Hereditary papillary renal cell carcinoma (ORPHA:47044)
A rare familial renal cancer syndrome characterized by a predisposition for developing bilateral and multifocal classic type papillary renal cell carcinomas (formerly known as type 1 papillary renal cell carcinoma until the 2022 WHO classification of renal tumors).
Epidemiology
Renal cell carcinoma (RCC) accounts for approximately 2% of all malignancies with about 400,000 new cases diagnosed annually worldwide. Papillary RCC, accounting for 15% of cases, is the second most common form of RCC after clear cell RCC (75%). Hereditary cases account for about 5% of all RCC and include a dozen of syndromes with four major conditions: von Hippel-Lindau (VHL), Birt-Hogg-Dubé (BHD), hereditary leiomyomatosis and renal cell cancer (HLRC) and hereditary papillary renal cell carcinoma (HPRC). Less than 60 kindreds with HPRC have been reported to date in the literature and the prevalence is unknown (estimated at 1/500,000).
Clinical description
HPRC is a highly penetrant autosomal dominant disease predisposing to the occurrence of bilateral and multifocal classic papillary RCC. Recently biphasic squamoid alveolar papillary RCC (an emerging variant of papillary RCC) have also been described in association with the disease. Most of the tumors are low-grade, but a small subset of tumors may be high-grade and metastasize. In addition, numerous microscopic papillary adenomas are commonly seen in the background renal parenchyma. In HPRC, renal tumors occur over a wide age range from 19 to 66 years but typically occur later than other forms of hereditary RCC (median age of 41 years). Unlike other major hereditary renal cancer syndromes, there are no extrarenal manifestations in HPRC.
Etiology
HPRC is associated with activating germline mutations in the MET proto-oncogene (7q31) encoding the hepatocyte growth factor-responsive tyrosine kinase receptor. The activation subsequently triggers downstream signaling pathways that promote cell survival, proliferation and inhibition of apoptosis. Tumorigenesis in HPRC patients is most frequently associated with duplication of the chromosome 7 carrying the mutated MET allele (trisomy 7).
Diagnostic methods
Diagnosis is suspected in patients with bilateral or multifocal classic type papillary RCC even in absence of familial history and can be confirmed by detection of a germline mutation in the MET gene. Papillary RCC are classically poorly enhancing on computed tomography (CT) scan and magnetic resonance imaging (MRI) is more performant for their diagnosis.
Differential diagnosis
No other known syndrome predisposes to occurrence of classic type papillary renal cell carcinomas without extrarenal manifestations. In Birt-Hogg Dubé syndrome, such renal tumors can sometimes occur but are associated with other characteristic histologic types (hybrid chromophobe-oncocytomas RCC and chromophobe RCC) as well typical cutaneous and pulmonary lesions. With the advent of multi-gene renal cancer panel tests, the distinction is easily made in case of atypical presentation.
Antenatal diagnosis
There is no indication to prenatal diagnostic testing or preimplantation genetic testing.
Genetic counseling
The transmission is autosomal dominant. At-risk individuals have a 50% chance of transmitting the pathogenic variant to their offspring. Genetic testing is recommended for relatives from the age of 18 years.
Management and treatment
Clinical management should include regular surveillance, preferably by contrast-enhanced MRI, to allow early detection of renal carcinomas. The surveillance should be offered to patients and at-risk relatives, every 1-2 years starting at age 30, until the largest tumor reaches 3 cm, at which time nephron-sparing surgery (tumor excision or partial nephrectomy) is recommended. Percutaneous thermal ablation may provide a safe and alternative treatment to surgery for small tumors.
Prognosis
Compared to other hereditary renal cell carcinomas, HPRC tend to be of indolent nature but patients have a risk of recurrent tumors throughout life with need of often repeated surgeries. In some cases, multiplicity of tumors may ultimately lead to binephrectomy and dialysis. In case of metastatic disease, MET pathway inhibitors have shown promising results.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Pr Stéphane RICHARD