney cancer VonHippel Lindau disease Clear cell carcinoma The VHL gene in 3p25 25‑45%

Birt‑Hogg‑Dubé syndrome Chromophobe carcinomas Hybrid neoplasms Oncocytoma

The FLNC gene in 17p11 25‑34%

Hereditary papillary

carcinoma Type 1 papillary carcinoma

Papillary adenoma The MET gene in 7q31 100%

Bourneville disease Angiomyolipoma

Epithelioid angiomyolipoma Chromophobe carcinoma

Leiomyomatous stroma carcinoma

The TSC1 gene in 9q34 The TSC2 gene in 16p13

1 to 4%

Table 5. The INCa PREDIR network criteria for oncogenetic consultation (1 or more criteria) [13].

Criteria for recommending oncogenetic counselling Age of onset < 45 years

Subtype other than clear cell carcinoma Multiple renal tumours

Bilateral renal tumours Family history of kidney cancer

Extra‑renal manifestations that suggest a personal or hereditary syndrome

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carcinoma and 25% of patients have a final diagnosis of clear cell carcinoma [39].

• For nuclear grading, the performance of kidney biopsy ranged from 43% to 93%. For renal tumours of < 4 cm, grade concordance was 86% with a simplified high/low grade classification. In the majority of cases, the grade error consisted of an underestimation compared to the surgical specimen [40,41].

• Major complications were rare (2%) [38].

• Biopsy needle track seeding was exceptional [42].

• The rate of non‑contributivebiopsies could be as high as 20%.

Indications

The performance of biopsy varies greatly in France and it is difficult to specifically delineate the indications. There are more and more questions concerning the « medico-legal » aspect of biopsy which could prevent surgery of of benign tumour.

The CCAFU recommends a biopsy for renal tumours when the histological diagnosis is likely to impact further management. It is also recommended to inform the patient about the possibility of performing a biopsy, and its capacities and limitations. Table 6 summarises the indications for which biopsies are recommended or not. Levels of evidence and recommendations are indicated in Table recommendation 3.

The place of biopsy in small tumours

For tumours < 4 cm, the diagnostic contribution of the biopsy is 90% [41,43]. Sensitivity and specificity for the diagnosis of malignancy are > 95%. The concordance for the histological subtype is 96% and for the grade 87% [44].

Recently, several studies have suggested that biopsy may change the management of small renal masses, particularly by reducing the rate of interventions for benign tumours [40].

Concerning oncocytomas, several series have reported reassuring results concerning the surveillance strategy after biopsy confirmation [45‑50]. Oncocytomas grow slowly (0.1 to 0.5 cm/year), but the negative predictive value of biopsy is not excellent, with histological correla- tions between biopsy and surgical specimen ranging from 65% to 100%.

Summary of the level of evidence Level Percutaneous biopsy has a high performance

for the diagnosis of malignancy Strong Percutaneous biopsy is associated with low

morbidity Strong

Recommendations Level

For small renal tumours, it is recommended to inform the patient of the possibility of biopsy, its complications and diagnostic limitations

weak

It is recommended to biopsy renal tumours when the results are likely to influence the therapeutic decision

Strong

Treatment of small renal tumours T1a (< 4 cm)

The place of partial nephrectomy (PN)

Value and objectives

PN is the standard technique for small renal masses. It should meet three requirements: oncological control, preservation of renal function and limitation of perioperative complications.

Oncological control

PN provides oncological control identical to RN [51]. After PN for T1a tumour, the 5‑year relapse‑free survival is

> 95% [51].

A positive surgical margin increases the risk of local recurrence but does not seem to have any impact on disease‑specific survival [52,53,54]. In case of a positive surgical margin, simple surveillance by regular imaging examinations is recommended. Immediate total nephrectomy is not necessary [53,55]. In case of an aggressive tumour of high grade and/or with large positive margin, RN can be discussed in the MTM.

The treatment of local recurrence has been poorly evaluated. RN, a second PN or ablation therapy can be decided depending on the time to recurrence, histological type, and grade [55].

