Renal Cell Carcinoma

5. DIAGNOSTIC EVALUATION

5.1. Symptoms

Many renal masses remain asymptomatic until the late disease stages. The majority of RCCs are detected incidentally by non-invasive imaging investigating various non-specific symptoms and other abdominal diseases [98] (LE: 3). In a prospective observational cohort study, 60% of patients overall, 87% of patients with stage 1a renal tumours and 36% of patients with stage III or IV disease presented incidentally [99]. The classic triad of flank pain, visible haematuria, and palpable abdominal mass is rare (6-10%) and correlates with aggressive histology, advanced disease, and poorer outcomes [99-101] (LE: 3). Paraneoplastic syndromes are found in approximately 30% of patients with symptomatic RCCs [102] (LE: 4). Some symptomatic patients present with symptoms caused by metastatic disease, such as bone pain or persistent cough [103] (LE: 3).

5.1.1. Physical examination

Physical examination has a limited role in RCC diagnosis. However, the following findings should prompt radiological examinations:

• palpable abdominal mass;
• palpable cervical lymphadenopathy;
• non-reducing varicocele and bilateral lower extremity oedema, which suggests venous involvement.

5.1.2. Laboratory findings

Commonly assessed laboratory parameters are serum creatinine, glomerular filtration rate (GFR), complete cell blood count, erythrocyte sedimentation rate, liver function study, alkaline phosphatase, lactate dehydrogenase (LDH), serum corrected calcium [104], coagulation study, and urinalysis (LE: 4). For central renal masses abutting or invading the collecting system, urinary cytology and possibly endoscopic assessment should be considered in order to exclude urothelial cancer (LE: 4).

Split renal function should be estimated using renal scintigraphy in the following situations [105,106] (LE: 2b):

• when renal function is compromised, as indicated by increased serum creatinine or significantly decreased GFR;
• when renal function is clinically important; e.g., in patients with a solitary kidney or multiple- or bilateral tumours.

Renal scintigraphy is an additional diagnostic option in patients at risk of future renal impairment due to comorbid disorders.

5.2. Imaging investigations

Most renal tumours are diagnosed by abdominal US or CT performed for other medical reasons [98] (LE: 3). Renal masses are classified as solid or cystic based on imaging findings.

5.2.1. Presence of enhancement

With solid renal masses, the most important criterion for differentiating malignant lesions is the presence of enhancement [107] (LE: 3). Traditionally, US, CT and MRI are used for detecting and characterising renal masses. Most renal masses are diagnosed accurately by imaging alone.

5.2.2. Computed tomography or magnetic resonance imaging

Computed tomography or MRI are used to characterise renal masses. Imaging must be performed unenhanced, in an early arterial phase, and in a parenchymal phase with intravenous contrast material to demonstrate enhancement. In CT imaging, enhancement in renal masses is determined by comparing Hounsfield units (HU) before, and after, contrast administration. A change of fifteen HU, or more, in the solid tumour parts demonstrates enhancement and thus vital tumour parts [108] (LE: 3). Computed tomography or MRI allows accurate diagnosis of RCC but cannot reliably distinguish oncocytoma and fat-free AML from malignant renal neoplasms [109-112] (LE: 3). Abdominal CT provides information on [113]:

• function and morphology of the contralateral kidney [114] (LE: 3);
• primary tumour extension;
• venous involvement;
• enlargement of locoregional LNs;
• condition of the adrenal glands and other solid organs (LE: 3).

Abdominal contrast-enhanced CT angiography is useful in selected cases when detailed information on the renal vascular supply is needed [115,116]. If the results of CT are indeterminate, CEUS is a valuable alternative to further characterise renal lesions [117-120] (LE: 1b).

Magnetic resonance imaging may provide additional information on venous involvement if the extent of an IVC tumour thrombus is poorly defined on CT [121-124] (LE: 3). In MRI, especially high-resolution T2-weighted images provide a superior delineation of the uppermost tumour thrombus, as the inflow of the enhanced blood may be reduced due to extensive occlusive tumour thrombus growth in the IVC. The T2-weighted image with its intrinsic contrast allows a good delineation [124].

