Renal Cell Carcinoma

Synonyms: RCC, hypernephroma, Grawitz tumour

It is the commonest of the tumours of the kidney in adults, accounting for 85% of renal cancers. In children, Wilms' tumour is the commonest. Benign tumours of the kidney are rare. Renal cell carcinomas arise from the proximal tubule cells. Its old name of hypernephroma reflects that it was believed to arise from adrenal gland.¹

Histological sub-types^1,2

Renal cell carcinoma comprises 70% of all renal tumours which can be broken down into:

• Clear cell (70%)
• Chromophil (eosinophil, basophil) (15%)
• Chromophobe (5%)
• Collecting duct carcinoma (2%)
• Renal oncocytoma (5%)

The other 3% comprise:

• Transitional cell carcinoma
• Wilms' tumour
• Angiomyolipoma- commonly seen in patients with tuberous sclerosis
• Leiyomyosarcoma
• Sarcoma
• Adenoma- frequently found as an incidental finding at post mortem, if diagnosed during life treated with partial nephrectomy due to histological similarity to adenocarcinoma

• Renal tumours account for approximately 2% of all malignancies.
• Males are more likely to be affected than females with a ratio of 2:1.
• More than 6,600 people are diagnosed with kidney cancer each year in the UK and there are around 3,600 deaths.^5,6
• The peak age of incidence for renal carcinoma is 60 to 80 years old.
• Several risk factors have been identified including smoking, obesity, hypertension, long term dialysis and Von Hippel-Lindau syndrome.
• Occupations associated with an increased risk include workers exposed to cadmium or asbestos and coke oven workers in the iron and steel industries.⁷
• Hereditary renal cancers tend to be multiple, bilateral and occur at an earlier age than others.⁸
• 2% of sporadic cases have bilateral tumours.
• In the UK there has been an increase of 22% over 10 years while in the USA there has been an increase of 50% in 30 years. There appear to be a number of factors and some are preventable, especially obesity.

Risk factors

Risk factors include increased age, male sex, smoking, obesity,⁹ long-term dialysis,¹⁰ and several genetic syndromes including familial clear cell carcinoma, von Hippel-Lindau syndrome, and tuberose sclerosis.¹¹ Exposure to asbestos, petroleum products and dry cleaning agents appears to increase the risk.¹² Cadmium and organic solvents are also implicated.¹³

• The classic triad of haematuria, loin pain and abdominal mass is seen less commonly today.
• More than 50% of adult renal tumours are detected when using ultrasound to investigate non-specific features.¹⁴ The most common of these are: hypertension, cachexia, weight loss, pyrexia, neuromyopathy, amyloidosis, elevated ESR, anaemia, abnormal LFTs, hypercalcaemia and polycythaemia.⁴
• Other presentations include pyrexia of unknown origin and hypertension.
• Other symptoms can include fatigue and peripheral oedema.
• There is often no abnormality on examination.
• 25 to 30% of patients present with symptoms of metastatic disease.
• It may present with metastases in the form of haemoptysis, bone pain or pathological fracture.
• Only 10% present with the classic triad of haematuria, loin pain and a mass.

The differential diagnosis will depend upon the presentation. There are articles on abdominal mass, loin pain and gross haematuria that will discuss the various causes.

There are other histological types of renal tumours and this has influence on prognosis.²

• Urinalysis, cytology, culture and sensitivity should be performed to exclude urinary tract infection.
• U&E and creatinine should be arranged to assess renal function (but if one kidney is functioning well it should be normal).
• Full blood count may detect iron deficiency anaemia (from haematuria) or polycythaemia (some renal tumours produce renin and increase haematocrit).
• Renal ultrasound is the best initial imaging technique. If a solid tumour is found, CT scanning with contrast should then be arranged. MRI can be useful to assess spread and for staging.¹⁵
• Intravenous urogram (IVU) may be needed, especially to show any obstruction to flow. IVU is not a good way to search for a clear cell carcinoma.
• CT or MRI scan should be reserved for assessment of locally invasive disease, possible venous involvement, renal insufficiency or allergy to intravenous contrast.⁴ Helical CT is used to assess patients on long-term dialysis as they are at risk of developing the disease.
• Cystoscopy can exclude bladder tumours as a cause of haematuria.¹⁶
• Renal angiography may possibly be required to assess the blood supply.
• Chest x-ray- classical cannon ball secondaries may be seen in the lung. They are discrete circular metastases. Chest CT is more sensitive.
• Skeletal survey may be required for bone metastases.