Table 6. Situations in which a biopsy is recommended.

Situations in which a biopsy is recommended Before thermal ablation therapy

Before any systemic treatment if there is no histological evidence

Before a difficult partial nephrectomy where there is a high risk of total nephrectomy

In case of diagnostic uncertainty on imaging

(lymphoma, sarcoma, « pseudotumour » of the kidney or renal metastasis of another type of tumour) In case of an imperative indication

Situations in which a biopsy is not recommended Suspicion of urothelial carcinoma

Majorajor risk of haemorrhage

Cystic tumour without a solid component Suspicion of angiomyolipoma

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Preservation of renal function

PN allows optimal preservation of the renal parenchyma, which limits the deterioration of renal function [56]. This functional preservation reduces the risk of cardiovascular events and may increase overall survival compared to RN [57,58,59,60]. Kidney preservation is also associated with a positive psychological impact and improvement in quality of life (61).

duration of ischaemia – The impact of the duration of ischaemia on the decline in renal function is discussed matter of debate. Renal ischaemia may have a more detrimental effect in patients with pre‑existing renal insufficiency [60].

The data in the literature is contradictory, but it is advisable to limit the period of clamping of the renal pedicle to less than 25 min [62]. Non‑clamping or selective clamping techniques have not been shown to provide better renal preservation than total clamping < 25 minutes [63,64].

Preservation of parenchymal volume – Preservation of healthy kidney parenchyma appears to be the most important factor in maintaining kidney function [62,65].

Tumour enucleation techniques that preserve a minimal margin of healthy tissue do not appear to increase the rate of local recurrence, but their contribution to preserving renal function is uncertain [10,66,67].

Morbidity

PN is associated with a significant morbidity, which is approximately 20% according to the literature. The two most feared complications are secondary bleeding (false aneurysm) and urinary fistula. The rate of serious complications after PN can be as high as 11%. The risk of complications is influenced by many factors: tumour complexity, age, co‑morbidities, the surgeon’s experience, the volume of the centre, the type of surgical approach [68,69].

Technique: open vs. laparoscopic vs. robot-assisted laparoscopic approach

Regardless of PN approach (open vs. laparoscopic vs. robotic‑

assisted), there is no difference in terms of disease‑specific survival and overall survival [70,71].

Compared to the open approach, laparoscopy reduces blood loss and length of stay. Conversely, the operating and ischaemia times are longer. Postoperative complications and long‑term renal function are similar [70,71]. This is a technically difficult approach that is hardly used any more.

Some teams propose preoperative tumour embolisation to facilitate the surgical procedure and reduce postoperative complications, but this is a technique that is still under development and its dissemination remains modest [73].

Compared to the open approach, robot-assisted lapa- roscopy has an advantage in terms of blood loss, length of stay, complications and the duration of ischaemia. The rate of positive margins and residual renal function are similar [71,74,75].

Compared to the laparoscopic approach, the robot‑

assisted approach has an advantage in terms of the duration of ischaemia, conversion to the open approach, changes in glomerular filtration rate and length of stay [76]. There is also a benefit in terms of the rate of conversion to RN, especially for complex and hilar tumours [71,76,77]

The centre effect in France

A 2010 prospective study conducted at French university and private hospital facilities suggested a centre effect of PN with an increase in morbidity and the rate of positive margins in smaller centres [78]. A more recent CCAFU study also showed better results for robot‑assisted PN in larger centres [25,79].

While it is difficult to make recommendations on a possible threshold, the CCAFU encourages teams to organise them- selves so that PN is performed only by a few expert surgeons according to the volume of activity.

Levels of evidence and recommendations concerning the indications for PN in T1a tumours are provided in Table recommendation 4.

