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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK169222_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK169222_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK169222_"><span class="title" itemprop="name">Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Cancer Genetics Editorial Board</span>.</p><p class="small">Published online: July 6, 2015.</p><p class="small">Created: <span itemprop="datePublished">November 1, 2013</span>.</p></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="CDR0000574548__774">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of kidney cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000574548__775">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="CDR0000574548__4"><h2 id="_CDR0000574548__4_">Introduction</h2><p id="CDR0000574548__6">[<i>Note: Many of the medical and scientific terms used in this summary are found in the <a href="http://www.cancer.gov/cancertopics/genetics-terms-alphalist" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI Dictionary of Genetics Terms</a>. When a linked term is clicked, the definition will appear in a separate window.</i>]</p><p id="CDR0000574548__7">Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2015, about 61,560 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 14,080 deaths.[<a class="bk_pop" href="#CDR0000574548_rl_4_1">1</a>] This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1.[<a class="bk_pop" href="#CDR0000574548_rl_4_2">2</a>] RCC is distinct from kidney cancer that involves the renal pelvis or renal medulla, and it only applies to cancer that forms in the lining of the kidney bed (i.e., in the renal tubules). Genetic <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046063/" class="def">mutations</a> have been identified as the cause of inherited cancer risk in some RCC cancer–prone families; these mutations are estimated to account for only 1% to 2% of RCC cases overall.[<a class="bk_pop" href="#CDR0000574548_rl_4_3">3</a>] It is likely that other undiscovered genes and background genetic factors contribute to the development of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460148/" class="def">familial</a> RCC in conjunction with nongenetic risk factors. About 80% of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic</a> RCC is of clear cell histopathology.[<a class="bk_pop" href="#CDR0000574548_rl_4_2">2</a>] Non–renal cell cancers of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary.</p><p id="CDR0000574548__560">RCC occurs in both sporadic and heritable forms. The following four major <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominantly inherited</a> RCC syndromes have been identified:</p><ul id="CDR0000574548__561"><li class="half_rhythm"><div>von Hippel-Lindau syndrome (VHL).</div></li><li class="half_rhythm"><div>Hereditary leiomyomatosis and renal cell cancer (HLRCC).</div></li><li class="half_rhythm"><div>Hereditary papillary renal cancer (HPRC).</div></li><li class="half_rhythm"><div>Birt-Hogg-Dubé syndrome (BHD).</div></li></ul><p id="CDR0000574548__562">These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062894/">Renal Cell Cancer Treatment</a> for more information and the PDQ summary on <a href="/books/n/pdqcis/CDR0000062937/">Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment</a> for more information about sporadic kidney cancer.) </p><div id="CDR0000574548__12"><h3>Natural History Varies by Histopathology</h3><p id="CDR0000574548__13">The natural history of each of the RCCs varies according to the characteristic histopathology of the renal tumors that arise in the specific syndrome. Although it is useful to follow the predominant reported natural history of each syndrome, each individual <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> will need to be evaluated and monitored for occasional individual variations. The individual prognosis will depend upon the characteristics of the renal tumor at the time of detection and intervention and will differ for each syndrome (VHL, HPRC, BHD, and HLRCC). Prognostic determinants at diagnosis include the stage of the RCC, whether the tumor is confined to the kidney, primary tumor size, Fuhrman nuclear grade, and multifocality.[<a class="bk_pop" href="#CDR0000574548_rl_4_4">4</a>-<a class="bk_pop" href="#CDR0000574548_rl_4_6">6</a>]</p></div><div id="CDR0000574548__14"><h3>Family History as a Risk Factor for RCC</h3><p id="CDR0000574548__15">Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease. The relative risk (RR) is estimated to be 2.5 for a sibling of an RCC-affected patient. This observation was reproducible in a number of studies.[<a class="bk_pop" href="#CDR0000574548_rl_4_7">7</a>,<a class="bk_pop" href="#CDR0000574548_rl_4_8">8</a>] Analysis of renal carcinomas up to the year 2000 in the Sweden Family-Cancer Database, which includes all Swedes born since 1931 and their biological parents, led to the observation that risk of RCC was particularly high in the siblings of those affected with RCC. The higher RR in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[<a class="bk_pop" href="#CDR0000574548_rl_4_7">7</a>] Investigators in Iceland studied all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). In addition, they used an extensive computerized database to perform a unique genealogic study that included more than 600,000 Icelandic individuals. The results revealed that nearly 60% of RCC patients in Iceland during this time period had either a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460150/" class="def">first-degree relative</a> or a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000485395/" class="def">second-degree relative</a> with RCC.[<a class="bk_pop" href="#CDR0000574548_rl_4_8">8</a>]</p><p id="CDR0000574548__16">Because RCC accounts for only about 4% of all adult malignancies in the United States,[<a class="bk_pop" href="#CDR0000574548_rl_4_2">2</a>,<a class="bk_pop" href="#CDR0000574548_rl_4_9">9</a>] the presence of two or more family members with RCC may suggest a hereditary etiology. Having a relative affected with kidney cancer is one of the known epidemiologic risk factors for this disease. There is a 2.5 times greater chance of RCC arising in a sibling of an affected individual than in someone in the general population.[<a class="bk_pop" href="#CDR0000574548_rl_4_7">7</a>,<a class="bk_pop" href="#CDR0000574548_rl_4_8">8</a>,<a class="bk_pop" href="#CDR0000574548_rl_4_10">10</a>] Young age at onset is also a clue to possible hereditary etiology. In contrast with sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of kidney cancer are generally diagnosed at an earlier age. In a review from the National Cancer Institute of over 600 cases of hereditary kidney cancer, the median age at diagnosis was 37 years, with 70% of the cases being diagnosed at age 46 years or younger,[<a class="bk_pop" href="#CDR0000574548_rl_4_11">11</a>] compared with a median age at diagnosis of 64 years in the overall population.[<a class="bk_pop" href="#CDR0000574548_rl_4_12">12</a>]. Bilaterality and multifocality are common in most heritable RCC, except in HLRCC. </p><p id="CDR0000574548__749">There is no consensus regarding whom to refer for genetic consultation for a possible hereditary kidney cancer syndrome, although the following organizations have offered guidance:</p><ul id="CDR0000574548__750"><li class="half_rhythm"><div>American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[<a class="bk_pop" href="#CDR0000574548_rl_4_13">13</a>]</div></li><li class="half_rhythm"><div><a href="http://www.vhl.org/wordpress/medical-professionals/when-to-suspect-vhl/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VHL Alliance</a>.</div></li><li class="half_rhythm"><div>Kidney Cancer Research Network of Canada.[<a class="bk_pop" href="#CDR0000574548_rl_4_14">14</a>]
