Renal cancer

With the increasing use of CT and USS radiology techniques, over 50% of renal cancers are now diagnosed incidentally, however a classic triad – haematuria, flank pain, abdominal mass – is still seen in practice:

Advanced disease may present with paraneoplastic phenomena, such as hypercalcaemia, erythrocytosis and unexplained fever.

80% of renal malignancies are made up of the clear cell histological subtype, with the remaining 20% subdivided into:

• papillary type I renal cancer;
• papillary type II renal cancer (see Presentation: Patient with renal cell cancer);
• multilocular cystic renal neoplasm of low malignant potential;
• collecting duct carcinoma;
• renal medullary carcinoma;
• MiT family translocation renal cell carcinomas;
• succinate dehydrogenase-deficient renal cell carcinoma;
• mucinous tubular and spindle cell carcinoma; and
• tubulocystic renal cell carcinoma.

Somatic (tumour) genetics and renal cancer

Somatic variants are those that have arisen in the tumour and are not present constitutionally (in the germline) so cannot be passed onto offspring.

Most cases of renal cancer are caused by somatic pathogenic variants acquired during an individual’s lifetime, resulting in loss of function of the tumour suppressor gene VHL. This results in an accumulation of hypoxia inducible factor alpha (HIF) leading to upregulation of hypoxia response genes such as platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).

Somatic genomic testing is available to aid in the diagnosis of different renal cancer subtypes, available from the National Genomic Testing Directory and summarised below.

• Somatic testing of FH or SDHx (SDHA, SDHB, SDHC, SDHD) genes may be offered in cases where immunohistochemistry testing indicates loss of expression of the respective protein and where constitutional genomic testing has not identified an underlying causative constitutional pathogenic variant.
• Somatic testing of VHL, TCEB-1, TSC1/TSC2, MET or BRAF may be indicated to assist in diagnosis when morphology alone is inconclusive.
• Somatic testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic renal cell cancer patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
• All patients with solid tumours who have exhausted all standards of care testing and treatment are now eligible for whole genome sequencing (WGS) in order to explore clinical trial options.

Constitutional (germline) genetics and renal cancer

In contrast to the sporadic cases, 3%–5% of renal cancer cases have an underlying inherited genetic cause. Cases of renal cancer may therefore cluster in families. Often, it is not possible to identify a genetic cause, however in some families a tumour predisposition syndrome is identified and inherited in an autosomal dominant pattern.

• Consult the National Genomic Test Directory eligibility criteria to ensure your patient is eligible for testing using the inherited renal cancer panel (R224), which includes a number of genes associated with kidney cancer predisposition syndromes, many of which are associated with increased risks of other cancers and/or non-cancerous features. Many of the genes included on the inherited renal cancer panel may be tested as single gene tests or on overlapping panels.
• Kidney cancer predisposition syndromes (and overlapping indications) include:
  • Fumarate hydratase (FH) related tumour syndromes (R365), including hereditary leiomyomatosis and renal cell cancer: autosomal dominant tumour predisposition syndromes associated with increased risks of kidney cancer (particularly type II papillary renal cancer), as well as uterine and cutaneous leiomyomatosis and, rarely, paraganglioma/phaeochromocytoma.
    • Cutaneous and uterine leiomyosarcoma have very rarely been reported in carriers of pathogenic constitutional FH variants.
  • Von Hippel-Lindau (VHL) syndrome (R225): an autosomal dominant tumour predisposition syndrome associated with renal cell carcinoma, retinal angioma, spinal or cerebellar hemangioblastoma, adrenal or extra-adrenal pheochromocytoma, multiple renal and/or pancreatic cysts, endolymphatic sac tumours, papillary cystadenomas of the epididymis or broad ligament, and neuroendocrine tumours of the pancreas.
  • Inherited phaeochromocytoma and paraganglioma (R223): an autosomal dominant tumour predisposition syndrome associated with paraganglioma, phaeochromocytoma and SDH-deficient renal cell cancer.
  • Birt Hogg Dubé syndrome (overlap with R190 Pneumothorax – familial): an autosomal dominant tumour predisposition syndrome associated with an increased risk of kidney cancer (most commonly mixed chromophobe/oncocytic histology), multiple lung cysts and/or pneumothoraces, and cutaneous features (including fibrofolliculomas, acrochordons, angiofibromas, collagenomas).
  • BAP1 tumour predisposition syndrome (overlap with R422 BAP1 associated tumour predisposition syndrome): an autosomal dominant tumour predisposition syndrome associated with increased risks of kidney cancer, uveal and cutaneous melanoma and malignant mesothelioma.
  • Hereditary type 1 papillary renal cancer: an autosomal dominant cancer predisposition syndrome caused by pathogenic constitutional variants in MET with phenotype limited to type 1 papillary kidney cancer predisposition.
  • PTEN hamartoma tumour syndrome (R213): an autosomal dominant syndrome variably associated with macrocephaly, mucocutaneous features, hamartomas and cancer predisposition.
  • Cancers of the renal pelvis/ureter (usually transitional cell cancer) have also been described as part of Lynch syndrome (R210 inherited MMR deficiency).
    • Consider further assessment if the patient has a family history of colorectal, endometrial or other Lynch syndrome associated cancers.

If a constitutional (germline) pathogenic variant is identified in a renal cancer predisposition gene, there are also implications for management of the patient’s future cancer risk and that of their relatives.

• Pathogenic variants in most known renal cancer predisposition genes are inherited in an autosomal dominant pattern and there is therefore a 50% chance that offspring will inherit the associated condition.
• Certain kidney cancer predisposition genes (FH, SDHB) are also associated with autosomal recessive conditions, which will need to be taken into consideration if the carrier is in a consanguineous relationship.

For clinicians

• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: Renal cancer treatment guidelines

References:

• Escudier B, Porta C, Schmindinger M and others. ‘Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up‘. Annals of Oncology 2019: volume 30, issue 5, pages 706–720. DOI: 10.1093/annonc/mdz056

For patients

• Kidney Cancer UK Charity
• Cancer Research UK: Kidney cancer clinical trials information