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</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"></div><div class="body"><div class="t">Hereditary Papillary Renal Carcinoma (PDQ®): Health Professional Version</div><div class="j">PDQ Cancer Information Summaries [Internet]</div></div><div class="tail"></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 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class="fm-sec"><h1 id="_NBK568504_"><span class="title" itemprop="name">Hereditary Papillary Renal Carcinoma (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contribs">PDQ Cancer Genetics Editorial Board.</p><p class="fm-aai"><a href="#_NBK568504_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000803600__782">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary papillary renal carcinoma (HPRC). It is intended as a resource to inform and assist clinicians who care for HPRC patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000803600__783">This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000803600__285"><h2 id="_CDR0000803600__285_">Introduction</h2><p id="CDR0000803600__68">Hereditary papillary renal carcinoma (HPRC) is an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000793860/" class="def">autosomal dominant</a>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000754220/" class="def">syndrome</a> that predisposes individuals to bilateral and multifocal papillary renal cell carcinoma (RCC) (formerly known as type 1 papillary RCC).[<a class="bibr" href="#CDR0000803600_rl_285_1" rid="CDR0000803600_rl_285_1">1</a>]</p><p id="CDR0000803600__3158">Individuals are at the greatest risk of developing HPRC if they have a biological relative with bilateral, multifocal papillary RCC and/or a known activating <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783960/" class="def">pathogenic variant</a> in the tyrosine kinase <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460145/" class="def">domain</a> of the <i>MET</i> proto-oncogene.[<a class="bibr" href="#CDR0000803600_rl_285_2" rid="CDR0000803600_rl_285_2">2</a>,<a class="bibr" href="#CDR0000803600_rl_285_3" rid="CDR0000803600_rl_285_3">3</a>]</p><p id="CDR0000803600__534">No specific environmental risk factors have been reported to cause <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000809370/" class="def">hereditary</a> or <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic</a> papillary RCC. </p><div id="CDR0000803600_rl_285"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_285_1">Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8308957" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8308957</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_285_2">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/9140397" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9140397</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_285_3">Zbar B, Glenn G, Lubensky I, et al.: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153 (3 Pt 2): 907-12, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7853572" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7853572</span></a>]</div></li></ol></div></div><div id="CDR0000803600__671"><h2 id="_CDR0000803600__671_">Genetics</h2><div id="CDR0000803600__295"><h3><i>MET</i> Gene</h3><p id="CDR0000803600__774">The <i>MET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">gene</a> is located on <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046470/" class="def">chromosome</a> 7q31.2 and encodes a protein with 1,390 amino-acids.[<a class="bibr" href="#CDR0000803600_rl_671_1" rid="CDR0000803600_rl_671_1">1</a>]
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The functional MET receptor is a heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa). The primary single-chain precursor protein is posttranslationally cleaved to produce the alpha and beta subunits,[<a class="bibr" href="#CDR0000803600_rl_671_2" rid="CDR0000803600_rl_671_2">2</a>] which are disulfide-linked to form the mature receptor. Two <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000390290/" class="def">transcript</a>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000776887/" class="def">variants</a>, which encode different isoforms, have been found for this gene.</p><p id="CDR0000803600__775">The beta subunit of MET possesses tyrosine kinase activity and was identified as the cell-surface receptor for hepatocyte growth factor (HGF).[<a class="bibr" href="#CDR0000803600_rl_671_3" rid="CDR0000803600_rl_671_3">3</a>] MET transduces signals from the extracellular matrix into the cytoplasm by binding to the HGF ligand; it also regulates cell proliferation, scattering, morphogenesis, and survival.[<a class="bibr" href="#CDR0000803600_rl_671_4" rid="CDR0000803600_rl_671_4">4</a>]
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Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460145/" class="def">domain</a>, which provides docking sites for downstream signaling molecules. After activation by its ligand, MET interacts with the PI3K subunit PI3KR1, PLCG1, SRC, GRB2, or STAT3, or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades, including RAS-ERK, PI3K/AKT, and PLC-gamma/PKC.[<a class="bibr" href="#CDR0000803600_rl_671_4" rid="CDR0000803600_rl_671_4">4</a>] The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities.[<a class="bibr" href="#CDR0000803600_rl_671_4" rid="CDR0000803600_rl_671_4">4</a>]</p></div><div id="CDR0000803600__298"><h3>Prevalence and Founder Effects</h3><p id="CDR0000803600__299"> A novel <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783960/" class="def">pathogenic variant</a> was identified in <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460146/" class="def">exon</a> 16 of the <i>MET</i> gene in two large <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000754220/" class="def">hereditary</a> papillary renal carcinoma (HPRC) families in North America. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">Affected</a> members of the two families shared the same <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000485392/" class="def">haplotype</a> located within and immediately distal to the <i>MET</i> gene, suggesting a common ancestor (<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783962/" class="def">founder effect</a>).[<a class="bibr" href="#CDR0000803600_rl_671_5" rid="CDR0000803600_rl_671_5">5</a>] However, HPRC families with identical <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">germline</a>