Magnetic resonance imaging is indicated in patients who are allergic to intravenous CT contrast medium and in pregnancy without renal failure [124,125] (LE: 3). Magnetic resonance imaging allows the evaluation of a dynamic enhancement without radiation exposure. Advanced MRI techniques such as diffusion-weighted (DWI) and perfusion-weighted imaging are being explored for renal mass assessment [126]. Recently, the use of multiparametric MRI (mpMRI) to diagnose ccRCC via a clear cell likelihood score (ccLS) in SRMs was reported [127]. The ccLS is a 5-tier classification that denotes the likelihood of a mass representing ccRCC, ranging from ‘very unlikely’ to ‘very likely’. The authors prospectively validated the diagnostic performance of ccLS in 57 patients with cT1a tumours and found a high diagnostic accuracy. The diagnostic performance of mpMRI-based ccLS was further validated in a larger retrospective cohort (n = 434) across all tumour sizes and stages [128], and ccLS was found to be an independent prognostic factor for identifying ccRCC.

For the diagnosis of complex renal cysts (Bosniak IIF–III) MRI may be preferable. The accuracy of CT is limited in these cases, with poor sensitivity (36%) and specificity (76%; κ = 0.11); MRI, due to a higher sensitivity for enhancement, showed a 71% sensitivity and 91% specificity (κ = 0.64). Contrast-enhanced US showed high sensitivity (100%) and specificity (97%), with a negative predictive value of 100% (κ = 0.95) [74].

In younger patients who are worried about the radiation exposure of frequent CT scans, MRI may be offered as alternative although only limited data exist correlating diagnostic radiation exposure to the development of secondary cancers [129].

A SR and meta-analysis [130] compared the diagnostic performance of CEUS vs. contrast-enhanced CT (CECT) and contrast-enhanced MRI (CEMRI) in the assessment of benign and malignant cystic and solid renal masses. Sixteen studies were included in the pooled analysis. The results suggested comparable diagnostic performance of CEUS compared with CECT (pooled sensitivity 0.96 [95% CI: 0.94-0.98], vs. 0.90 [95% CI: 0.86-0.93], for studies with a final diagnosis of benign or malignant renal masses by pathology), and CEUS vs. CEMRI (pooled sensitivity 0.98 [95% CI: 0.94-1.0], vs. 0.78 [95% CI: 0.66-0.91], for studies with final diagnosis by pathology report or reaffirmed diagnosis by follow-up imaging without pathology report). However, there were significant limitations in the data, including very few studies for CEMRI, clinical and statistical heterogeneity and inconsistency, and high risks of confounding.

5.2.3. Other investigations and emerging technologies

Renal arteriography and inferior venacavography have a limited role in the work-up of selected RCC patients (LE: 3). In patients with any sign of impaired renal function, an isotope renogram and total renal function evaluation should be considered to optimise treatment decision-making [105,106] (LE: 2a). 18FDG Positron-emission tomography (PET) is not recommended in primary staging. [117,131] (LE: 1b).

Emerging technologies for differentiation of RCC subtypes has a growing body of evidence with regard to prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-CT [132], ⁹⁹TC sestamibi SPECT/CT and ⁸⁹Zr-DFO-Girentuximab PET-CT [39,40,133]. Additionally some of these modalities are being evaluated for staging purposes [40]. Currently, the level of published evidence is not sufficient in terms of external validation to allow any guideline recommedation to be made.

5.2.4. Radiographic investigations to evaluate RCC metastases

Chest CT is accurate for chest staging [90,91,134-136] (LE: 3). Use of nomograms to calculate risk of lung metastases have been proposed based on tumour size, clinical stage and presence of systemic symptoms [137,138]. These are based on large, retrospective datasets, and suggest that chest CT may be omitted in patients with cT1a and cN0, and without systemic symptoms, anaemia or thrombocythemia, due to the low incidence of lung metastases (< 1%) in this group of patients. There is a consensus that most bone metastases are symptomatic at diagnosis; thus, routine bone imaging is not generally indicated [134,139,140] (LE: 3). However, bone scan, brain CT, or MRI may be used in the presence of specific clinical or laboratory signs and symptoms [139,141,142] (LE: 3). A prospective comparative blinded study involving 92 consecutive mRCC patients treated with first-line vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) (median follow-up 35 months) found that whole-body DWI/MRI detected a statistically significant higher number of bony metastases compared with conventional thoraco-abdomino-pelvic contrast-enhanced CT, with higher number of metastases being an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) [143].