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</div></li></ul></div><div id="CDR0000574548__21"><h3>Other Risk Factors for RCC</h3><p id="CDR0000574548__22">Studies of environmental and lifestyle factors contributing to the risk of RCC focus almost exclusively on sporadic (i.e., nonhereditary) RCC. Smoking, hypertension, and obesity are the major environmental and lifestyle risk factors associated with RCC.[<a class="bk_pop" href="#CDR0000574548_rl_4_9">9</a>] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046586/" class="def">somatic mutations</a> in the <i>VHL</i> gene.[<a class="bk_pop" href="#CDR0000574548_rl_4_15">15</a>] Dietary intake of vegetables and fruits has been inversely associated with RCC. Greater intake of red meat and milk products have been associated with increased RCC risk, although not consistently.[<a class="bk_pop" href="#CDR0000574548_rl_4_16">16</a>]</p></div><div id="CDR0000574548_rl_4"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000574548_rl_4_1">American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. <a href="http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed July 1, 2015.</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_2">DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_3">Hung RJ, Moore L, Boffetta P, et al.: Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev 16 (6): 1287-90, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17548699" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17548699</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_4">Vira MA, Novakovic KR, Pinto PA, et al.: Genetic basis of kidney cancer: a model for developing molecular-targeted therapies. BJU Int 99 (5 Pt B): 1223-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17441915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17441915</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_5">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="CDR0000574548_rl_4_6">Zbar B, Glenn G, Merino M, et al.: Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol 177 (2): 461-5; discussion 465, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17222609" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17222609</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_7">Hemminki K, Li X: Familial risks of cancer as a guide to gene identification and mode of inheritance. Int J Cancer 110 (2): 291-4, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15069696" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15069696</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_8">Gudbjartsson T, Jónasdóttir TJ, Thoroddsen A, et al.: A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas. Int J Cancer 100 (4): 476-9, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12115533" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12115533</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_9">McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10768591" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10768591</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_10">Teh BT, Giraud S, Sari NF, et al.: Familial non-VHL non-papillary clear-cell renal cancer. Lancet 349 (9055): 848-9, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9121264" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9121264</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_11">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="CDR0000574548_rl_4_12">National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute, 2014. <a href="http://seer.cancer.gov/statfacts/html/kidrp.html" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 5, 2014.</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_13">Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25394175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25394175</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_14">Reaume MN, Graham GE, Tomiak E, et al.: Canadian guideline on genetic screening for hereditary renal cell cancers. Can Urol Assoc J 7 (9-10): 319-23, 2013 Sep-Oct. [<a href="/pmc/articles/PMC3854468/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3854468</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24319509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24319509</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_15">Brauch H, Weirich G, Hornauer MA, et al.: Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst 91 (10): 854-61, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10340905" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10340905</span></a>]</div></li><li><div class="bk_ref" id="CDR0000574548_rl_4_16">Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct. [<a href="/pmc/articles/PMC3077538/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3077538</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18836333" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18836333</span></a>]</div></li></ol></div></div><div id="CDR0000574548__24"><h2 id="_CDR0000574548__24_">Major Heritable Renal Cell Cancer Syndromes</h2><p id="CDR0000574548__468">Four major heritable renal cell cancer syndromes (von Hippel-Lindau syndrome [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé syndrome [BHD], and hereditary papillary renal cancer [HPRC]) with <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominant</a> inheritance are listed in <a class="figpopup" href="/books/NBK169222.1/table/CDR0000574548__484/?report=objectonly" target="object" rid-figpopup="figCDR0000574548484" rid-ob="figobCDR0000574548484">Table 1</a>, along with their <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460209/" class="def">susceptibility genes</a>. VHL and HLRCC are summarized in detail in the following sections of this summary. Sections describing the other major syndromes are in progress.</p><div id="CDR0000574548__484" class="table"><h3><span class="title">Table 1. Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK169222.1/table/CDR0000574548__484/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000574548__484_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Syndrome (Inheritance Pattern)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Gene Locus, Gene Type (Protein)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Renal Tumor Pathology (Cumulative Cancer Risk)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Non-renal Tumors and Associated Abnormalities</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">von Hippel-Lindau syndrome
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(VHL) (AD)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>VHL</i> 3p26, tumor suppressor
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(pVHL)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">ccRCC (multifocal)