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<i>MET</i> pathogenic variants who do not share a common ancestral haplotype have also been reported.[<a class="bibr" href="#CDR0000803600_rl_671_6" rid="CDR0000803600_rl_671_6">6</a>]</p></div><div id="CDR0000803600__300"><h3>Penetrance of <i>MET</i> Pathogenic Variants</h3><p id="CDR0000803600__301">HPRC is highly <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339344/" class="def">penetrant</a> (approaching 100%).[<a class="bibr" href="#CDR0000803600_rl_671_5" rid="CDR0000803600_rl_671_5">5</a>-<a class="bibr" href="#CDR0000803600_rl_671_7" rid="CDR0000803600_rl_671_7">7</a>]</p></div><div id="CDR0000803600__303"><h3>Genotype-Phenotype Correlations</h3><p id="CDR0000803600__304">All cases of HPRC have presented with papillary renal cell carcinoma, and no other histological subtypes have been detected.[<a class="bibr" href="#CDR0000803600_rl_671_5" rid="CDR0000803600_rl_671_5">5</a>,<a class="bibr" href="#CDR0000803600_rl_671_6" rid="CDR0000803600_rl_671_6">6</a>,<a class="bibr" href="#CDR0000803600_rl_671_8" rid="CDR0000803600_rl_671_8">8</a>-<a class="bibr" href="#CDR0000803600_rl_671_10" rid="CDR0000803600_rl_671_10">10</a>] The papillary RCC seen in HPRC (previously known as type 1 papillary RCC) has a distinct morphology, including the presence of small cells with basophilic cytoplasms arranged in a single layer on thin papillae. Extrarenal manifestations associated with this condition have not been reported.</p></div><div id="CDR0000803600_rl_671"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_671_1">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. [<a href="/pmc/articles/PMC299079/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC299079</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/2819873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2819873</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_2">Komada M, Hatsuzawa K, Shibamoto S, et al.: Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett 328 (1-2): 25-9, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8344430" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8344430</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_3">Bottaro DP, Rubin JS, Faletto DL, et al.: Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251 (4995): 802-4, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/1846706" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1846706</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_4">Gherardi E, Birchmeier W, Birchmeier C, et al.: Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12 (2): 89-103, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22270953" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22270953</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_5">Schmidt L, Junker K, Weirich G, et al.: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 58 (8): 1719-22, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9563489" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9563489</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_6">Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15371818" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15371818</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_7">Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014. [<a href="/pmc/articles/PMC3912328/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3912328</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24378414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24378414</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_8">Zbar B, Glenn G, Lubensky I, et al.: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153 (3 Pt 2): 907-12, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7853572" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7853572</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_9">Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8308957" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8308957</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_671_10">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/9140397" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9140397</span></a>]</div></li></ol></div></div><div id="CDR0000803600__296"><h2 id="_CDR0000803600__296_">Molecular Biology</h2><p id="CDR0000803600__302">All <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">germline</a>
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<i>MET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783960/" class="def">pathogenic variants</a> in hereditary papillary renal carcinoma (HPRC) reported to date are <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783964/" class="def">missense variants</a> in the tyrosine kinase <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460145/" class="def">domain</a>; this leads to constitutive activation of the MET kinase and drives the development of papillary renal cell carcinoma (RCC).[<a class="bibr" href="#CDR0000803600_rl_296_1" rid="CDR0000803600_rl_296_1">1</a>-<a class="bibr" href="#CDR0000803600_rl_296_3" rid="CDR0000803600_rl_296_3">3</a>]</p><p id="CDR0000803600__297"> Renal tumors from HPRC-<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> patients commonly show polysomy of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046470/" class="def">chromosome</a> 7 upon <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000270737/" class="def">cytogenetic</a> analysis.[<a class="bibr" href="#CDR0000803600_rl_296_4" rid="CDR0000803600_rl_296_4">4</a>]
