Hereditary Papillary Renal Carcinoma

Hereditary papillary renal carcinoma is an autosomal dominant syndrome caused by activating germline variants in the MET proto oncogene, with multiple bilateral type 1 papillary renal cell carcinomas. It is rare, and tumours are slow growing in early stages, allowing organ preserving surgery.

Pathophysiology. Gain-of-function variants in the tyrosine kinase domain of MET make the hepatocyte growth factor receptor active, driving cell proliferation and tumour formation in kidney tubules.

Penetrance is age related and near complete by old age. Tumours are small, multifocal and often bilateral.

Metastatic disease can respond to MET-directed treatment.

• Often no symptoms and found on imaging
• Haematuria, flank pain or mass when large
• Multiple bilateral type 1 papillary renal tumours, from microscopic foci to large masses
• Onset usually from the 30s to 60s
• Family history of renal cancer, typically papillary type

• Genetic testing of MET (kinase domain) with deletion and duplication analysis, in people with bilateral or multifocal type 1 papillary renal cancer or a family history.
• Renal imaging: contrast enhanced MRI or CT of the abdomen, and renal ultrasound.
• Histology: type 1 papillary renal cell carcinoma with MET activation features.
• Exclusion of other syndromes: testing for FH, FLCN, VHL and SDH genes when the histology is atypical.
• Cascade testing of adult relatives.

Differential diagnosis.

• Hereditary leiomyomatosis and renal cell cancer syndrome (type 2 papillary)
• Birt-Hogg-Dubé syndrome
• Von Hippel-Lindau disease
• Sporadic papillary renal cell carcinoma
• Tuberous sclerosis complex (angiomyolipoma, renal cell cancer)
• Succinate dehydrogenase deficient renal cell cancer

• Surveillance of carriers: MRI of the kidneys yearly, or every 1 to 2 years, from about 30 years.
• Surgical threshold: active surveillance while the largest tumour is under 3 cm, then nephron sparing surgery (partial nephrectomy, ablation) once the largest tumour reaches 3 cm, preserving kidney function.
• Renal function: avoid nephrotoxic drugs, monitor eGFR yearly, and prepare for dialysis or transplant in end stage kidney disease after multiple resections.
• Metastatic disease: MET-directed treatment such as savolitinib 600 mg orally daily (400 mg if under 50 kg), or cabozantinib 60 mg orally daily, in a specialist centre. Immune checkpoint combinations are also used.
• Genetic counselling: 50% chance of the variant for each child.

Special groups.

• Patients with prior partial nephrectomy: surveillance imaging for local recurrence every 6 to 12 months.

Monitoring. Yearly MRI of the abdomen, creatinine and eGFR, blood pressure, and urinalysis.

Referral and escalation. Refer to clinical genetics and a urological oncology service. Urgent for haematuria, flank pain, a rapidly growing lesion, or any lesion over 3 cm.