Renal Cell Carcinoma
Written by Esther Yuk Lim Yap
Last Reviewed: September 2019
Review Due: September 2020
DEFINITION1-3
Based on the 2016 WHO classification, there are three main histological subtypes:
Clear cell (majority of RCCs, 75-85%)
Papillary (Type 1 and Type 2, 10-15%)
Chromophobe (5-10%)
Both clear cell and papillary RCCs originate from the proximal tubules whereas chromophobe RCCs originate from the intercalated cells in the collecting system.
AETIOLOGY1,4
Advanced age
Incidence peaking between 60-70 years old
Gender
Male predominance of 1.5:1
Positive family history
Especially in 1st-degree relatives
Lifestyle risk factors
Smoking (best-established risk factor) and obesity (risk increases with an increase in BMI)
Hypertension
2.5 times increased risk of RCC if systolic BP > 160mmHg
Genetic mutations
e.g., Von Hippel Lindau (VHL) gene mutation in clear cell RCC, MET gene mutation in papillary RCC, and chromosomal loss in chromophobe RCC
SIGNS AND SYMPTOMS2,5
Patients can be asymptomatic with renal masses, however with advances in non-invasive imaging, over half of RCCs present as incidental findings.
Haematuria
Collecting system infiltration can result in clot formation (significant bleeding) with colic
Palpable mass
Felt in the abdomen or flank, usually more obvious in thinner individuals
[The classic triad of frank haematuria, flank pain and an abdominal mass is strongly indicative of advanced disease and only occurs in 6-10% of RCCs]
Irreducible scrotal varicoceles
Involvement of the gonadal vein
​
Bilateral lower limb oedema, ascites and liver function abnormalities
IVC invasion
Paraneoplastic syndrome
Occurs in 1/3 of patients due to secretion of ectopic hormones, resulting in clinical consequences of hypertension (renin production), polycythaemia (erythropoietin production), and hypercalcaemia (PTHrP production)
PATHOPHYSIOLOGY1,3
Pathogenesis of RCC remains poorly understood but multiple theories exist for different histology patterns.
For clear cell RCCs, the typical abnormality is chromosomal 3p deletion. This segment contains genes such as VHL, BAP-1 and PBRM1 genes. VHL and PBRM1 gene products are tumour suppressors whereas the BAP1 gene plays a role in the ubiquitin-mediated proteolysis pathway. In sporadic clear cell RCC, two-thirds of patients present with VHL gene alterations.
For papillary RCCs, MET genetic mutations and chromosome 7 duplication occurs in the majority of Type 1 subtypes. Fumarate hydratase (FH) genetic mutations occur in Type 2 papillary RCC.
For chromophobe RCCs, a study reveals a combination of chromosomal loss such as 1, 2, 6, 10 etc.
Investigations
laboratory1-5
Full blood count
Red blood cell count (RBC), haemoglobin (Hb)
Anaemia of chronic disease (Hb) or erythrocytosis (RBC) - secondary to EPO production
Urea and electrolytes – serum creatinine (Cr)
Increased creatinine - prior to or as a result of RCC
Serum lactate dehydrogenase (LDH)
Elevated in advanced disease
Serum corrected calcium
Elevated in advanced disease
Glomerular filtration rate (GFR)
Baseline kidney function
imaging1,2,4
Renal ultrasound
Screening tool to differentiate between solid and cystic masses
​
Computed tomography (CT) of abdomen and pelvis
Definitive imaging modality to detect enhancement of malignant lesions post-intravenous contrast administration. Provides information on tumour size, lymph node status and lung metastases for staging.
​
Magnetic resonance imaging
additional test to further explore the extension of a tumour thrombus in the IVC
Histology4
Percutaneous biopsy of renal tumour
Biopsy of renal tumour – performed in potential candidates for systemic therapy in the setting of advanced disease. Also reserved for unclassified lesions or small masses in which ablation or active surveillance is considered
Prognosis
Anatomical factors
Tumour, Node, Metastasis (TNM) staging – advanced staging correlates with worse prognosis
Histological factors
RCC subtype – worst prognosis in clear cell RCC
Fuhrman nuclear grade – independent predictor of poor outcomes
Sarcomatoid changes – associated with aggressive, high-grade RCCs
Presence of tumour necrosis
Microvascular and collecting system invasion
Clinical factors
Co-morbidities
Cachexia
Laboratory parameters (presence of anaemia, neutrophil-lymphocyte ratio, platelet count, CRP and albumin)
The 5-year survival rate after successful resection is around 50%, however, metastases may present many years after nephrectomy.
Features of perinephric and lymphatic invasion are associated with a poor prognosis.
treatment4
Treatment for patients with RCC are stratified based on TNM staging (T1 and T2 vs. T3, T4 and metastatic disease)
For localised disease (T1-T2), radical nephrectomy (open or laparoscopic) is preferred. Nephron-sparing surgery can be considered if there is a risk of impaired kidney function.
Ablative techniques are usually reserved for non-surgical candidates (e.g., frail elderly patients) or for those with a solitary kidney.
For locally advanced (T3-T4) disease, radical nephrectomy with the objective of total excision is the first-line treatment. Patients suitable for adjuvant treatment with systemic therapy should be referred appropriately to tertiary centres.
For metastatic disease, options include:
Cytoreductive nephrectomy
For patients with good performance status 4
Adjuvant immunotherapy
(IL-2, IFN-α) for those at high risk of relapse post nephrectomy
Metastasectomy
Systemic therapy
Such as VEGF inhibitors (sunitinib, pazopanib) for patients unsuitable for surgery
For patients palliative care, palliative nephrectomy and tumour embolisation can be performed for symptomatic relief.
EPIDEMIOLOGY1
-
Accounts for 2-3% of all cancers and 85% of primary renal cancers
-
Highest incidence in developed Western countries such as North America (baseline risk of 1 in 10000) and Europe
REFERENCES
1. Shah AY. Renal cell carcinoma. 2017 Nov [reviewed 2019 July; cited 2019 Aug 18]. In: BMJ Best Practice [Internet]. London: BMJ Publishing Group Ltd. c2019 -. 71p.
2. Ljungberg B, Albiges L, Bensalah K, Bex A, Giles RH, Hora M et al. Guidelines on renal cell carcinoma. European Association of Urology, 2019.
3. Atkins MB, Choueiri TK. Epidemiology, pathology, and pathogenesis of renal cell carcinoma. 2019 Mar 5. [reviewed 2019 Jul; cited 2019 Aug 18]. In: UpToDate [Internet]. Waltham (MA): UpToDate, Inc. c2019
4. British Association of Urological Surgeons (BAUS): Section of Oncology, British Uro-oncology Group (BUG). Multi-disciplinary Team (MDT) Guidance for Managing Renal Cancer [Internet]. 2012 May [cited 2019 Aug 18]. 57p.
5. Atkins MB. Clinical manifestations, evaluation, and staging of renal cell carcinoma. 2018 Nov 13. [reviewed 2019 Jul; cited 2019 Aug 18]. In: UpToDate [Internet]. Waltham (MA): UpToDate, Inc. c2019