Summary of the level of evidence Level of evidence For T1a tumours ≤ 4 cm, partial nephrectomy

is similar to radical nephrectomy in terms of disease‑specific survival

Strong

For T1a tumours ≤ 4 cm, partial nephrectomy preserves kidney function better than total nephrectomy

Strong

Partial nephrectomy can be performed by an open, laparoscopic, or robot‑assisted approach depending on the expertise of the surgeon and the technical facilities available

Strong

The minimally invasive approach is associated with less morbidity than the open approach

Strong

Robot‑assisted partial nephrectomy is associated with a decrease in postoperative complications, duration of ischaemia and blood loss compared to laparoscopic and open approaches.

Strong

Partial nephrectomy is the recommended first‑line treatment for T1a tumours when technically feasible and is associated with acceptable morbidity

Strong

It can be performed by an open, laparoscopic,

or robotic‑assisted approach Strong

The place of radical nephrectomy (RN)

Value and objectives

RN is not recommended as a first‑line treatment for small renal tumours. It may be offered in case of a non‑functioning kidney, suspicion of a T3a tumour or significant complexity. If a tumour is considered to be too complex, it is recommended to refer the patient toan expert centre before deciding to perform a RN.

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Technique: open vs. laparoscopic vs. robot-assisted laparoscopic approach

The oncological outcomes of the different approaches are equivalent [80]. Laparoscopy is associated with a shorter hospital stay, a reduction in the use of analgesics and a reduction in intraoperative bleeding [81]. Trans‑ and retroperitoneal laparoscopic approaches have equivalent oncological and quality of life outcomes [82]. Very few studies compared the robot‑assisted technique with standard laparoscopy, for which the results seem to be equivalent [83].

The place of ablation therapy

Small renal tumours can be treated by ablation therapy (AT).

A preliminary diagnostic biopsy is recommended. There are different AT techniques:

• Radiofrequency and microwaves,

• Cryotherapy.

• Recently, irreversible electroporation or stereotactic radiotherapy.

The indications for AT are summarised in table 7 AT can be considered as an option for patients with tumours that can be fully treated. The long‑term technical and functional results of AT are good [51,84,85]. There are no randomised studies that compare AT to PN and published retrospective studies have many biases. However, local oncological control after AT appears to be lower than with PN [51,84,85,86,87]. Some retrospective studies suggest better preservation of renal function in comparison to PN [88,89]. The rate of overall and major complications appears to be lower for AT than for PN [39,92,93].

Comparison of AT to PN – There are no randomised studies that compare the two techniques. All the recommendations are based on retrospective studies. A recent meta‑analysis of 26 studies and 11 systematic reviews was published by the EAU Renal Cell Cancer Guidelines Panel. The conclusion was that the level of evidence was very low for AT and that it was difficult in this context to make recommendations in comparison to PN. The CCAFU recommends that patients be informed that AT provides good oncology outcomes even if they are inferior to those provided by PN, but that long‑term data is uncertain.

The place of active surveillance

Active surveillance (AS) is defined as the regular monitoring of the size of a renal tumour by repeated imaging examinations (ultrasound, CT scan or MRI). Treatment may be offered if the tumour increases in size [94].

Biopsy is not a systematically required for AS.

The indications are:

• Elderly patients.

• Patients with significant co‑morbidities.

• Small renal tumours < 4 cm [265].

There are no randomised trials of AS in patients with small renal masses. However, several prospective registry studies are available [95,96].

The DISSRM’s main multicentre registry studied the feasibility of AS for tumours < 4 cm and reported similar overall (92 vs. 75%; p = 0.06) and disease‑specific (99% vs 100%; p = 0.3) survival at 5 years between patients treated immediately (with PN or AT) and those who were initially monitored [97].

The update of this data at 7 years confirmed the feasibility of AS, reporting similar disease‑specific survival between PN and AS [98]. However, a non‑controlled prospective study by MD Anderson reported a decrease in overall survival at 2 years for surveillance (versus surgery) for tumours larger than 3 cm, suggesting a 3 cm threshold for AS [99].

In terms of quality of life, compared to patients who had a procedure immediately (surgery or ablation therapy), patients on AS were in poorer physical health (but they were older patients with co‑morbidities) and showed more anxiety [100,101].

