Renal cancer

Key clinical points

Introduction

Epidemiology

Aetiology

Differential diagnosis

Key clinical points

NICE cancer referral guidelines for renal cancer suggest the following:

Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for renal cancer if they are aged 45 and over and have:
unexplained visible haematuria without urinary tract infection or
visible haematuria that persists or recurs after successful treatment of urinary tract infection.

Introduction

Renal (kidney) cancer is the 7th most common cancer in men, and the 10th most common in women. Malignancy can arise from the renal parenchyma/cortex, but also from the urothelial cells of the renal pelvis. Renal cell carcinoma (RCC) accounts for >80% of all kidney cancers.

The typical presentation is with a triad of haematuria, loin pain, and a palpable abdominal mass. However, the majority of RCCs are detected incidentally on ultrasound or CT imaging.

Management of early tumours is with surgery, whilst systemic treatment with VEGF inhibitors and/or immunotherapy is used for metastatic disease.

The overall 5-year survival for RCC is >68% however this depends largely on stage at diagnosis, as well as on key prognostic factors.

Epidemiology

Incidence: 21.00 cases per 100,000 person-years
Peak incidence: 60-70 years
Sex ratio: more common in males 1.7:1

Condition	Relative incidence
Renal cancer	1
Bladder cancer	0.81





















<1	1-5	6+	16+	30+	40+	50+	60+	70+	80+

Aetiology

Important risk factors for RCC include:

Cigarette smoking
Obesity
Hypertension

RCC is also more common in patients:

With end-stage renal failure
On dialysis
Post-kidney transplantation
With tuberous sclerosis

Around 3% of all RCCs are and several autosomal dominant syndromes have been described - von Hippel–Lindau (VHL) disease being the most common.

Evidence is accumulating to suggest a protective role for additional factors such as trichloroethylene and caffeine.

Pathophysiology

There are several subtypes of RCC, associated with distinct cytogenetic abnormalities:

Clear cell (75%)
Papillary (10%)
Chromophobe (5%)

As clear cell RCC is the most common, its pathophysiology is well described. Knowledge of clear cell RCC has been aided by looking into hereditary RCC syndromes such as Von Hippel-Lindau syndrome, in which mutations of the VHL tumour supressor gene (located on chromosome 3) predispose to a variety of benign and malignant tumours.

The VHL protein targets and breaks down hypoxia-inducible factor (HIF).
In the absence of VHL, HIF is not broken down and promotes the transcription of hypoxia-related genes including vascular endothelial growth factor (VEGF); platelet-derived growth factor (PDGF), which is a known oncogene; and epidermal growth factor receptors (EGFR), which promote cell growth.
After the loss of VHL alleles (either acquired hereditarily or sporadically), accumulation of other genetic defects leads to promotion of tumour development.
These HIF-controlled genes have been targeted by new molecular treatments.

Clinical features

Over 50% of RCCs are detected incidentally on ultrasound and CT imaging.

However, the classical triad associated with RCC is:

Flank pain
Haematuria: may be micro or macroscopic
Palpable abdominal mass
This presentation is uncommon (occurs in roughly 10%) and suggests locally advanced disease.

Other clinical signs of RCC may include:

Scrotal varicocele: usually left sided due to obstruction of the left gonadal vein
Lower limb oedema: due to compression of the inferior vena cava

Patients may uncommonly present with symptoms of metastatic disease, such as bone pain.

Patients may also presents with paraneoplastic syndromes (20-30%) which are non-specific to RCC. These include:

Hypercalcaemia: due to bony metastasis, or production of PTHrP by tumour cells
Unexplained fever (found in 20-30% patients): thought to be mediated by cytokines including TNF-α and IL-6.
Stauffer's syndrome: hepatic dysfunction (elevated ALT/AST) in the absence of liver metastases, which resolves on nephrectomy.
Cushing's syndrome: caused by excess production of ACTH by tumour cells
Polycythaemia: due to excess EPO production by tumour cells
Neuromyopathies: may be sensory or motor. Degree of severity varies from nonspecific myalgia to bilateral phrenic nerve paralysis.

Referral criteria

NICE cancer referral guidelines for renal cancer suggest the following:

Investigations

Laboratory investigations

Suspicion of RCC shoulder prompt measurement of routine lab investigations including: LDH, FBC, LFTs, U&Es and calcium.
These are useful in order to identify the presence of metastatic disease and/or paraneoplastic syndromes.