The incidence of brain metastasis without neurological symptoms was retrospectively evaluated in 1,689 mRCC patients, selected to be included in 68 clinical trials between 2001-2013 [144]. All patients had a mandatory brain screening by CT/MRI. Seventy-two patients (4.3%) were diagnosed with occult brain metastases, of whom 39% multi-focal. Most patients (61%) were International Metastatic Renal Cancer Database Consortium (IMDC) intermediate risk and 26% were favourable risk. A majority (86%) of the patients had > 2 extracranial metastatic sites, including lung metastases in 92%. After predominantly radiotherapy, performed in 93% of patients, a median OS of 10.3 months (range 7.0–17.9 months) was observed.

5.2.5. Bosniak classification of renal cystic masses

This system classifies renal cysts into five categories, based on CT imaging appearance, to predict malignancy risk [145,146] (LE: 3), and also advocates treatment for each category (Table 5.1). An updated Bosniak classification (2019) strengthened the classification and included MRI diagnostic criteria [75]; however, it requires further validation. According to a Meta-analysis based on 471 patients, the risk of maliganacy of Bosniak IIF-III, may be higher than with the old classification [147]. Until further validation, the imaging report should therefore identify which classification has been used. Lastly, the management of cystic renal tumours is also discussed in Section 3.5.8.

Table 5.1: Bosniak classification of renal cysts updated 2019 [75]

5.3. Renal tumour biopsy

5.3.1. Indications and rationale

Percutaneous renal tumour biopsy can reveal histology of radiologically indeterminate renal masses and can be considered in patients who are candidates for AS of small masses, to obtain histology before ablative treatments, and to select the most suitable medical and surgical treatment strategy in the setting of metastatic disease [148-153] (LE: 3).

A multicentre study assessing 542 surgically removed SRMs showed that the likelihood of benign findings at pathology is significantly lower in centres where biopsies are performed (5% vs. 16%), suggesting that biopsies can reduce surgery for benign tumours and the potential for short-term and long-term morbidity associated with these procedures [154]. In a recent series of patients who underwent a percutaneous biopsy for a SRM, active treatment (surgery or cryotherapy) was avoided in 50/182 patients (27.5%) because of a benign diagnosis at biopsy [155].

Renal biopsy is not indicated in comorbid and frail patients who can be considered only for conservative management (watchful waiting) regardless of biopsy results. Due to the high diagnostic accuracy of abdominal imaging, renal tumour biopsy is not necessary in patients with a contrast-enhancing renal mass for whom surgery is planned (LE: 4).

Core biopsies of cystic renal masses have a lower diagnostic yield and accuracy and are not recommended, unless areas with a solid pattern are present (Bosniak IV cysts) [148,151,156] (LE: 2b/3). Histological characterisation by percutaneous biopsy of undefined retroperitoneal masses at imaging may be useful for decision making, especially in the younger patient population.

5.3.2. Technique

Percutaneous sampling can be performed under local anaesthesia with needle core biopsy and/or fine needle aspiration (FNA). Biopsies can be performed under US or CT guidance, with a similar diagnostic yield [151,157] (LE: 2b). Eighteen-gauge needles are ideal for core biopsies, as they result in low morbidity and provide sufficient tissue for diagnosis [148,152,158] (LE: 2b). A coaxial technique allowing multiple biopsies through a coaxial cannula should always be used to avoid potential tumour seeding [148,152] (LE: 3).

Core biopsies are preferred for the characterisation of solid renal masses while a combination with FNA can provide complimentary results and improve accuracy for complex cystic lesions [156,159,160] (LE: 2a). A SR and meta-analysis of the diagnostic performance and complications of renal tumour biopsy was performed by the Panel, including 57 publications and a total of 5,228 patients. Needle core biopsies were found to have better accuracy for the diagnosis of malignancy compared with FNA [156]. Other studies showed that solid pattern, larger tumour size and exophytic location are predictors of a diagnostic core biopsy [148,151,157] (LE: 2b).

5.3.3. Diagnostic yield and accuracy

In experienced centres, core biopsies have a high diagnostic yield, specificity, and sensitivity for the diagnosis of malignancy. The above-mentioned meta-analysis showed that sensitivity and specificity of diagnostic core biopsies for the diagnosis of malignancy are 99.1% and 99.7%, respectively [156] (LE: 2b). However, 0–22.6% of core biopsies are non-diagnostic (8% in the meta-analysis) [149-153,157,158,161] (LE: 2a). If a biopsy is non-diagnostic, and radiologic findings are suspicious for malignancy, a further biopsy or surgical exploration should be considered (LE: 4). Repeat biopsies have been reported to be diagnostic in a high proportion of cases (83–100%) [148,162-164].