Surveillance is possible for T1b tumours, even though only very fragmented data is available. It is reserved for elderly and inoperable patients [102].

Levels of evidence and indications for AS and AT for small renal tumours are provided in Table recommendation 5.

The management of a small renal mass is summarized in figure 1.

Summary of the level of evidence Level In active surveillance cohorts, tumour growth

is slow and the risk of metastatic disease is low (1% ‑ 2%)

Strong

The level of evidence from studies on ablative therapies is very low, which limits the scope of the recommendations

Strong

Ablative therapies may be considered as an option for elderly patients with

co‑morbidities who have a small renal tumour of < 4 cm

weak

Patients who are offered AT should be

informed of a slightly higher risk of recurrence and the lack of reliable long‑term data

weak

Active surveillance may be considered as an option for elderly patients with co‑morbidities who have a small renal tumour < 4 cm

weak Table 7. Indications for ablation therapy.

Commonly accepted indications for ablation therapies Small renal tumours of less than 4 cm in elderly patients with co‑morbidities

Local recurrences after partial nephrectomy Multiple renal tumours, especially in the context of hereditary syndromes

Patients with advanced renal failure

Indications that can be discussed if necessary Small cystic or mixed tumours

Some tumours > 4 cm in diameter Tumours arising on kidney transplants Multiple synchronous tumours

Metastatic kidney cancer in case of a dissociated response to antiangiogenic or immunotherapy treatment

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decision algorithm

Management of small renal masses

Not eligible for surgical treatment

* After a second opinion from an expert centre - Signiÿcant co-morbidities

Ablative therapy Surveillance

- Kidney destroyed - Technical impossibility*

Radical nephrectomy Reference treatment

Partial nephrectomy

Eligible for surgical treatment Multidisciplinary team meeting

- Patient characteristics: age, co-morbidities, hereditary cancers

- Renal biopsy: if modifying management, systematic before ablative therapy, optional before surveillance - Tumour characteristics: appearance, complexity score

- Renal function: risk of renal failure, functionality of the tumour kidney, single kidney

Exceptional situation

Figure 1. Algotithm for the management of a small renal tumour.

survival benefit, a randomised study by the EORTC showed no benefit [116,117].

In terms of surgical technique, no difference was reported in oncologic control between laparoscopic RN and open SN.

Laparoscopy reduces blood loss, postoperative pain, length of hospital stay and convalescence [118]. Robot‑assisted laparoscopy has oncological and functional outcomes that are comparable to standard laparo scopy [119,120]. No oncological difference was found between the retroperitoneal and the trans‑peritoneal approach [121,122].

The place of thermal ablation

Few studies have reported the results of TA for tumours larger than 4 cm and length of follow‑up are short [123,124]. The data is insufficient to recommend their use in this indication.

Treatment recommendations for cT1‑2 N0 M0 tumours are shown in Table recommendation 6.

If possible, partial nephrectomy

is recommended for cT1b tumours Strong Radical nephrectomy is recommended

for localised cT1b‑T2 tumours for which partial nephrectomy is not technically feasible or in case of a non‑functioning kidney

Strong

Laparoscopy is associated with less morbidity than the open approach and should be used for radical nephrectomy for cT1b‑T2 tumours

Strong

Treatment of localised renal tumours

> 4 cm

The place of partial nephrectomy

PN and RN have identical oncological outcomes for tumours >

4 cm. PN improves the preservation of renal function but seems to be associated with higher perioperative morbidity [103‑105].

The complexity of the tumour can be assessed by morphometric scores (RENAL score, PADUA score, C‑Index).

These scores could be of interest to predict alteration ofrenal function and prognosis in case of tumours > 7 cm [106‑108].

An increase in tumour size and complexity is associated with an increase in the risk of pT3a tumour and local recurrence [107,109,110].

The robot‑assisted laparoscopic approach appears to decrease the morbidity of PN for tumours > 4 cm. It is associated with less bleeding, fewer complications and a shorter hospital stay than open surgery [111,112]. The associated intraoperative morbidity is comparable to that of RN [113].