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(24%–45%)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">CNS hemangioblastoma, retinal angiomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of epididymis and broad ligament</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Hereditary leiomyomatosis and renal cell cancer (HLRCC)
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(AD)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>FH</i> 1q42.1, tumor suppressor
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(fumarase)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">‘HLRCC-type RCC’
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may be new entity
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(formerly called papillary type 2)
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(unknown frequency)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000765494/" class="def">Cutaneous leiomyomas</a>, uterine leiomyomas (fibroids)</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;">Birt-Hogg-Dubé syndrome (BHD) (AD)
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</td><td colspan="1" rowspan="2" style="vertical-align:top;"><i>FLCN</i> 17p11.2, tumor suppressor (folliculin)</td><td colspan="1" rowspan="2" style="vertical-align:top;">Chromophobe
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oncolytic hybrid, papillary
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clear cell
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oncocytoma
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(15%–30%)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Cutaneous: fibrofolliculomas, trichodiscomas
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Pulmonary: lung cysts, spontaneous pneumothoraces
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Hereditary papillary renal cancer (HPRC)
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(AD)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>MET</i> 7q34, proto-oncogene (hepatocyte growth factor receptor)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Papillary type 1 (approaching 100%)</td><td colspan="1" rowspan="1" style="vertical-align:top;">None known</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.</p></div></dd><dt></dt><dd><div><p class="no_margin">Merck Manual 18th edition.[<a class="bk_pop" href="#CDR0000574548_rl_24_1">1</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin">Choyke et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>]; Lindor et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_3">3</a>]; Lonser et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>]; Rennebeck et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_5">5</a>]; Schmidt et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_6">6</a>]</p></div></dd></dl></div></div></div><p id="CDR0000574548__237">Autosomal dominant mode of inheritance is the pattern of transmission reported within the families <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> by these major renal cell cancer (RCC) syndromes. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for VHL, BHD, HLRCC, and HPRC. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044961/" class="def">Genetic counseling</a> is a prerequisite for genetic testing. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062865/">Cancer Genetics Risk Assessment and Counseling</a> for more information.)</p><div id="CDR0000574548__29"><h3>Von Hippel-Lindau Syndrome</h3><div id="CDR0000574548__238"><h4>Introduction</h4><p id="CDR0000574548__30">VHL (<a href="/omim/193300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">Germline</a>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046063/" class="def">mutations</a> in the <i>VHL</i> gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system (CNS) hemangioblastomas, retinal angiomas, clear cell RCCs (ccRCCs) and cysts, pheochromocytomas, cysts and neuroendocrine tumors (NETs) of the pancreas, endolymphatic sac tumors (ELSTs), and cystadenomas of the epididymis (males) and of the broad ligament (females).[<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_7">7</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_8">8</a>] A multidisciplinary approach is required for the evaluation, and in some cases the management, of individuals with VHL. Specialists involved in the care of individuals with VHL may include urologic oncology surgeons, neurosurgeons, general surgeons, ophthalmologists, endocrinologists, neurologists, medical oncologists, genetic counselors, and medical geneticists.</p></div><div id="CDR0000574548__581"><h4>Genetics</h4><div id="CDR0000574548__582"><h5><i>VHL</i> gene</h5><p id="CDR0000574548__255">The <i>VHL</i> gene is a tumor suppressor gene located on the short arm of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046470/" class="def">chromosome</a> 3 at cytoband 3p25-26.[<a class="bk_pop" href="#CDR0000574548_rl_24_9">9</a>] <i>VHL</i> disease-causing mutations occur in all three <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460146/" class="def">exons</a> of this gene. Most affected individuals inherit a germline mutation of <i>VHL</i> from an affected parent and a normal ("wild-type") <i>VHL</i> from their <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460224/" class="def">unaffected</a> parent. VHL-associated tumors conform with Knudson’s “two-hit” hypothesis,[<a class="bk_pop" href="#CDR0000574548_rl_24_10">10</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_11">11</a>] in which the clonal origin or first transformed cell of the tumor occurs only after both <i>VHL</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339337/" class="def">alleles</a> in a cell are inactivated. The inherited germline mutation in <i>VHL</i> represents the first "hit," which is present in every cell in the body. The second “hit” is a somatic mutation, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, <i>VHL</i> allele, creating a clonal neoplastic cell of origin, which then proliferates into a tumor mass.</p><div id="CDR0000574548__257"><h5>Prevalence and rare founder effects</h5><p id="CDR0000574548__258">The prevalence of VHL has been estimated to be 1 per 35,000 and 1 per 40,000 persons in the general population.[<a class="bk_pop" href="#CDR0000574548_rl_24_12">12</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_13">13</a>] Thus, the number of VHL-affected individuals in the United States is estimated at between 6,000 and 7,000. Precise quantification of this number is a challenge because it requires comprehensive screening of potentially at-risk blood relatives of individuals diagnosed with VHL. Within this population, the large number of unique mutations in this small three-exon gene indicates that most family clusters have not arisen from a single founder. A founder effect was reported when a large U.S. family was compared with a family in Germany, both of whom had pheochromocytoma-predominant VHL.[<a class="bk_pop" href="#CDR0000574548_rl_24_14">14</a>]</p></div><div id="CDR0000574548__259"><h5>Penetrance of mutations</h5><p id="CDR0000574548__260"><i>VHL</i> mutations are highly penetrant and overall penetrance is greater than 90% by age 65 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_12">12</a>] Almost all <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460132/" class="def">carriers</a> develop one or more types of syndrome-related neoplasms.