It is important that patients with known hereditary papillary renal carcinoma (HPRC) undergo regular surveillance. Papillary renal cell carcinomas (RCCs), particularly type 1 papillary RCCs, possess specific imaging characteristics that differ from clear cell RCCs. Type 1 papillary renal tumors are generally hypovascular and enhance only 10 to 30 Hounsfield units after intravenous administration of contrast material. Papillary renal tumors can be mistaken for renal cysts, unless evaluated by careful attenuation measurements before and after contrast enhancement. Ultrasonography can be particularly misleading if no other imaging tests are used because the small renal tumors in HPRC are often isoechoic and may be missed on repeat examinations.
If kidney function is normal and the patient is not allergic to contrast, cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is considered the best initial imaging technique for identifying these hypovascular renal tumors. Renal ultrasonography is often inadequate for detecting papillary tumors, even when the tumor is clearly present on CT or MRI. Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.
At-risk individuals are generally recommended to undergo periodic kidney imaging throughout their lifetimes, even when renal tumors are not present. Therefore, MRI is typically recommended to minimize the lifetime dose of radiation. One approach that has been used is to perform initial cross-sectional imaging at baseline. If there are no renal tumors present, imaging can be performed periodically. If a renal tumor smaller than 3 cm is found, imaging is repeated within the first year to assess the growth rate of the tumor. Imaging frequency can be adapted to prevent the largest tumor from exceeding 3 cm depending on the growth characteristics of the tumor and the current tumor size.
Generally, patients with HPRC-associated renal tumors are candidates for radiological surveillance until one or more of the tumors reach 3 cm. At that point, surgical intervention is recommended. For more information, see the Treatment section.
Genetic testing for HPRC is available at Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. A health professional (usually a physician, geneticist, or genetic counselor) intermediary between the patient and the laboratory is chosen. Genetic counseling is performed, and informed consent obtained. The genetic counselor will contact the laboratory and coordinate genetic testing.
Genetic testing for HPRC may be recommended if an individual has one or more of the following:
- A family history of HPRC.
- A biologically related family member who tested positive for a pathogenic variant in the tyrosine kinase domain of MET.
- A personal history of greater than one papillary type 1 RCC, a papillary type 1 RCC with incipient lesions of the surrounding parenchyma, or a papillary type 1 RCC diagnosed before age 45 years.
Bidirectional DNA sequencing of the METgene using amplified genomic DNA is done to identify sequence variants in the coding exons of MET. All HPRC-associated MET pathogenic variants identified to date are located in the four exons encompassing the tyrosine kinase domain. Therefore, initially analyzing only these four exons may identify most sequence variants while reducing the cost and time involved in analyzing the entire 21-exon gene.[5,6,7] Some CLIA-approved genetic testing laboratories now offer diagnostic cancer gene panels, which use next-generation sequencing technology to examine the entire MET gene.
Genetic testing enables early definitive diagnosis of the HPRC syndrome, after which at-risk individuals can be guided to regular surveillance for syndrome-associated phenotypes.
Once HPRC renal tumors reach 3 cm in size, a nephron-sparing partial nephrectomy is usually recommended to minimize the risk of metastasis. There are no curative options available for patients with unresectable extra-renal spread of disease. However, there has been significant interest in developing MET-directed systemic therapy for patients with HPRC. Foretinib, a dual MET/VEGFR2 kinase inhibitor with additional activity against a variety of other tyrosine kinases, was evaluated in a multicenter phase II trial in patients with metastatic papillary RCC or bilateral multifocal papillary RCC. The overall response rate in patients with papillary RCC was 13.5%. However, patients with germline MET pathogenic variants were particularly sensitive to this agent, with 5 of 10 patients demonstrating a partial response, as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. In patients without germline MET pathogenic variants, only 5 of 57 demonstrated a partial response to foretinib. More-selective MET inhibitors are currently under investigation for the treatment of papillary RCC.
- Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003.
- Vikram R, Ng CS, Tamboli P, et al.: Papillary renal cell carcinoma: radiologic-pathologic correlation and spectrum of disease. Radiographics 29 (3): 741-54; discussion 755-7, 2009 May-Jun.
- Choyke PL, Walther MM, Glenn GM, et al.: Imaging features of hereditary papillary renal cancers. J Comput Assist Tomogr 21 (5): 737-41, 1997 Sep-Oct.
- Walther MM, Choyke PL, Glenn G, et al.: Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 161 (5): 1475-9, 1999.
- Park M, Dean M, Kaul K, et al.: Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci U S A 84 (18): 6379-83, 1987.
- Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997.
- Duh FM, Scherer SW, Tsui LC, et al.: Gene structure of the human MET proto-oncogene. Oncogene 15 (13): 1583-6, 1997.
- Choueiri TK, Vaishampayan U, Rosenberg JE, et al.: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 31 (2): 181-6, 2013.