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 

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