Imaging

Imaging is paramount to diagnosis, regardless of presentation.
Ultrasound (USS) is an appropriately sensitive initial imaging - especially for distinguishing RCC from benign lesions - however it is not sufficient to confirm diagnosis. Overall detection rate for RCC is as low as 71% with conventional ultrasound, and CT is essential if ultrasound or clinical findings are suspicious for RCC.
CT with contrast is the definitive test most commonly used for initial diagnosis of renal malignancy. Contrast-enhanced CT has 100% specificity and ≥90% sensitivity for characterising a malignant renal mass.
MRI may provide additional information in determining local advancement, such as adrenal invasion and vena cava involvement by tumour or thrombus.

Differential diagnosis

Depending on the patient's presentation, differential diagnoses may include:

Benign renal cyst: distinguished on imaging using Bosniak classification (determines risk of malignancy based on tumour appearance). If borderline score, interval imaging may be used to identify any change in tumour appearance.
Angiomyolipoma (benign neoplasm): Clinically indistinguishable from RCC. Patients usually asymptomatic. Distinguished on CT/MRI as small (<1 cm) lesions with characteristic features, such a particular fat distribution).
Ureteric malignancy: presents more frequently with macroscopic haematuria. USS will distinguish from RCC.
Bladder cancer: presents with dysuria and frank haematuria. USS will distinguish from RCC.
Congenital renal abnormalities: distinguished from RCC using CT and particularly MRI.

Staging

Imaging:

In order to accurately stage a RCC, contrast-enhanced CT chest, abdominal and pelvis is necessary.
Bone scan and brain imaging (CT or MRI) are not recommended routinely, unless indicated by clinical or laboratory signs or symptoms.

Biopsy:

A core biopsy provides histopathological confirmation of malignancy.
Complications, such bleeding or tumour seeding are rare.
The biopsy sample provides the final histopathological diagnosis, classification, grading and evaluation of prognostic factors.

Staging of RCC

The widely used TNM classification is used to stage RCC

T (primary tumour):

TX: primary tumour cannot be assessed
T0: no evidence of primary tumour
T1: tumour confined to the kidney, and ≤7 cm in greatest dimension
T2: tumour confined to the kidney, and >7 cm in greatest dimension
T3: tumour extends into major veins or perinephric tissue, but not into the ipsilateral adrenal gland and not beyond Gerota fascia
T4: tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).

N (regional lymph nodes, including hilar, abdominal para-aortic, and paracaval lymph nodes)

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: metastasis in regional lymph node(s).

M (distant metastasis)

M0: no distant metastasis
M1: distant metastasis.

Management

The following is based on the ESMO (European Society for Medical Oncology) Clinical Practice Guidelines for diagnosis, treatment and follow-up 2019.

Management of early-stage RCC (T1 and T2):

Surgery is the mainstay for localised disease
Partial nephrectomy is the preferred option in organ-confined tumours measuring up to 7 cm (T1)
Ablative therapies are options for patients with small tumours (<􏰁3 cm); especially for those who present a high surgical risk or with compromised renal function.
Radical nephrectomy is the preferred option for T2 tumours.

Management of locally advanced RCC (T3 and T4):

Radical nephrectomy is the standard of care
Neo-adjuvant and adjuvant therapy for patients with non-metastatic RCC is not currently recommended, however clinical trials are examining this.

Management of metastatic RCC:

Surgery in the form of cytoreductive nephrectomy is generally only indicated in patients with good performance status and with few isolated sites of distant disease.
The mainstay of treatment is systemic therapy.
First line treatment is determined by risk (low/intermediate/high)
Low risk patients: VEGF inhibitors such as sunitinib, bevacizumab or pazopanib.
Intermediate and high risk patients: dual immunotherapy with ipilimumab and nivolumab

Complications

Complications may result from the malignancy itself, or from treatment.

Complications of RCC:

Anaemia (up to 30%)
Hypercalcaemia
Polycythaemia
SIADH
Cushing's syndrome
Stauffer's syndrome (liver dysfunction due to paraneoplastic syndrome in the absence of liver metastases)
IVC obstruction due to malignant invasion
Limbic encephalitis: rare disorder characterised by personality changes,, depression, seizures and memory loss.

Adverse effects of systemic treatment:

Immunotherapy: common side effects include auto-immune like presentations, such as rash, pneumonitis, colitis, thyroid dysfunction and hypophysitis. Complications can present over a year after treatment.
VEGF inhibitors: can cause widely varied side effects including mucositis, leukopaenia, peripheral neuropathy, fever, arthralgia, electrolyte imbalance.

Prognosis

The overall 5-year survival for RCC is >68% however this depends largely on stage at diagnosis, as well as on key prognostic factors.

Early-stage disease has excellent prognosis, with greater than 90% survival at 5 years.
Up to 30% of patients who have curative surgery will go on to develop metastatic disease.
The increasing use of new systemic treatments such as VEGF inhibitors and immunotherapy is has been shown to improve the survival rates for metastatic RCC in recent years.