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Polysomy 7 in the HPRC renal tumor tissue results from nonrandom duplication of the chromosome bearing the
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wild-type <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339337/" class="def">allele</a>.[<a class="bibr" href="#CDR0000803600_rl_296_5" rid="CDR0000803600_rl_296_5">5</a>] Approximately 15% to 20% of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic</a> papillary RCCs (which all shared what was previously called type 1 papillary RCC morphology) have <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000781854/" class="def">somatic</a>
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<i>MET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460164/" class="def">missense mutations</a>.[<a class="bibr" href="#CDR0000803600_rl_296_1" rid="CDR0000803600_rl_296_1">1</a>,<a class="bibr" href="#CDR0000803600_rl_296_6" rid="CDR0000803600_rl_296_6">6</a>,<a class="bibr" href="#CDR0000803600_rl_296_7" rid="CDR0000803600_rl_296_7">7</a>]</p><div id="CDR0000803600_rl_296"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_296_1">Schmidt L, Junker K, Nakaigawa N, et al.: Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18 (14): 2343-50, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10327054" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10327054</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_296_2">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/9140397" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9140397</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_296_3">Miller M, Ginalski K, Lesyng B, et al.: Structural basis of oncogenic activation caused by point mutations in the kinase domain of the MET proto-oncogene: modeling studies. Proteins 44 (1): 32-43, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11354004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11354004</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_296_4">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. [<a href="/pmc/articles/PMC299079/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC299079</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/2819873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2819873</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_296_5">Zhuang Z, Park WS, Pack S, et al.: Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20 (1): 66-9, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9731534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9731534</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_296_6">Linehan WM, Spellman PT, Ricketts CJ, et al.: Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 374 (2): 135-45, 2016. [<a href="/pmc/articles/PMC4775252/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4775252</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26536169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26536169</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_296_7">Pal SK, Ali SM, Yakirevich E, et al.: Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling. Eur Urol 73 (1): 71-78, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/28592388" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28592388</span></a>]</div></li></ol></div></div><div id="CDR0000803600__672"><h2 id="_CDR0000803600__672_">Clinical Manifestations</h2><div id="CDR0000803600__776"><h3>Kidney Cancer</h3><p id="CDR0000803600__777">The only recognized manifestation of hereditary papillary renal carcinoma (HPRC) is kidney cancer. The mean and median age at onset are 42 and 41 years, respectively.[<a class="bibr" href="#CDR0000803600_rl_672_1" rid="CDR0000803600_rl_672_1">1</a>]
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The age at onset may vary widely between families (range, 19–66 y), perhaps influenced by specific <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotypes</a>.[<a class="bibr" href="#CDR0000803600_rl_672_2" rid="CDR0000803600_rl_672_2">2</a>]
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Unlike <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic tumors</a>, which occur more frequently in males, both sexes appear to be similarly <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> by HPRC-associated renal cell carcinoma (RCC). Renal tumors in HPRC are most commonly bilateral and multifocal.[<a class="bibr" href="#CDR0000803600_rl_672_3" rid="CDR0000803600_rl_672_3">3</a>,<a class="bibr" href="#CDR0000803600_rl_672_4" rid="CDR0000803600_rl_672_4">4</a>]
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In contrast with many other RCC syndromes, renal cysts are less common in HPRC.[<a class="bibr" href="#CDR0000803600_rl_672_3" rid="CDR0000803600_rl_672_3">3</a>,<a class="bibr" href="#CDR0000803600_rl_672_4" rid="CDR0000803600_rl_672_4">4</a>] However, the presentation of HPRC is similar to other forms of kidney cancer in that small tumors may present incidentally, whereas large lesions can cause the classic triad of flank pain, hematuria, and an abdominal mass. When HPRC renal tumors become large, they can metastasize, most commonly to the lungs.