</p></div><div id="CDR0000574548__239"><h5>Risk factors for VHL</h5><p id="CDR0000574548__241">Each offspring of an individual with VHL has a 50% chance of inheriting the mutated <i>VHL</i> allele from their affected parent. The primary factors affecting the chances of developing VHL are: 1) a relative with VHL; 2) a germline mutation in the <i>VHL</i> gene; 3) a family member with one of the manifestations of VHL (e.g., CNS hemangioblastomas). (Refer to the <a href="#CDR0000574548__280">Genetic diagnosis</a> section of this summary for more information.)</p></div><div id="CDR0000574548__263"><h5>Genotype-phenotype correlations</h5><p id="CDR0000574548__475">There are a few highly predictive, direct <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotype</a>-<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> correlations.[<a class="bk_pop" href="#CDR0000574548_rl_24_15">15</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_16">16</a>]</p><p id="CDR0000574548__264">For example, pheochromocytoma without RCCs is the VHL pattern found in a large family with a single nucleotide change at position 505.[<a class="bk_pop" href="#CDR0000574548_rl_24_8">8</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_15">15</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_17">17</a>] A similar family outside the United States was identified and found to have a common ancestor (i.e., a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000570712/" class="def">founder mutation</a>).[<a class="bk_pop" href="#CDR0000574548_rl_24_17">17</a>] However, no common ancestor was identified for several other mutations that occurred in multiple families. In general, founder mutations do not comprise a significant fraction of all <i>VHL</i> mutations. Single nucleotide changes at position 712 and 713 are “hot spots” for mutations leading to pheochromocytomas.[<a class="bk_pop" href="#CDR0000574548_rl_24_17">17</a>] Mutation types leading to clinical VHL include <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460164/" class="def">missense</a>, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000671174/" class="def">nonsense</a>, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460152/" class="def">frameshifts</a>, insertions, partial and complete <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460141/" class="def">deletions</a>, and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000766216/" class="def">splice-site mutations</a> of <i>VHL</i>.</p></div><div id="CDR0000574548__265"><h5>De novo mutations and mosaicism</h5><p id="CDR0000574548__567">When a VHL diagnosis is made in an individual whose ancestors (biological parents and their kindred) do not have VHL, this may result from a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460142/" class="def">de novo</a> (new) <i>VHL</i> mutation in the affected individual. Patients diagnosed with VHL, who have no family history of VHL, have been estimated to comprise about 23% of VHL kindreds.[<a class="bk_pop" href="#CDR0000574548_rl_24_18">18</a>] A new mutation is by definition a postzygotic event, because it is not transmitted from a parent. </p><p id="CDR0000574548__266">Depending on the embryogenesis stage at which the new mutation occurs, there may be different somatic cell lineages carrying the mutation; this influences the extent of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460197/" class="def">mosaicism</a>. Mosaicism is the presence in an individual of two or more cell lines that differ in genotype but which arise from a single zygote.[<a class="bk_pop" href="#CDR0000574548_rl_24_19">19</a>] If the postzygotic de novo mutation affects the gonadal cell line, there is a risk of transmitting a germline mutation to offspring.[<a class="bk_pop" href="#CDR0000574548_rl_24_18">18</a>]</p></div><div id="CDR0000574548__26"><h5>Allelic disorder</h5><p id="CDR0000574548__27"><i>VHL</i>-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or compound heterozygous mutations in <i>VHL</i> in which affected individuals develop abnormally high numbers of red blood cells. The affected individuals have biallelic mutations in the <i>VHL</i> gene. The typical VHL syndromic tumors do not occur in these affected individuals.[<a class="bk_pop" href="#CDR0000574548_rl_24_20">20</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_22">22</a>]</p></div></div><div id="CDR0000574548__588"><h5>Other genetic lesions</h5><p id="CDR0000574548__595">In sporadic RCC, other genetic lesions have been found. These include <i>PBRM1</i>, <i>SETD2</i>, and <i>BAP1</i> and may have relevance in RCC arising in VHL patients. Future studies will define their significance in the hereditary patient population.[<a class="bk_pop" href="#CDR0000574548_rl_24_23">23</a>] </p></div></div><div id="CDR0000574548__583"><h4>Molecular biology</h4><p id="CDR0000574548__596">The <i>VHL</i> gene product, pVHL, is a 213 amino acid protein that regulates hypoxia-inducible factors (HIFs), maintains a normal extracellular matrix, is involved in microtubule and centrosome regulation, and regulates the cell cycle.[<a class="bk_pop" href="#CDR0000574548_rl_24_24">24</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_26">26</a>] These functions are described in more detail in the following paragraphs. </p><div id="CDR0000574548__597"><h5>HIF1-alpha and HIF2-alpha</h5><p id="CDR0000574548__598">pVHL regulates protein levels of HIF1-alpha and HIF2-alpha in the cell by acting as an E3 ubiquitin ligase for HIF. In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome. </p><p id="CDR0000574548__599">Under hypoxic conditions, hydroxylation does not occur; HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex and are not ubiquitinated. The resulting high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of proteins. Loss of functional pVHL creates a pseudohypoxic state, with uncontrolled HIF1-alpha and HIF2-alpha protein levels, and resultant inappropriate transcription of HIF-dependent genes.</p><p id="CDR0000574548__600">HIF1-alpha and HIF2-alpha possess distinct functional characteristics, and a shift towards a HIF2-alpha–dominant phenotype occurs in RCC. HIF1-alpha and HIF2-alpha may preferentially upregulate Myc activity.[<a class="bk_pop" href="#CDR0000574548_rl_24_27">27</a>] Hypoxia activated factor has been shown to increase HIF2-alpha transactivation [<a class="bk_pop" href="#CDR0000574548_rl_24_28">28</a>] and HIF1-alpha instability.[<a class="bk_pop" href="#CDR0000574548_rl_24_29">29</a>] Preferential loss of chromosome 14q, the locus for the<i> HIF1-alpha</i> gene, results in decreased levels of HIF1-alpha.[<a class="bk_pop" href="#CDR0000574548_rl_24_30">30</a>]</p></div><div id="CDR0000574548__601"><h5>Microtubule regulation and cilia centrosome control</h5><p id="CDR0000574548__602">Emerging data point to the importance of pVHL-mediated control of the primary cilium and the cilia centrosome cycle. The nonmotile primary cilium acts as a mechanosensor, is a regulator of cell signaling, and controls cellular entry into mitosis.[<a class="bk_pop" href="#CDR0000574548_rl_24_31">31</a>] Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation.[<a class="bk_pop" href="#CDR0000574548_rl_24_32">32</a>] Loss of pVHL results in loss of the primary cilium.[<a class="bk_pop" href="#CDR0000574548_rl_24_33">33</a>] pVHL binds to and stabilizes microtubules [<a class="bk_pop" href="#CDR0000574548_rl_24_34">34</a>] in a glycogen synthase 3–dependent fashion.[<a class="bk_pop" href="#CDR0000574548_rl_24_35">35</a>] Loss of pVHL or expression of mutated pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.[<a class="bk_pop" href="#CDR0000574548_rl_24_26">26</a>] </p></div><div id="CDR0000574548__603"><h5>Cell cycle control</h5><p id="CDR0000574548__604">pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[<a class="bk_pop" href="#CDR0000574548_rl_24_24">24</a>] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> damage.[<a class="bk_pop" href="#CDR0000574548_rl_24_36">36</a>] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[<a class="bk_pop" href="#CDR0000574548_rl_24_37">37</a>] pVHL binds to, stabilizes, and transactivates p53 [<a class="bk_pop" href="#CDR0000574548_rl_24_38">38</a>] in a phosphorylation-dependent fashion.[<a class="bk_pop" href="#CDR0000574548_rl_24_39">39</a>] The importance of these findings is underscored by the findings that p53 is an important regulator of mitotic checkpoints, and loss of p53 permits aneuploid cells to survive.[<a class="bk_pop" href="#CDR0000574548_rl_24_40">40</a>]</p></div><div id="CDR0000574548__605"><h5>Extracellular matrix control</h5><p id="CDR0000574548__606">Functional pVHL is needed to form an extracellular fibronectin matrix.[<a class="bk_pop" href="#CDR0000574548_rl_24_41">41</a>] Additionally, pVHL directly binds to, phosphorylates, and regulates fibronectin.[<a class="bk_pop" href="#CDR0000574548_rl_24_42">42</a>] Collagen IV homeostasis is also regulated by pVHL. pVHL isoforms that are collagen IV binding–incompetent demonstrated a malignant phenotype.[<a class="bk_pop" href="#CDR0000574548_rl_24_25">25</a>]</p></div><div id="CDR0000574548__607"><h5>Animal models of VHL</h5><p id="CDR0000574548__608">No representative VHL animal models are currently available. <i>Vhlh</i> gene knockout in mice did not produce RCC or hemangioblastomas.[<a class="bk_pop" href="#CDR0000574548_rl_24_43">43</a>] Murine homologues of the R200W-induced polycythemia in mice, phenocopying Chuvash polycythemia.[<a class="bk_pop" href="#CDR0000574548_rl_24_44">44</a>] A R167Q homologue did not generate RCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_45">45</a>] Coordinate inactivation of <i>Vhlh</i> and <i>Pten</i> resulted in a higher rate of cyst formation, but, once again, no obvious RCC was observed.[<a class="bk_pop" href="#CDR0000574548_rl_24_46">46</a>] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including <i>PBRM1</i>,[<a class="bk_pop" href="#CDR0000574548_rl_24_47">47</a>] <i>SETD2</i>,[<a class="bk_pop" href="#CDR0000574548_rl_24_48">48</a>] and <i>BAP1</i> [<a class="bk_pop" href="#CDR0000574548_rl_24_49">49</a>] provide new avenues for developing relevant animal models of at least some VHL disease manifestations.</p></div></div><div id="CDR0000574548__584"><h4>Clinical manifestations</h4><div id="CDR0000574548__247"><h5>Age ranges and cumulative risk of different syndrome-related neoplasms</h5><p id="CDR0000574548__248">The age at onset of VHL varies both from family to family and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. The youngest age at onset of specific VHL syndrome components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. Examples of reported mean ages and age ranges of the following manifestations are summarized in Table 2.</p><div id="CDR0000574548__486" class="table"><h3><span class="title">Table 2. Neoplasms in von Hippel-Lindau Syndrome: Mean Age at Diagnosis and Cumulative Risk in Patients Affected</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK169222.1/table/CDR0000574548__486/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000574548__486_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Neoplasm</th><th colspan="1" rowspan="1" style="vertical-align:top;">Mean Age
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(Range) in y
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</th><th colspan="1" rowspan="1" style="vertical-align:top;">Cumulative Risk
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(%)
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</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Renal cell cancer </b></td><td colspan="1" rowspan="1" style="vertical-align:top;">37 (16–67) </td><td colspan="1" rowspan="1" style="vertical-align:top;">24–45</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Pheochromocytoma </b></td><td colspan="1" rowspan="1" style="vertical-align:top;">30 (5–58) </td><td colspan="1" rowspan="1" style="vertical-align:top;">10–20</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Pancreatic tumor or cyst </b></td><td colspan="1" rowspan="1" style="vertical-align:top;">36 (5–70)</td><td colspan="1" rowspan="1" style="vertical-align:top;">35–70</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Retinal hemangioblastoma</b>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">25 (1–67) </td><td colspan="1" rowspan="1" style="vertical-align:top;">25–60</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Cerebellar hemangioblastoma </b></td><td colspan="1" rowspan="1" style="vertical-align:top;">33 (9–78)</td><td colspan="1" rowspan="1" style="vertical-align:top;">44–72</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Brainstem hemangioblastoma</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">32 (12–46)</td><td colspan="1" rowspan="1" style="vertical-align:top;">10–25</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Spinal cord hemangioblastoma</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">33 (12–66)</td><td colspan="1" rowspan="1" style="vertical-align:top;"> 13–50</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Endolymphatic sac tumor</b>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">22 (12–50)</td><td colspan="1" rowspan="1" style="vertical-align:top;">10</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from Choyke et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>] and Lonser et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>]</p></div></dd></dl></div></div></div><p id="CDR0000574548__592">(Refer to the <a href="#CDR0000574548__563">Clinical diagnosis</a> section of this summary for more information.)</p></div><div id="CDR0000574548__261"><h5>VHL familial phenotypes</h5><p id="CDR0000574548__262">Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[<a class="bk_pop" href="#CDR0000574548_rl_24_13">13</a>] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[<a class="bk_pop" href="#CDR0000574548_rl_24_14">14</a>] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_50">50</a>] These specific VHL phenotypes are summarized below.</p><div id="CDR0000574548__575" class="table"><h3><span class="title">Table 3. Genotype-Phenotype Classification of Families With von Hippel-Lindau Syndrome<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK169222.1/table/CDR0000574548__575/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000574548__575_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Type </th><th colspan="1" rowspan="1" style="vertical-align:top;">Clinical Characteristics</th></tr></thead><tbody><tr><td colspan="1" rowspan="4" style="vertical-align:top;">1