Therefore, PN should be prioritized in T1b tumours whenever technically feasible.

The place of radical nephrectomy

RN is indicated when PN is not technically feasible (tumour complexity, tumour too large, insufficient surgical expertise) or when the kidney is no longer functional.

It is not necessary to perform an adrenalectomy unless adjacent tissue involvement is detected during surgery or an abnormality suggestive of a secondary lesion is noted on the preoperative imaging [114,115].

Lymphadenectomy is not recommended for cN0 patients.

While some retrospective studies have suggested a possible

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Recommendations Level Adrenalectomy is not recommended

for radical nephrectomy for cT1b‑T2 tumour in the absence of radiological and/or intraoperative evidence of involvement

Strong

Lymphadenectomy is not recommended in case of nephrectomy for cT1b‑T2 N0 tumours

Strong

Ablative therapies are not recommended

for the treatment of cT1b‑T2 tumours Strong

Treatment of locally advanced kidney cancer

Definition of locally advanced kidney cancer

Locally advanced kidney cancers are those that are neither intracapsular (pT1, pT2) nor metastatic (M1).

Principles of radical nephrectomy

Technique: open vs. laparoscopic and robot- assisted laparoscopic

In this case, surgery has a curative intent. The main objective with any technique is to achieve negative surgical margins [125]. The standard approach for locally advanced renal tumours is the open approach. Several series have reported the feasibility of the laparoscopic or robot‑assisted laparoscopic approach, which can be used provided that macroscopicnegative margins can be obtained [126‑128].

Value and indications for lymphadenectomy

Lymphadenectomy is recommended in case of macroscopic adenopathies identified on preoperative imaging or during surgery [129]. Surgical excision of identified adenopathies in a non‑metastatic patient could be of prognostic as well as therapeutic interest (oligometastasis) [130,131].

In the absence of identified adenopathy, the oncological value of lymph node dissection has not been demonstrated, with a rate of positive lymph nodes from lymphadenectomy ranging from 3% to 21% [4,7‑9]. If lymph node involvement is proven, the survival rate after nephrectomy is 10% to 45%

at 5 years [134].

The role of adjuvant and neoadjuvant therapies

Patients with locally advanced tumours have a high risk of metastatic progression. It is recognized that after surgery, 30%

to 40% of patients will progress to metastatic disease [135].

Most randomised studies that have investigated the value of adjuvant anti‑angiogenic therapy in patients at high risk

for relapse after nephrectomy have reported negative results (Table 8) [138]. Only the S‑Trac study, which evaluated the benefit of treatment with sunitinib in patients at high risk for relapse, demonstrated an increase in disease‑free survival but no benefit in overall survival in the sunitinib group [139].

Adjuvant therapy may increase overall survival in the high‑risk patient population, but there is no consensus on the definition of this population [140,141]. Many studies are under way that examine the value of adjuvant immunotherapy in cancers with a high risk of recurrence after surgery [142].

A systematic review of the literature that examined the value of adjuvant radiotherapy found that it was associated with a decrease in the risk of local recurrence, but without any impact on overall or disease‑specific survival [143].

Neoadjuvant use of targeted therapies provides a limited response to the primary tumour (9‑28%) and this therapeutic strategy is not recommended [144‑146]. The place of neo adjuvant immunotherapies is being evaluated and they should only be used in clinical trials or discussed in MTM on a case‑by‑case basis [147]. They should be considered with caution as they may be associated with increased surgical difficulties associated with peritumoral inflammatory changes following immunotherapy [148].

Special situations

Invasion of adjacent organs

Invasion of adjacent organs is difficult to predict [149]. Many cT4 patients are over‑staged and may benefit from surgical resection. Survival at this stage is less than 10% at 5 years, and the existence of negative margins is an important prognostic factor [150‑152].

