Renal Cell Carcinoma

Renal cell carcinoma, most common in older males with a history of smoking, is the most common primary malignancy of the kidney characterised by clear or granular cells and often presents as a solid enhancing mass in the upper pole.

Description

Renal cell carcinoma (RCC) is a type of kidney cancer that originates in the lining of the proximal convoluted tubule, which is part of the kidney’s very small tubes that transport waste molecules from the blood to the urine. It is the most common type of kidney cancer in adults, accounting for approximately 90-95% of cases. RCC can grow to substantial sizes within the retroperitoneum before causing symptoms, allowing the tumour to remain undetected until it becomes significantly large.¹

Pathogenesis

RCC arises from the renal parenchyma, and a number of different subtypes have been identified based on histological features. These include:

• Clear Cell: Most common and aggressive subtype (70-75% of RCCs). It is characterised by cells that appear clear or pale in colour when viewed under a microscope, a feature attributable to their high lipid and glycogen content. Associated with von Hippel-Lindau disease.
• Papillary: 10-15% of RCCs. Papillary RCC is further divided into type 1 and type 2, with differing histological and genetic features. Often seen bilaterally/multifocally. Associated with chronic haemodialysis and renal transplant.
• Chromophobe: 5% of RCCs. The cells of chromophobe RCC have certain characteristic features, including a distinct cell border and a pale, reticular cytoplasm. It arises from the intercalated cells of the ducts (similar to oncocytomas, hence its histological resemblance). Good prognosis. Associated with Birt-Hogg-Dube syndrome.
• Collecting Duct, Renal Medullary Carcinoma, and Sarcomatoid: These are less common forms of RCC, each accounting for less than 1% of cases. They have distinct histological features and often a more aggressive clinical course. Renal medullary carcinoma is associated with sickle cell trait and sickle cell disease.²

Epidemiology, Risk Factors and Associations

• RCC typically presents in adults aged 50-70 years, with a higher prevalence in males.
• The strongest risk factor is tobacco smoking.
• Other major risk factors include obesity, hypertension, chronic kidney disease and kidney transplant.
• There’s also an increased risk in individuals with certain inherited syndromes:
  • von Hippel-Lindau disease – 50-70% of patients will develop renal cysts as well as bilateral multicentric renal cell carcinoma (typically clear cell subtype).
  • Hereditary papillary renal carcinoma – autosomal dominant, mutations in the MET proto-oncogene causing multiple bilateral papillary tumours.
  • Birt-Hogg-Dube syndrome – Autosomal dominant, mutations of the BHD gene encoding folliculin, constellation of skin (fibrofolliculomas, trichodiscomas and acrochordons), pulmonary (cysts or blebs), and renal tumours
  • Tuberous sclerosis

Clinical Features

The classic triad of symptoms in RCC is haematuria, flank pain, and a palpable abdominal mass (seen late in the disease and is relatively uncommon).

Paraneoplastic syndromes include:

• Polycythaemia due to excessive erythropoietin production.
• Hypertension due to renin secretion
• Hyperparathyroidism due to secretion of parathyroid hormone-like substances, causing hypercalcaemia

Non-specific symptoms may include:

• Weight loss, fever, hypertension, and night sweats.

Complications

• Local invasion: RCC can locally invade surrounding structures, including the renal vein, inferior vena cava, and perinephric fat. This can lead to hematuria, pain, and increased risk of surgical complications during nephrectomy.
• Metastasis: Common sites include the lungs, bones, liver, brain, and adrenal glands. Approximately 30-40% of RCC patients present with metastasis at diagnosis, significantly worsening the prognosis and often requiring systemic therapy.
• Paraneoplastic syndromes seen in 25% cases (in order of prevalence):
  • Hypercalcaemia (due to parathyroid hormone-related protein (PTHrP) production)
  • Hypertension (due to renin secretion)
  • Polycythaemia (caused by erythropoietin production)
  • Stauffer Syndrome (hepatic dysfunction characterised by abnormal liver function tests and hepatomegaly, not due to hepatic metastasis).
  • Limbic encephalitis
• Vascular Complications: Tumour thrombus can extend into the inferior vena cava (IVC), leading to IVC obstruction, lower extremity edema, and increased risk of pulmonary embolism.
• Bone Metastasis: Bone metastases can cause severe pain, pathological fractures, and spinal cord compression, often requiring a combination of surgery, radiation, and systemic therapies.
• Pulmonary Complications: Lung metastasis can lead to symptoms like cough, hemoptysis, and respiratory distress, while pleural effusion may develop secondary to metastatic spread or direct extension into the pleura.
• Neurological Complications: Brain metastasis can cause headaches, seizures, and neurological deficits, while spinal cord compression due to vertebral metastases can lead to pain, weakness, and potential paralysis.
• Renal Failure: Advanced RCC can lead to loss of renal function, either due to direct tumour burden or nephrectomy, potentially necessitating dialysis or kidney transplantation.
• Haemorrhage: Intratumoral haemorrhage can cause significant pain and drop in hematocrit levels, while severe retroperitoneal haemorrhage can be life-threatening.
• Infection: Necrosis within the tumour can lead to secondary infection, resulting in abscess formation and sepsis, often requiring antibiotics and sometimes surgical drainage.