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Retinal hemangioblastomas
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">CNS hemangioblastomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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Renal cell cancers</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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Pancreatic neoplasms and cysts</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">2A</td><td colspan="1" rowspan="1" style="vertical-align:top;">Pheochromocytomas
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Retinal hemangioblastomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">CNS hemangioblastomas
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</td></tr><tr><td colspan="1" rowspan="5" style="vertical-align:top;">2B</td><td colspan="1" rowspan="1" style="vertical-align:top;">Pheochromocytomas
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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Retinal hemangioblastomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">CNS hemangioblastomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Renal cell cancers</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Pancreatic neoplasms and cysts
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">2C
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Pheochromocytomas only</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CNS = central nervous system.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Lonser et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>]</p></div></dd></dl></div></div></div></div></div><div id="CDR0000574548__585"><h4>Tissue manifestations</h4><p id="CDR0000574548__532"><div class="milestone-start" id="CDR0000574548__531"></div>More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass.[<a class="bk_pop" href="#CDR0000574548_rl_24_51">51</a>] Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2 or 4) and minimally invasive,[<a class="bk_pop" href="#CDR0000574548_rl_24_52">52</a>] and their rate of growth varies widely.[<a class="bk_pop" href="#CDR0000574548_rl_24_53">53</a>] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a cyst to a solid lesion was rare.[<a class="bk_pop" href="#CDR0000574548_rl_24_51">51</a>] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL.</p><p id="CDR0000574548__533">Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[<a class="bk_pop" href="#CDR0000574548_rl_24_53">53</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_54">54</a>] RCCs often remain asymptomatic for long intervals.</p><p id="CDR0000574548__664">Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>] Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas).[<a class="bk_pop" href="#CDR0000574548_rl_24_55">55</a>] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[<a class="bk_pop" href="#CDR0000574548_rl_24_56">56</a>]</p><div id="CDR0000574548__713"><h5>Retinal hemangioblastomas</h5><p id="CDR0000574548__735">Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[<a class="bk_pop" href="#CDR0000574548_rl_24_57">57</a>]
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Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 35.9 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_58">58</a>]
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These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children younger than 10 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_58">58</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_59">59</a>]</p><p id="CDR0000574548__736">Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[<a class="bk_pop" href="#CDR0000574548_rl_24_57">57</a>] The median number of lesions per affected eye is approximately six.[<a class="bk_pop" href="#CDR0000574548_rl_24_60">60</a>]
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Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[<a class="bk_pop" href="#CDR0000574548_rl_24_61">61</a>]</p><p id="CDR0000574548__737">Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [<a class="bk_pop" href="#CDR0000574548_rl_24_57">57</a>] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[<a class="bk_pop" href="#CDR0000574548_rl_24_62">62</a>]
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Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[<a class="bk_pop" href="#CDR0000574548_rl_24_60">60</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_63">63</a>]</p></div><div id="CDR0000574548__714"><h5>Cerebellar and spinal hemangioblastomas</h5><p id="CDR0000574548__715">Hemangioblastomas are the most common disease manifestation in patients with VHL, potentially affecting more than 70% of individuals. In a prospective study of 225 patients with known hemangioblastomas, lesions were distributed in the cerebellum (45%), spinal cord (36%), cauda equine (11%), brainstem (7%), supratentorium (1%), and nerve roots (0.3%).[<a class="bk_pop" href="#CDR0000574548_rl_24_64">64</a>] Increased tumor burden was associated with partial deletions in the <i>VHL</i> gene (<i>P</i> = .005) and male sex (<i>P</i> = .002). One hundred sixty-two patients (72%) exhibited new CNS hemangioblastomas during the study, yielding a median of 0.3 new lesions per year per patient in this group. New lesions were associated with younger age (<i>P</i> = .001) and more tumors at study entrance (<i>P</i> = .0001). Forty-nine percent of lesions grew during the observation period. Growth was salutatory in 72%, exponential in 22%, linear in 6% of lesions. Faster growth was associated with male sex (<i>P</i> = .001), symptomatic tumors (<i>P</i> = .0001), and tumors associated with cysts (<i>P</i> = .0001). </p></div><div id="CDR0000574548__716"><h5>Pheochromocytomas and paragangliomas</h5><p id="CDR0000574548__738">The rate of pheochromocytoma formation in the VHL patient population is approximately 25%,[<a class="bk_pop" href="#CDR0000574548_rl_24_65">65</a>] with bilaterality occurring in some patients. Of patients with VHL pheochromocytomas, 44% developed disease in both adrenal glands.[<a class="bk_pop" href="#CDR0000574548_rl_24_66">66</a>] One study reported a mean age at onset for pheochromocytoma in VHL patients of 30 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>]
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Rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL disease,[<a class="bk_pop" href="#CDR0000574548_rl_24_67">67</a>] and approximately two-thirds will experience physical manifestations.[<a class="bk_pop" href="#CDR0000574548_rl_24_65">65</a>] Missense <i>VHL</i> gene mutations correlated with the risk of pheochromocytoma in patients with VHL,[<a class="bk_pop" href="#CDR0000574548_rl_24_65">65</a>] with a low incidence of pheochromocytoma in patients with complete deletion of the <i>VHL</i> gene. The rate of <i>VHL</i> germline mutation in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL disease.[<a class="bk_pop" href="#CDR0000574548_rl_24_68">68</a>]</p><p id="CDR0000574548__739">Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[<a class="bk_pop" href="#CDR0000574548_rl_24_69">69</a>] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[<a class="bk_pop" href="#CDR0000574548_rl_24_66">66</a>]</p><p id="CDR0000574548__756">The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas in one series was 31 years, and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions (19 vs. 34 years; <i>P</i> < .001).[<a class="bk_pop" href="#CDR0000574548_rl_24_70">70</a>]</p></div><div id="CDR0000574548__717"><h5>Endolymphatic sac tumors (ELSTs)</h5><p id="CDR0000574548__754">ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[<a class="bk_pop" href="#CDR0000574548_rl_24_71">71</a>]