[<a class="bibr" href="#CDR0000803600_rl_672_5" rid="CDR0000803600_rl_672_5">5</a>]</p></div><div id="CDR0000803600_rl_672"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_672_1">Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014. [<a href="/pmc/articles/PMC3912328/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3912328</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24378414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24378414</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_672_2">Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15371818" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15371818</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_672_3">Zbar B, Glenn G, Lubensky I, et al.: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153 (3 Pt 2): 907-12, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7853572" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7853572</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_672_4">Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8308957" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8308957</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_672_5">Lubensky IA, Schmidt L, Zhuang Z, et al.: Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 155 (2): 517-26, 1999. [<a href="/pmc/articles/PMC1866853/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1866853</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10433944" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10433944</span></a>]</div></li></ol></div></div><div id="CDR0000803600__535"><h2 id="_CDR0000803600__535_">Histopathology</h2><p id="CDR0000803600__536">Papillary renal cell carcinomas (RCCs) often have heterogenous morphological features. Type 1 papillary RCC was a unique classification within the papillary RCC family, but recent World Health Organization pathology updates have removed this designation. All hereditary papillary renal carcinomas (HPRCs) share type 1 papillary morphology, which is defined by small basophilic cells with pale cytoplasm, small oval nuclei, and inconspicuous nucleoli organized in single layers in papillae and tubular structures.[<a class="bibr" href="#CDR0000803600_rl_535_1" rid="CDR0000803600_rl_535_1">1</a>,<a class="bibr" href="#CDR0000803600_rl_535_2" rid="CDR0000803600_rl_535_2">2</a>] The HPRC <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> is only seen in individuals with this distinct type 1 papillary renal carcinoma histopathology. Incipient microscopic lesions, including adenomas and papillary lesions, are commonly found in the adjacent renal parenchyma. It has been estimated that patients with HPRC may develop up to 3,400 renal tumors or incipient lesions per kidney.[<a class="bibr" href="#CDR0000803600_rl_535_3" rid="CDR0000803600_rl_535_3">3</a>] These pathological findings should raise suspicion for a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000781852/" class="def">germline variant</a> in the <i>MET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">gene</a>.[<a class="bibr" href="#CDR0000803600_rl_535_4" rid="CDR0000803600_rl_535_4">4</a>,<a class="bibr" href="#CDR0000803600_rl_535_5" rid="CDR0000803600_rl_535_5">5</a>] Hereditary and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic</a> type 1 papillary RCCs with <i>MET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783960/" class="def">pathogenic variants</a> have similar, distinctive type 1 papillary morphological phenotypes, which include the presence of macrophages and psammoma bodies.[<a class="bibr" href="#CDR0000803600_rl_535_6" rid="CDR0000803600_rl_535_6">6</a>] In HPRC, papillary tumors are often well differentiated/low grade. However, high-grade tumors can also be observed in HPRC patients.[<a class="bibr" href="#CDR0000803600_rl_535_7" rid="CDR0000803600_rl_535_7">7</a>] </p><div id="CDR0000803600_rl_535"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_535_1">Delahunt B, Eble JN: Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10 (6): 537-44, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9195569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9195569</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_535_2">Störkel S, Eble JN, Adlakha K, et al.: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80 (5): 987-9, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9307203" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9307203</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_535_3">Ornstein DK, Lubensky IA, Venzon D, et al.: Prevalence of microscopic tumors in normal appearing renal parenchyma of patients with hereditary papillary renal cancer. J Urol 163 (2): 431-3, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10647647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10647647</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_535_4">Schmidt L, Junker K, Weirich G, et al.: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 58 (8): 1719-22, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9563489" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9563489</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_535_5">Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15371818" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15371818</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_535_6">Lubensky IA, Schmidt L, Zhuang Z, et al.: Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 155 (2): 517-26, 1999. [<a href="/pmc/articles/PMC1866853/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1866853</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10433944" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10433944</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_535_7">Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12511666" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12511666</span></a>]</div></li></ol></div></div><div id="CDR0000803600__305"><h2 id="_CDR0000803600__305_">Management</h2><div id="CDR0000803600__306"><h3>Surveillance </h3><p id="CDR0000803600__537">It is important that patients with known hereditary papillary renal carcinoma (HPRC) undergo regular <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000496506/" class="def">surveillance</a>. Papillary renal cell carcinomas (RCCs) possess specific imaging characteristics that differ from clear cell RCCs. 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.[<a class="bibr" href="#CDR0000803600_rl_305_1" rid="CDR0000803600_rl_305_1">1</a>]</p><p id="CDR0000803600__538">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.[<a class="bibr" href="#CDR0000803600_rl_305_2" rid="CDR0000803600_rl_305_2">2</a>] Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.[<a class="bibr" href="#CDR0000803600_rl_305_3" rid="CDR0000803600_rl_305_3">3</a>]</p><p id="CDR0000803600__470">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.