• Spread is into adjacent structures of the adrenal glands, liver, spleen, colon or pancreas. Local lymph nodes are often involved.
• It may extend into the renal vein and then into the inferior vena cava.
• The lungs are the commonest site of metastases. The classical picture of cannon ball secondaries is almost diagnostic.
• It is one of the carcinomas to metastasise to bone where it produces osteolytic lesions.

The current consensus is to use the TNM 2002 system as recommended by the European Guidelines.⁴

Localised disease

• Surgery is the basis of treatment, with or without radiotherapy and/or chemotherapy depending on the stage of the tumour. Radical nephrectomy that includes the removal of the tumour-bearing kidney remains the gold standard curative therapy for patients with localised renal cell carcinoma and offers a reasonable chance of curing the disease.
• In selected cases with lymph node disease limited to the retroperitoneal space, extended lymphadenectomy might improve a patient’s clinical prognosis.
• Nephron-sparing surgery should be considered for patients with a localised tumour less than 4cm in diameter, an anatomical or functional solitary kidney, and patients with a contralateral kidney affected by a condition that might impair renal function in future. It involves partial nephrectomy with preservation of as much functioning kidney tissue as possible.
• Laparoscopic surgery may be involved and NICE has reported on both laparoscopic nephrectomy and laparoscopic partial nephrectomy.^17,18 These should be limited to centres with appropriate expertise.
• Minimally-invasive surgery (e.g. image-guided percutaneous radiofrequency (RF) ablation,
  cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound ablation) are being investigated for patients not suitable for open or laparoscopic surgery with smaller peripheral tumours.
• Indications for tumour embolisation include patients with gross haematuria who are not fit for surgical intervention and prior to surgical resection of large paravertebral metastases. There is no benefit in performing tumour embolisation before routine radical nephrectomy.
• The adrenal gland can usually be spared, except in the case of large upper pole tumour in which there is a high risk of adrenal invasion.
• Solitary metastases, usually in the lung, can occasionally be resected.

Metastatic disease

• Tumour nephrectomy is recommended in otherwise fit patients with metastatic disease, combined with IFN-alpha.
• Metastasectomy is recommended where disease is resectable in otherwise fit patients. It should also be performed in patients with residual and resectable metastatic lesions previously responding to immunotherapy and/or a limited (solitary) lesion.
• Radiotherapy for the treatment of brain metastases (whole brain irradiation or stereotactic
• approach) and osseous lesions may be helpful as palliative therapy in selected patients.
• Immunotherapy - Interferon-alpha (INF-alpha) or interleukin 2 (ILN-2) can be considered in selected patients with a clear cell subtype histology. The addition of chemotherapy does not seem to improve survival rate.
• New developments - recent advances in molecular biology have led to the development of novel approaches to management of widespread metastatic disease including:
  • Sunitinib - advised as first-line therapy in good and intermediate risk patients
  • Sorafenib - advised as a second-line treatment
  • Temsirolimus - advised as first-line treatment in poor-risk patients

Paraneoplastic syndromes may develop:

• Polycythaemia due to erythropoietin production
• Hypercalcaemia due to production of a parathormone-like hormone

• Four factors influence prognosis:
  • Anatomical - these are gathered together in the TNM 2002 staging classification system.
  • Histological - these include the Fuhrman nuclear grade, histological subtype, presence of sarcomatoid features, microvascular invasion, tumour necrosis and collecting system invasion.^1,19
  • Clinical - this depends on the presence of paraneoplastic syndromes (see above).
  • Molecular - several molecular markers are being investigated but are not yet in widespread clinical use.
• The prognosis is worst for patients with metastases at presentation and best for patients with small tumours confined to the kidney.
• Large lesions tend to be higher grade and to metastasise more frequently. Poorly marginated or necrotic lesions also tend to be of higher grade.
• Inoperable carcinomas have a 5-year survival rate of less than 2%.
• The overall 5 year survival rate for renal carcinoma is now nearly 60%, but actual survival depends on the stage of the disease at diagnosis and the grade of the tumour cells.
• Young people tend to do better. Patients with stage 1 disease at diagnosis have a 5 year survival rate of 94%, whereas patients with distant metastases at the time of diagnosis have a five year survival rate of less than 5%.
• If renal cell carcinoma recurs, it is usually within 2 years after surgery, with the lung being the commonest site. Larger tumour diameter, T stage, stage group, and nuclear grade are important factors for recurrence.²⁰

• Cigarette smoking remains the major culprit but the incidence of smoking is not rising in parallel with the number of cases of renal cell carcinoma.
• Obesity is increasing in Europe and the USA. Morbid obesity doubles the risk. People who are overweight, but not obese, are 35% more likely to develop it. One study in the European Union attributed 25% of all kidney cancers to being overweight.²¹