Renal cell carcinoma

Renal cell carcinoma (RCC) is the most common histological type of renal cancer in adults, accounting for 80+%. It's a malignant epithelial tumor that arises from the kidney tubules. It's usually discovered incidentally. When symptomatic, it usually presents with a classic triad of haematuria (with normal and not dysmorphic RBCs), costovertebral pain and/or a palpable mass in the flank.

It's a relatively rare malignancy, with an incidence of 15/100 000 new cases every year. It's mostly a disease of elderly men. Most are diagnosed with localised disease. Up to 70% of cases are incidentally diagnosed on imaging.

Malignancy of the renal pelvis is usually urothelial carcinoma and is therefore more similar to bladder cancer. It is not considered a renal cancer.

Risk factors

It's usually idiopathic, bue some risk factors are known:

• Smoking
• Cystic diseases of the kidney (polycystic kidney disease)
• Obesity
• Hypertension

Pathology

Renal cell carcinomas are adenocarcinomas which arise from the tubular epithelium. The most common types are clear cell carcinoma (80%+ of cases) and papillary carcinoma (10% of cases). Other types include:

• Chromophobe RCC – 5% of cases
• Cystic RCC – 2.5% of cases
• Collecting duct RCC – 1% of cases

Clear cell RCC gets its name from the clear cytoplasm of the tumor cells that is visible on histology. This is due to the tumor cells’ high fat content, which also makes the tumor yellow on macroscopy. Clear cell RCC can have capsule and be well-demarcated, so it can mimic the morphology of a benign tumor. It typically occurs in the lower pole. Clear cell RCC has worse prognosis than the next two subtypes.

Loss of the tumor suppressor VHL on chromosome 3p25 is involved in clear cell RCC, either sporadic or hereditary as is the case in von Hippel-Lindau disease. 50% of people with this disease develop clear cell RCC. VHL-disease related clear cell RCC usually occurs as multiple and bilateral tumors.

Papillary RCC gets its name from the papillary growth pattern it shows. These tumors appear in multiple foci and bilaterally. The MET proto-oncogene on chromosome 7q31 is associated with papillary RCC, both in hereditary and sporadic forms.

Chromophobe RCC gets its name from the chromophobe histology, i.e. the tumor cells stain darkly. The tumor cells have usually lost multiple chromosomes, making them hypoploid. This type has good prognosis.

Cystic RCC is a rare type of RCC that is commonly misdiagnosed as a benign renal cyst. It has an excellent prognosis after surgical removal.

Collecting duct RCC is a very rare subtype. It’s very aggressive and has a particularly bad prognosis.

Grading

The Furhman system is used as grading system for kidney tumors. It’s based mostly on how prominent the nucleoli are – the more prominent, the higher the grade. A grade IV RCC has sarcomatoid or rhabdoid appearance.

Metastasis

As RCC commonly grows to the renal vein and IVC is metastasis to the lungs and bone most frequent. The tumor grows as a solid column inside the renal vein, sometimes extending as far as the IVC or the heart. As for lymph nodes it first spreads to retroperitoneal lymph nodes.

RCC can also cause a left-sided varicocele, a pathological dilation of the venous plexus of the scrotum. This tumor commonly spreads locally to the renal vein, where it can block the point the left testicular vein drains into the renal vein. This blockage causes pressure to build up in the venous plexus of the scrotum which may be felt as a soft lump.

Paraneoplastic syndromes

RCC can cause various paraneoplastic syndromes:

• Hypertension – as it can produce renin
• Hypercalcaemia – as it can produce parathyroid hormone-related protein (PTHrP)
• Polycythaemia – as it can produce EPO
• Secondary hypercortisolism (Cushing syndrome) – as it can produce ACTH
• Anaemia

Clinical features

Renal cell carcinoma may be asymptomatic in the initial stages, causing it to mostly be found incidentally. Up to 25% of cases already have distant metastases at diagnosis.

When symptomatic, renal cell carcinoma has a typical triad of symptoms:

• Haematuria (with normal and not dysmorphic RBCs)
• Costovertebral pain
• Palpable mass in the flank

..., however it's rare for RCC to present with the triad. It may also cause non-specific symptoms like fever and weight loss.

Diagnosis and evaluation

Non-dysmorphic haematuria, is usually present. There are no specific tumour markers.

Imaging

CT with contrast is required to make the diagnosis, but ultrasound is sometimes the first imaging modality used. Ultrasound may show an expanding hyperechoic or hypoechoic process. On CT renal cell carcinoma is visible as the tumour enhances with contrast. Invasion of the renal vein is common. Following the diagnosis, CT of the thorax should be made to look for metastasis.

Staging

The TNM staging of kidney tumors depend on the size, renal vein involvement and local invasion. 7 cm in size is the border between T1 and T2 tumours. Kidney tumors commonly infiltrate the fatty capsule and when they do they are T3. If they infiltrate beyond the renal fascia (Gerota fascia) the cancer is considered T4 and therefore inoperable.

Biopsy

Biopsi is often indicated, but is not necessary if the imaging findings are very typical for malignancy. If imaging cannot rule out benign tumour, biopsy is indicated.

Management

The main treatment for non-metastatic disease is surgical removal or resection of the kidney. Adjuvant therapy is not recommended. Some may be monitored with active surveillance. For metastatic disease, targeted therapy and immunotherapy are indicated. Complete metastasectomy may improve survival.

Surgical treatment

Nephron-sparing surgery refers to partial nephrectomy and is recommended over radical nephrectomy if the conditions allow for it, usually if the tumour is < 4 cm. Partial nephrectomy preserves kidney function and is especially useful when the patient only has one kidney or there are bilateral tumours.

For T2-T4 tumours, radical nephrectomy is indicated.

Cytoreductive nephrectomy refers to radical or partial nephrectomy in the setting of metastatic disease. The intention is to remove as many tumour cells as possible. In some cases, it may lead to regression of metastases.

Nephrectomy may also be performed palliatively, for example in case of paraneoplastic syndromes.

If there is metastatic disease but the metastases are available for surgical removal, studies have shown a survival benefit for complete metastasectomy. This should be considered in patients with metastatic disease.

Thermal ablation

Thermal ablation is an alternativ to partial nephrectomy for small tumours (< 3 cm). It involves destroying the tumour with heat, radiowaves, or cold.

Radiotherapy

Radiotherapy may be used palliatively for metastatic disease, especially for painful skeletal metastases

Active surveillance

Active surveillance, meaning regular follow-up with imaging to look for progression and initiating curative treatment if progression occurs, is an option for small tumours, as these rarely metastasise. This should especially be considered for elderly.

Watchful waiting

Watchful waiting refers to performing no surveillance but rather doing nothing and waiting until symptoms appear or become unbearable, at which point one can consider palliative treatment. This is especially useful for those who would not tolerate intensive cancer treatment.

Immunotherapy

Immune checkpoint inhibitors have revolutionised treatment of metastastic RCC. They are sometimes combined with tyrisone kinase inhibitors for metastatic disease. Commonly used drugs are anti-PD-1 and anti-CTLA-4 antibodies.

Targeted therapy

Targeted therapy may be combined with immune checkpoint inhibitors for palliative therapy of metastatic RCC. These are tyrosine kinase inhibitors like cabozanitinib, sunitinib, or lenvatinib.