[<a class="bibr" href="#CDR0000803600_rl_305_4" rid="CDR0000803600_rl_305_4">4</a>] 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.</p><p id="CDR0000803600__780">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 <a href="#CDR0000803600__681">Treatment</a> section.</p></div><div id="CDR0000803600__309"><h3>Genetic Testing</h3><p id="CDR0000803600__310">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. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044961/" class="def">Genetic counseling</a> is performed, and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044677/" class="def">informed consent</a> obtained. The genetic counselor will contact the laboratory and coordinate genetic testing.</p><p id="CDR0000803600__307">Genetic testing for HPRC may be recommended if an individual has one or more of the following:</p><ul id="CDR0000803600__474"><li class="half_rhythm"><div>A family history of HPRC.</div></li><li class="half_rhythm"><div>A biologically related family member who tested positive for a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000783960/" class="def">pathogenic variant</a> in the tyrosine kinase <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460145/" class="def">domain</a> of <i>MET</i>.</div></li><li class="half_rhythm"><div>A personal history of greater than one papillary RCC (especially with the previously designated type 1 papillary RCC morphology), a papillary RCC with incipient lesions of the surrounding parenchyma, or a papillary RCC diagnosed before age 45 years.</div></li></ul><p id="CDR0000803600__3160">One report suggested that it may be beneficial to expand testing for HPRC beyond familial cases.[<a class="bibr" href="#CDR0000803600_rl_305_5" rid="CDR0000803600_rl_305_5">5</a>] In a series of 158 patients from France, 5% of nonfamilial papillary RCC cases had a germline <i>MET</i> pathogenic variant.</p><div id="CDR0000803600__311"><h4><i>MET</i> genetic testing</h4><p id="CDR0000803600__312">Bidirectional <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> sequencing of the <i>MET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">gene</a> using amplified genomic DNA is done to identify sequence <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000776887/" class="def">variants</a> in the coding <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460146/" class="def">exons</a> of <i>MET</i>. All HPRC-associated <i>MET</i> 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.[<a class="bibr" href="#CDR0000803600_rl_305_6" rid="CDR0000803600_rl_305_6">6</a>-<a class="bibr" href="#CDR0000803600_rl_305_8" rid="CDR0000803600_rl_305_8">8</a>] Some CLIA-approved genetic testing laboratories now offer diagnostic cancer <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000763019/" class="def">gene panels</a>, which use <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000763024/" class="def">next-generation sequencing</a> technology to examine the entire <i>MET</i> gene.</p><p id="CDR0000803600__313">Genetic testing enables early definitive diagnosis of the HPRC syndrome, after which at-risk individuals can be guided to regular surveillance for syndrome-associated <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotypes</a>.</p><p id="CDR0000803600__3161">Individuals with variants of unknown significance (VUS) in the <i>MET</i> tyrosine kinase domain warrant special consideration. A recent genotype-phenotype study demonstrated that three <i>MET</i> VUS exhibited oncogenic MET signaling in preclinical models, suggesting pathogenicity.[<a class="bibr" href="#CDR0000803600_rl_305_5" rid="CDR0000803600_rl_305_5">5</a>] Families with papillary RCC and these <i>MET </i>VUS could benefit from a discussion about these findings and their implications.</p></div></div><div id="CDR0000803600__681"><h3>Treatment</h3><p id="CDR0000803600__778">
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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 extrarenal 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%.[<a class="bibr" href="#CDR0000803600_rl_305_9" rid="CDR0000803600_rl_305_9">9</a>] However, patients with <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">germline</a>
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<i>MET</i> 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 <i>MET</i> pathogenic variants, only 5 of 57 demonstrated a partial response to foretinib. Cabozantinib was approved for the treatment of metastatic kidney cancer in 2016.[<a class="bibr" href="#CDR0000803600_rl_305_10" rid="CDR0000803600_rl_305_10">10</a>] In a randomized phase II trial from the Southwest Oncology Group (SWOG), patients with metastatic papillary RCC had improved outcomes with cabozantinib when compared with sunitinib in the S1500 trial. Ongoing research will evaluate the role of MET activation in RCC treatment response.[<a class="bibr" href="#CDR0000803600_rl_305_11" rid="CDR0000803600_rl_305_11">11</a>]</p></div><div id="CDR0000803600_rl_305"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_305_1">Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12511666" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12511666</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_2">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/19448113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19448113</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_3">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/9294565" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9294565</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_4">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/10210376" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10210376</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_5">Sebai M, Tulasne D, Caputo SM, et al.: Novel germline MET pathogenic variants in French patients with papillary renal cell carcinomas type I. Hum Mutat 43 (3): 316-327, 2022. [<a