Accuracy of renal tumour biopsies for the diagnosis of tumour histotype is good. The median concordance rate between tumour histotype on renal tumour biopsy and on the surgical specimen of the following PN or RN was 90.3% in the pooled analysis [156].

Assessment of tumour grade on core biopsies is challenging. In the pooled analysis the overall accuracy for nuclear grading was poor (62.5%), but significantly improved (87%) using a simplified two-tier system (high vs. low grade) [156] (LE: 2a).

The ideal number and location of core biopsies are not defined. However, at least two good quality cores should be obtained and necrotic areas should be avoided to maximise diagnostic yield [148,151,165,166] (LE: 2b). Peripheral biopsies are preferable for larger tumours, to avoid areas of central necrosis [167] (LE: 2b). In cT2 or greater renal masses, multiple core biopsies taken from at least four separate solid enhancing areas in the tumour were shown to achieve a higher diagnostic yield and a higher accuracy to identify sarcomatoid features, without increasing the complication rate [168].

5.3.4. Morbidity

Overall, percutaneous biopsies have a low morbidity [156]. Tumour seeding along the needle tract has been regarded as anecdotal in large series and pooled analyses on renal tumour biopsies. Especially the coaxial technique has been regarded as a safe method to avoid any seeding of tumour cells. However, authors recently reported on seven patients in whom tumour seeding was identified on histological examination of the resection specimen after surgical resection of RCC following diagnostic percutaneous biopsy [169]. Six of the seven cases were of the pRCC type. The clinical significance of these findings is still uncertain but only one of these patients developed local tumour recurrence at the site of the previous biopsy [169].

Spontaneously resolving subcapsular/perinephric haematomas are reported in 4.3% of cases in a pooled analysis, but clinically significant bleeding is unusual (0-1.4%; 0.7% in the pooled analysis) and generally self-limiting [156].

Percutaneous biopsy of renal hilar masses is technically feasible with a diagnostic yield similar to that of cortical masses, but with significantly higher post-procedural bleeding compared with cortical masses [170].

5.3.5. Genetic assessment

Renal cancer can be related to an inherited or de novo monogenic germline alteration and this recognition has significant implications [171]. Hereditary kidney cancer is thought to account for 5-8% of all kidney cancer cases, although this number is likely an underestimation since a more recent study found germline mutations in up to 38% of all metastatic kidney cancer patients [172] (see Section 3.4.4. - Hereditary kidney tumours). Patients with a germline predisposition to kidney cancer often require multidisciplinary approaches, it is critical for clinicians to be familiar with how and when referral for counselling is warranted, methods of genetic testing, implications of the findings, screening of at-risk (non-renal) organs, and the screening protocol for family members. Well-defined renal cancer management strategies exist, and specific therapeutic strategies are available or in development (see Section 3.4.4). Lack of a syndromic manifestation does not exclude a genetic contribution to cancer development. Moreover, other genetic components or polymorphisms are heritable and may confer a mildly increased risk. When several risk alleles are present, they can significantly increase cancer risk.

Many factors are associated with an increased risk of hereditary renal cancer syndromes. For instance, even in the absence of clinical manifestations and personal/family history, an age of onset of 46 years or younger should trigger consideration for genetic counselling/germline mutation testing [46]. Moreover, presence of bilateral or multifocal tumours/cysts and/or a first- or second-degree relative with RCC and/or a close blood relative with a known pathogenic variant significantly increases the risk to detect hereditary cancer. The presence of renal cysts can be associated with BHD and VHL, and form part of the clinical diagnostic spectrum. Moreover, specific histologic characteristics can support differential diagnosis of a particular RCC syndrome (e.g., multifocal papillary histology, hereditary fumarate hydratase-deficient RCC, RCC with fumarate hydratase deficiency, multiple chromophobe, oncocytoma or oncocytic hybrid, succinate dehydrogenase-deficient RCC histology). Finally, additional tuberous sclerosis complex criteria should be assessed in individuals with AML [46,173-181].

If additional risk factors are established in a patient, referral to a comprehensive clinical care centre, or a hospital with demonstrated expertise in managing hereditary cancer syndromes, will provide a dedicated working team, tailored clinical decisions, research translational programme, appropriate patient psychosocial support, and prospective collection of clinical data and biological samples. This can contribute to a better patient’s care and further improvements in cancer care.

5.4. Summary of evidence and recommendations for the diagnostic assessment of RCC

5.5. Summary of evidence and recommendations for genetic assessment of RCC