Pathological Features

• Clear cell RCC is characterised by clear, round cells with a distinct cell membrane, arranged in nests or acini.
• Papillary RCC is marked by the growth of cells in a papillary or tubulopapillary architecture.
• Chromophobe RCC is characterised by large pale cells with prominent cell borders.

Histopathology

• Macroscopic
  • Clear Cell RCC: Expansive, arising from the cortex. Typically solitary, large, spherical (ball-type) often golden yellow due to lipid content, with frequent areas of necrosis and haemorrhage.
  • Papillary RCC: These tumours usually appear as multifocal, bilateral masses with a whitish cut surface.
  • Chromophobe RCC: They are typically large, homogeneous, well-circumscribed tumours with a light brown appearance.
  • Collecting Duct RCC and Renal Medullary Carcinoma: These tumours are usually grey-white and staghorn-shaped.
• Microscopic
  • Clear Cell RCC: Characterised by nests or sheets of cells with clear or eosinophilic cytoplasm, separated by a thin vascular network.
  • Papillary RCC: These tumours consist of papillae and tubules covered by small cells with scanty cytoplasm and a large nucleus.
  • Chromophobe RCC: The cells have clear, reticulated cytoplasm, perinuclear halos, and wrinkled nuclear membranes.
  • Collecting Duct RCC: Characterised by a tubulocystic pattern, with cells demonstrating high-grade nuclear features.
  • Renal Medullary Carcinoma: Characterised by a reticular or yolk sac-like pattern, with irregular large cells having prominent nucleoli.

Serology

• Clear Cell RCC: Often associated with increased production of erythropoietin and parathyroid hormone-related protein (PTHrP).
• Papillary RCC: Raised levels of serum amyloid A and C-reactive protein (CRP) can sometimes be detected.
• Chromophobe RCC: No specific serological markers known.
• Collecting Duct RCC and Renal Medullary Carcinoma: No specific serological markers known.

Genetics

• Clear Cell RCC: Characterised by mutations in the VHL (von Hippel-Lindau) gene, leading to increased angiogenesis.
• Papillary RCC: Frequently associated with MET gene mutations (type 1) or fumarate hydratase (FH) gene mutations (type 2).
• Chromophobe RCC: Characterised by multiple chromosomal losses and extreme hypodiploidy.
• Collecting Duct RCC: Associated with mutations in the SMARCB1 gene.
• Renal Medullary Carcinoma: Typically associated with sickle cell trait and loss of SMARCB1/INI1 expression.

Radiological Features

General Features

• Size of the tumour (> 3 cm) is the most important predictor of metastatic risk. < 3 cm
• RCC typically do not contain extracellular fat, however 80% of clear cell RCC have intracellular fat (i.e. seen on opposed-phase imaging)
• Bilateral or multifocal clear cell RCC suggests von Hippel-Lindau disease
• In a minority of clear cell RCC, infiltrative (aggressive and hypervascular) growth pattern may seen, preserving the renal contour but causing internal architecture distortion of the kidney mimicking transitional cell carcinoma
• Cystic RCC is rare: Clear cell is the most common subtype, followed by papillary and chromophobe RCC. Multilocular cystic RCC is of low malignant potential
• Cannonball metastases to the lung (one of the more common causes)
• Metastases to the bone are lytic
• Fat-containing RCC usually also contains calcifications

US

• Typically present as solid and hypoechoic masses compared to the renal cortex on ultrasound.
• Larger tumours may appear heterogeneous due to areas of necrosis, haemorrhage, or cystic degeneration.
• Colour Doppler may show increased vascularity in the tumour.