href="https://pubmed.ncbi.nlm.nih.gov/34882875" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34882875</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_6">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. [<a href="/pmc/articles/PMC299079/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC299079</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/2819873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2819873</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_7">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. [<a href="https://pubmed.ncbi.nlm.nih.gov/9140397" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9140397</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_8">Duh FM, Scherer SW, Tsui LC, et al.: Gene structure of the human MET proto-oncogene. Oncogene 15 (13): 1583-6, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9380410" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9380410</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_9">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. [<a href="/pmc/articles/PMC3532390/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3532390</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23213094" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23213094</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_10">Choueiri TK, Escudier B, Powles T, et al.: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373 (19): 1814-23, 2015. [<a href="/pmc/articles/PMC5024539/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5024539</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26406150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26406150</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_305_11">Pal SK, Tangen C, Thompson IM, et al.: A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet 397 (10275): 695-703, 2021. [<a href="/pmc/articles/PMC8687736/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8687736</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33592176" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33592176</span></a>]</div></li></ol></div></div><div id="CDR0000803600__673"><h2 id="_CDR0000803600__673_">Prognosis</h2><p id="CDR0000803600__321">Hereditary papillary renal carcinoma (HPRC)-related papillary renal cell carcinomas, particularly small tumors confined to the kidneys, tend to be indolent. Consequently, patients present later in life or die of other syndrome-unrelated causes before a renal tumor is diagnosed.[<a class="bibr" href="#CDR0000803600_rl_673_1" rid="CDR0000803600_rl_673_1">1</a>] <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000496506/" class="def">Surveillance</a>, presymptomatic <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046171/" class="def">screening</a> of individuals at risk of HPRC, and specialized cancer management (tailored to the biology of syndrome-associated kidney cancer) are expected to improve disease outcome.[<a class="bibr" href="#CDR0000803600_rl_673_2" rid="CDR0000803600_rl_673_2">2</a>]</p><div id="CDR0000803600_rl_673"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_673_1">Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12511666" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12511666</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803600_rl_673_2">Kiuru M, Kujala M, Aittomäki K: Inherited forms of renal cell carcinoma. Scand J Surg 93 (2): 103-11, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15285561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15285561</span></a>]</div></li></ol></div></div><div id="CDR0000803600__674"><h2 id="_CDR0000803600__674_">Future Directions</h2><p id="CDR0000803600__781">Development of blood-based early detection assays, and effective systemic therapy for either prevention or treatment of overt disease might provide new options for individuals with hereditary papillary renal carcinoma (HPRC). Because the <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339344/" class="def">penetrance</a> of tumors in HPRC is nearly 100%, this patient population might provide an exciting avenue to study chemoprevention using MET-directed strategies. There are currently no systemic therapy options approved by the U.S. Food and Drug Administration (FDA) that specifically address the needs of patients with HPRC-associated metastatic renal cell carcinoma (RCC). On the basis of limited data from the foretinib study,[<a class="bibr" href="#CDR0000803600_rl_674_1" rid="CDR0000803600_rl_674_1">1</a>] agents such as cabozantinib (a multitargeted tyrosine kinase inhibitor with activity against MET, which was approved by the FDA for use in patients with metastatic RCC who have progressed on VEGFR-targeted therapy) may be considered. Newer MET inhibitors with a more-selective target profile may be clinically active, while limiting off-target side effects, in patients with HPRC-associated RCC, and such agents are currently under evaluation (<a href="https://www.cancer.gov/clinicaltrials/NCT02019693" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT02019693</a>). Because redundant signaling pathways are often activated with targeted therapy, the mechanisms of resistance to MET inhibition should be further investigated.</p><div id="CDR0000803600_rl_674"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803600_rl_674_1">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. [<a href="/pmc/articles/PMC3532390/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3532390</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23213094" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23213094</span></a>]</div></li></ol></div></div><div id="CDR0000803600__3155"><h2 id="_CDR0000803600__3155_">Latest Updates to This Summary (02/16/2024)</h2><p id="CDR0000803600__3156">The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.</p><p id="CDR0000803600__3172">
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<b>
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<a href="#CDR0000803600__285">Introduction</a>