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ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[<a class="bk_pop" href="#CDR0000574548_rl_24_71">71</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_72">72</a>]
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Approximately 30% of VHL patients with ELSTs have bilateral lesions.[<a class="bk_pop" href="#CDR0000574548_rl_24_71">71</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_73">73</a>]</p><p id="CDR0000574548__770">ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[<a class="bk_pop" href="#CDR0000574548_rl_24_71">71</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_72">72</a>] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[<a class="bk_pop" href="#CDR0000574548_rl_24_72">72</a>] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[<a class="bk_pop" href="#CDR0000574548_rl_24_71">71</a>]</p><p id="CDR0000574548__755">Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[<a class="bk_pop" href="#CDR0000574548_rl_24_74">74</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_75">75</a>] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[<a class="bk_pop" href="#CDR0000574548_rl_24_72">72</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_74">74</a>]
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</p></div><div id="CDR0000574548__718"><h5>Broad/round ligament papillary cystadenomas</h5><p id="CDR0000574548__751">Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[<a class="bk_pop" href="#CDR0000574548_rl_24_76">76</a>] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[<a class="bk_pop" href="#CDR0000574548_rl_24_77">77</a>] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[<a class="bk_pop" href="#CDR0000574548_rl_24_78">78</a>] Therefore, any female with a broad ligament papillary cystadenoma should be referred for genetic counseling. These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior. </p></div><div id="CDR0000574548__719"><h5>Epididymal cysts</h5><p id="CDR0000574548__752">More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL disease.[<a class="bk_pop" href="#CDR0000574548_rl_24_79">79</a>] Among symptomatic patients, the most common presentation is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[<a class="bk_pop" href="#CDR0000574548_rl_24_80">80</a>]</p><p id="CDR0000574548__753">One group of investigators observed that epididymal tumorigenesis in VHL disease occurred in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells caused by developmental arrest of progenitor cells, followed by neoplastic papillary proliferation with activation/up-regulation of HIF and VEGF, associated with continuous reactive fibrovascular proliferation.[<a class="bk_pop" href="#CDR0000574548_rl_24_81">81</a>] In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. CAIX was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000574548_rl_24_77">77</a>]</p></div></div><div id="CDR0000574548__586"><h4>Management</h4><div id="CDR0000574548__277"><h5>Risk assessment for Von Hippel-Lindau syndrome</h5><p id="CDR0000574548__529">The primary risk factor for VHL (or any of the hereditary forms of renal cancer under consideration) is the presence of a family member affected with the disease. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460214/" class="def">Risk assessment</a> should also consider gender and age for some specific VHL-related neoplasms. For example, pheochromocytomas may have onset in early childhood,[<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>] as early as 8 years of age.[<a class="bk_pop" href="#CDR0000574548_rl_24_82">82</a>] Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%–26%), which are virtually pathognomonic for VHL, especially when bilateral, and are rare in the general male population. Epididymal cysts are also common in VHL, but they are reported in 23% of the general male population, making them a poor diagnostic discriminator.[<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>]</p><p id="CDR0000574548__530">Each offspring of an individual with VHL has a 50% chance of inheriting the mutated <i>VHL</i> allele from their affected parent. Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, then a patient with one or more specific VHL-type tumors (e.g., hemangioblastoma of the CNS or retina, pheochromocytoma, or ccRCC) may be diagnosed with VHL.</p><div id="CDR0000574548__278"><h5>Genetic testing</h5><p id="CDR0000574548__593">At-risk family members should be informed that genetic testing for VHL is available. A family member with a clinical diagnosis of VHL or who is showing signs and symptoms of VHL is offered genetic testing initially. Germline mutations in <i>VHL</i> are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point mutations in the <i>VHL</i> gene (~72% of all mutations).[<a class="bk_pop" href="#CDR0000574548_rl_24_83">83</a>] Using <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460219/" class="def">Southern blot</a> analysis and/or quantitative polymerase chain reaction to detect partial or complete gene deletions will detect <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000556486/" class="def">deleterious mutations</a> in the remaining 28% of <i>VHL</i> families.[<a class="bk_pop" href="#CDR0000574548_rl_24_83">83</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_84">84</a>] The technique has a detection rate approaching 100%.[<a class="bk_pop" href="#CDR0000574548_rl_24_83">83</a>] Newer techniques such as array comparative genomic hybridization (array CGH) are powerful tools for identifying genomic imbalances. Anecdotal evidence exists for the utility of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000763024/" class="def">next-generation sequencing</a> in cases of suspected mosaicism with a negative <i>VHL</i> genetic test.[<a class="bk_pop" href="#CDR0000574548_rl_24_85">85</a>]</p><p id="CDR0000574548__279">Genetic counseling is first provided, including discussion of the medical, economic, and psychosocial implications for the patient and their bloodline relatives. After counseling, the patient may choose to voluntarily undergo testing, after providing informed consent. Additional counseling is given at the time results are reported to the patient. When a <i>VHL</i> mutation is identified in a family member, their biologic relatives who then test negative for the same mutation are not carriers of the trait (i.e., they are true negatives) and are <b>not</b> predisposed to developing any VHL manifestations. Equally important, the children of true-negative family members are not as risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.