CT

• Non-contrast: RCCs are typically iso- to hyperdense (20 – 70 HU) compared to the normal renal parenchyma. Calcification may be seen. Larger lesions may be centrally necrotic. Bones metastases are lytic.
• Post-contrast:
  • Corticomedullary phase (25 – 70 secs) – Variable enhancement
  • Nephrographic phase (80 – 180 secs, most sensitive phase) – Usually washes out.
  • Excretory phase – Mainly for assessing collecting system anatomy for partial nephrectomy candidacy.
  • The tumour can appear heterogeneous with areas of necrosis or haemorrhage.
  • Clear cell RCC may enhance similarly with background renal parenchyma on corticomedullary phase, potentially obscuring it. It appears hypoattenuating on nephrographic phase.
• CT can also identify lymphadenopathy, venous invasion (renal vein or inferior vena cava), or distant metastases. RCC causes hypervascular metastases (therefore best appreciated on arterial phase imaging)
  • Extent of tumour invasion into the renal vein/IVC has implications on staging and surgery. Depending on level of thrombus, either an abdominothoracic incision or cardiac bypass may be needed

MRI

• T1: Usually low to intermediate signal intensity. Heterogenity suggests necrosis, haemorrhage and solid components.
• T2: Depends on histology:
  • Clear cell RCC: Hyperintense (high lipid and glycogen content)
  • Papillary RCC: Hypointense (papillary architecture, fibrous stroma, and iron/haemosiderin deposition)
• Gd+: Shows enhancement, particularly in the arterial phase. Enhancement of thrombus suggests tumour thombrus (rather than bland thrombus)
• DWI: Useful for differentiating RCC from benign lesions and for predicting the histologic grade of the tumour.

NM

• PET/CT: While not commonly used for primary diagnosis or staging, Fluorodeoxyglucose (FDG) PET/CT can be helpful in identifying metastatic disease, particularly when other imaging studies are inconclusive. RCC is typically colder than surrounding renal parenchyma on PET.

DSA

• Irregular, disorganised tumour neovascularity and contrast pooling

Staging & Grading

Tumour

• T1: Tumour is ≤7 cm and confined to the kidney.
  • T1a: Tumour is ≤4 cm.
  • T1b: Tumour is 4–7 cm.
• T2: Tumour is >7 cm and confined to the kidney.
  • T2a: Tumour is 7–10 cm.
  • T2b: Tumour is >10 cm.
• T3: Tumour extends into major veins or perinephric tissues, but not beyond Gerota’s fascia.
  • T3a: Tumour invades adrenal gland or perinephric tissues.
  • T3b: Tumour extends into the renal vein or vena cava below the diaphragm.
  • T3c: Tumour extends into the vena cava above the diaphragm.
• T4: Tumour invades beyond Gerota’s fascia.

Node

• N0: No regional lymph node involvement.
• N1: Involvement of a single regional lymph node.
• N2: Involvement of multiple regional lymph nodes.

Metastasis

• M0: No distant metastasis.
• M1: Presence of distant metastasis.

Differential Diagnosis

Imaging-based

See differential approach to Renal Masses.

• Oncocytoma – Enhancing renal mass with central scar, therefore difficult to differentiate from RCC on imaging alone, though typically more avid on PET. Association with Birt-Hogg-Dube syndrome. Vascular invasion and adenopathy exclude oncocytoma.
• Angiomyolipoma – Combination of fat and calcification favours RCC over AML.
• Renal Lymphoma – Manifests as a solitary renal mass, multifocal/bilateral renal masses, perinephric masses, or diffuse nephromegaly. Mass tends to preserve reniform morphology of kidney. Associated lymphadenopathy.
• Urothelial carcinoma of the renal pelvis – Typically hypoenhancing, ill-defined, infiltrative and centrally located in the kidney, maintaining the reniform shape (vs. cortical location, well-defined, often hyperenhancing mass which distorts the renal contour). Treated with nephrouretectomy (vs. partial or radial nephrectomy).
• Metastatic disease to the kidney from other primary cancers.
• Renal abscess or complex cyst.

Management

Treatment of RCC depends on the stage of the disease, the patient’s overall health, and the presence of any genetic syndromes. Options include:

• Surgery: This is the mainstay of treatment for localised RCC. Surgical options include radical nephrectomy (removal of the entire kidney), simple nephrectomy (removal of just the tumour and some surrounding tissue), and partial nephrectomy.
• Targeted Therapy: These are drugs that specifically target the changes in cells that cause them to become cancerous. They are often used in metastatic RCC.
• Immunotherapy: This involves using drugs to stimulate the body’s immune system to fight cancer cells. This can be used in the treatment of advanced RCC.
• Radiation therapy: While RCC is generally resistant to radiation, it can be used for palliation in metastatic disease.
• Ablative techniques: Procedures such as cryoablation or radiofrequency ablation can be used for small tumours or in patients who are not candidates for surgery.

References

1. Quaia, E., et al. (2020). Diagnostics and prognostic evaluation in renal cell tumors: the German S3 guidelines recommendations. World Journal of Urology. ↩︎
2. Swartz, M.A., Karth, J., Schneider, D.T., et al. (2002). Renal medullary carcinoma: clinical, pathologic, and genetic features. Cancer, 94(12), 3279-3286 ↩︎