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</b>
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</p><p id="CDR0000803600__3173">Added <a href="#CDR0000803600__68">text</a> to state that the bilateral and multifocal papillary renal cell carcinoma (RCC) seen in hereditary papillary renal carcinoma (HPRC) was formerly known as type 1 papillary RCC.</p><p id="CDR0000803600__3174">
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<b>
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<a href="#CDR0000803600__671">Genetics</a>
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</b>
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</p><p id="CDR0000803600__3179">Added <a href="#CDR0000803600__304">text</a> to state that the papillary RCC seen in HPRC was previously known as type 1 papillary RCC and has distinct morphology, including the presence of small cells with basophilic cytoplasms arranged in a single layer on thin papillae.</p><p id="CDR0000803600__3175">
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<b>
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<a href="#CDR0000803600__296">Molecular Biology</a>
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</b>
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</p><p id="CDR0000803600__3176">Revised <a href="#CDR0000803600__297">text</a> to state that the RCC seen in 15% to 20% of sporadic papillary RCCs was previously called type 1 papillary RCC.</p><p id="CDR0000803600__3177">
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<b>
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<a href="#CDR0000803600__305">Management</a>
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</b>
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</p><p id="CDR0000803600__3178">Revised <a href="/books/NBK568504/?report=reader#CDR0000803600__474">text</a> to state that genetic testing for HPRC may be recommended if an individual has a personal history of greater than one papillary RCC, especially those with the previously designated type 1 papillary RCC morphology.</p><p id="CDR0000803600__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/genetics" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Cancer Genetics Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000803600__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® Cancer Information for Health Professionals</a> pages.
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</p></div><div id="CDR0000803600__AboutThis_1"><h2 id="_CDR0000803600__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000803600__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000803600__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary papillary renal carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000803600__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000803600__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/genetics" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Cancer Genetics Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000803600__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000803600__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000803600__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Hereditary Papillary Renal Carcinoma are:</p><ul><li class="half_rhythm"><div>Alexandra Perez Lebensohn, MS, CGC (National Cancer Institute)</div></li><li class="half_rhythm"><div>Brian Matthew Shuch, MD (UCLA Health)</div></li><li class="half_rhythm"><div>Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)</div></li></ul><p id="CDR0000803600__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000803600__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000803600__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a <a href="/books/n/pdqcis/CDR0000685387/?report=reader">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000803600__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000803600__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000803600__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000803600__AboutThis_15">PDQ® Cancer Genetics Editorial Board. PDQ Hereditary Papillary Renal Carcinoma. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/publications/pdq/information-summaries/genetics/hprc-syndrome-hp-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/publications/pdq/information-summaries/genetics/hprc-syndrome-hp-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 33724750]</p><p id="CDR0000803600__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000803600__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000803600__AboutThis_19">The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000803600__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000803600__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div><div class="fm-sec"><h2 id="_NBK568504_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">PDQ Cancer Genetics Editorial Board</span>.</p><h3>Publication History</h3><p class="small">Published online: February 16, 2024.</p><p class="small">Created: <span itemprop="datePublished">March 8, 2021</span>.</p><h3>Version History</h3><ul class="simple-list" style="padding:0"><li><span class="bk_col_itm">NBK568504.5</span> February 16, 2024 (Displayed Version)</li><li><span class="bk_col_itm"><a href="/books/NBK568504.4/?report=reader">NBK568504.4</a></span> November 20, 2023</li><li><span class="bk_col_itm"><a href="/books/NBK568504.3/?report=reader">NBK568504.3</a></span> December 28, 2022</li><li><span class="bk_col_itm"><a href="/books/NBK568504.2/?report=reader">NBK568504.2</a></span> April 14, 2022</li><li><span class="bk_col_itm"><a href="/books/NBK568504.1/?report=reader">NBK568504.1</a></span> March 8, 2021</li></ul><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>PDQ Cancer Genetics Editorial Board. Hereditary Papillary Renal Carcinoma (PDQ®): Health Professional Version. 2024 Feb 16. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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