Vena caval tumour thrombus

Radical nephrectomy combined with vena cava thrombectomy is recommended [153]. A preoperative MRI can predict venous wall invasion [154]. Thrombectomy is associated with high mortality (5‑15%) and morbidity (35‑70%) which increase with the level of the thrombus [153]. An adequate technical support centre including the possibility of cardiopulmonary bypass and cardioplegia, and a trained multidisciplinary surgical team are essential for the optimal management of T3b and especially T3c tumours [155]. Survival rates at 5 years are 40‑65% and 0‑17% in case of metastases. Poor prognostic factors are: incomplete tumour resection, invasion of perirenal fat, lymph node metastases and invasion of the venous wall [156].

The recommendations for the treatment of locally advanced tumours are summarized in Table recommendation 7.

Treatment of metastatic kidney cancer IMDC classification (Heng)

The International Metastatic RCC Database Consortium [160]

(IMDC) classification is now the most widely used in clinical practice (table 9) [161]. It was also validated in second line

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[162] and in non‑clear cell carcinomas [163]. The medians for overall survival are 43, 23 and 8 months respectively in the good (0 factor), intermediate (1 or 2 factors) or poor (≥

3 factors) prognosis groups [161].

Treatment of metastatic kidney cancer

The place of immediate or deferred

cytoreductive nephrectomy (CN) in metastatic kidney cancer (mRCC)

Two early prospective randomised studies (EORTC and SWOG) have shown a significant improvement in survival Table 8. Summary table of targeted adjuvant therapy trials.

Inclusion criteria drug vs Placebo duration of

administration Relapse-free

survival Relapse-free survival (HR CI 95%, p) ASSURe

(Sunitinb) (157) pT1b high grade N0M0 or N+M0, conventional and non-conventional RCC

Sunitinib 50 mg/

Sorafenib 800 mg

1 year 47% vs 50%

in 5 years

1.02 [0.85‑1.22], p = 0.89

ASSURe (Sorafenib) (157)

pT1b high grade N0M0 or N+M0, conventional and non-conventional RCC

Sunitinib 50 mg/

Sorafenib 800 mg 1 year 49% vs 50%

in 5 years 0.99 [0.80‑1.17], p = 0.72

S-TRAC (139) Stage III‑IV UISS, conventional RCC

Sunitinib 50 mg 1 year 59% vs 51%

in 5 years

0.76 [0.59‑0.98], p = 0.03 PROTeCT

(600 mg) (158) pT2 high grade, pT3‑4 N0M0 or N+M0, Conventional RCC

Pazopanib 600 mg 1 year 67% vs 64%

in 3 years 0.94 [0.77‑1.15], p = 0.51 PROTeCT

(800 mg) (158) pT2 high grade, pT3‑4 N0M0 or N+M0, conventional RCC

Pazopanib 400 mg

×2/day 1 year 66% vs 56%

in 3 years 0.66 [0.49‑0.90], p = 0.01 ATLAS (159) ≥pT2 and/or N+ Axitinib 5 mg

×2/day 3 years 65% vs 69%

in 3 years 0.870 [0.66–1.14], p = 0.32 SORCe Leibovitch score

of 3-11

Conventional and non-conventional RCC

Sorafenib 400 mg

×2/day 1 year 54% vs 53%

in 5 years 1.01 [0.82‑1.23], p = 0.95

Table 9. Heng criteria.

HeNG criteria

Karnofsky Index (performance status) Less than 80%

Time between diagnosis and systemic

therapy Less than one

year

Haemoglobin concentration Below normal Corrected serum calcium Above normal

Platelet count Above normal

Polynuclear neutrophil count Above normal 0 factor: Good prognosis

1 or 2 factors: Intermediate prognosis 3 or more factors: Poor prognosis Table recommendation 7

In case of locally advanced tumours, surgical excision with negative margins is recommended

Strong

In case of locally advanced tumours, the therapeutic value of lymphadenectomy is uncertain. It can be recommended in case of pathological lymph nodes identified on preoperative imaging

weak

In case of a tumour with vena caval thrombus, nephrectomy combined with surgical

thrombectomy is recommended

Strong

No neoadjuvant therapy can be offered except

in clinical trials Strong

No adjuvant therapy is currently

recommended in France Strong