[<a class="bk_pop" href="#CDR0000574548_rl_24_7">7</a>]</p></div><div id="CDR0000574548__280"><h5>Genetic diagnosis</h5><p id="CDR0000574548__281">A germline mutation in the <i>VHL</i> gene is considered a genetic diagnosis. It is expected to carry a predisposition to clinical VHL and confers a 50% risk among offspring to inherit the <i>VHL</i> mutation. Approximately 400 unique mutations in the <i>VHL</i> gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the mutation. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a <i>VHL</i> mutation is identified, that specific mutation becomes the DNA marker for which other biological relatives may be tested. In cases where there is a clear VHL clinical diagnosis without a <i>VHL</i> mutation by usual testing of peripheral blood lymphocytes and without a history of VHL in the biological parents or in the parents’ <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460158/" class="def">kindreds</a>, then either a de novo mutation or mosaicism may be the cause. The latter may be detected by performing genetic testing on other bodily tissues, such as skin fibroblasts or exfoliated buccal cells.</p></div><div id="CDR0000574548__563"><h5>Clinical diagnosis</h5><p id="CDR0000574548__243">Diagnosis of VHL is frequently based on clinical criteria (see <a class="figpopup" href="/books/NBK169222.1/table/CDR0000574548__485/?report=objectonly" target="object" rid-figpopup="figCDR0000574548485" rid-ob="figobCDR0000574548485">Table 4</a>). If there is family history of VHL, then a previously unevaluated family member may be diagnosed clinically if they present with one or more specific VHL-related tumors (e.g., CNS or retinal hemangioblastoma, pheochromocytoma, ccRCC, or endolymphatic sac tumor). If there is no family history of VHL, then a clinical diagnosis requires that the patient have two or more CNS hemangioblastomas or one CNS hemangioblastoma and a visceral tumor or endolymphatic sac tumor. See <a class="figpopup" href="/books/NBK169222.1/table/CDR0000574548__485/?report=objectonly" target="object" rid-figpopup="figCDR0000574548485" rid-ob="figobCDR0000574548485">Table 4</a> for more diagnostic details.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_7">7</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_8">8</a>]</p><p id="CDR0000574548__244">Since 1998, when a cohort of 93 VHL families in whom all germline mutations were identified was reported, diagnoses have included a combined approach of clinical and genetic testing within families. The diagnostic strategy differs among individual family members. <a class="figpopup" href="/books/NBK169222.1/table/CDR0000574548__485/?report=objectonly" target="object" rid-figpopup="figCDR0000574548485" rid-ob="figobCDR0000574548485">Table 4</a> summarizes a combined approach of genetic testing and clinical diagnosis.</p><div id="CDR0000574548__485" class="table"><h3><span class="title">Table 4. Diagnostic Approaches to von Hippel-Lindau Syndrome (VHL) in Individuals With and Without a Family History</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK169222.1/table/CDR0000574548__485/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000574548__485_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Family History of VHL </th><th colspan="1" rowspan="1" style="vertical-align:top;"> Genetic Testing </th><th colspan="1" rowspan="1" style="vertical-align:top;">Clinical Diagnosis</th><th colspan="1" rowspan="1" style="vertical-align:top;"> Requirements for Clinical Diagnosis</th></tr></thead><tbody><tr><td colspan="1" rowspan="9" style="vertical-align:top;"><b>With a family history of VHL</b></td><td colspan="1" rowspan="9" style="vertical-align:top;">Test DNA for the same <i>VHL</i> gene mutation as previously identified in affected biologic relative(s)</td><td colspan="1" rowspan="9" style="vertical-align:top;">When <i>VHL</i> gene mutation is unknown for a biologic relative</td><td colspan="1" rowspan="1" style="vertical-align:top;"><b>One or more of the following is required for a clinical diagnosis:</b></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Epididymal or broad ligament cystadenomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- CNS hemangioblastoma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- ccRCC, multifocal</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Pheochromocytoma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Retinal angiomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Pancreatic neuroendocrine tumor</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Pancreatic cysts and/or cystadenomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Endolymphatic sac tumor</td></tr><tr><td colspan="1" rowspan="9" style="vertical-align:top;"><b>Without a family history of VHL</b></td><td colspan="1" rowspan="9" style="vertical-align:top;"> May be negative if the <i>VHL</i> mutation occurred postzygotically (e.g., <i>VHL</i> mosaicism) </td><td colspan="1" rowspan="9" style="vertical-align:top;">When <i>VHL</i> mutation is unknown or germline negative, but there are clinical signs compatible for VHL</td><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Either or both of the following are required for a clinical diagnosis:</b></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- CNS hemangioblastoma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Retinal angiomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>If only one of the above is present, then also one of the following:</b></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- ccRCC</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Pheochromocytoma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Pancreatic cysts and/or cystadenomas</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Endolymphatic sac tumor</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">- Epididymal or broad ligament cystadenomas</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CNS = central nervous system; ccRCC = clear cell renal cell cancer; VHL = von Hippel-Lindau syndrome. </p></div></dd><dt></dt><dd><div><p class="no_margin">Adapted and updated from Glenn et al. [<a class="bk_pop" href="#CDR0000574548_rl_24_8">8</a>] and Pithukpakorn and Glenn.[<a class="bk_pop" href="#CDR0000574548_rl_24_7">7</a>]</p></div></dd></dl></div></div></div></div></div><div id="CDR0000574548__293"><h5>Surveillance</h5><p id="CDR0000574548__294">Surveillance guidelines that have been suggested for various manifestations of VHL are summarized in <a class="figpopup" href="/books/NBK169222.1/table/CDR0000574548__487/?report=objectonly" target="object" rid-figpopup="figCDR0000574548487" rid-ob="figobCDR0000574548487">Table 5</a>. In general, these recommendations are based on expert opinion and consensus; most are not evidence-based. These modalities may be used for the initial clinical diagnostic testing and also for periodic surveillance of at-risk individuals for early detection of developing neoplasm. Periodic presymptomatic screening is advised for at-risk individuals. At-risk individuals are those testing positive for a <i>VHL</i> mutation and those individuals who choose not to be tested for a <i>VHL</i> mutation but have biologic relatives affected by VHL. The risk of inheriting the VHL predisposition in such persons may be as high as 50%.</p><div id="CDR0000574548__487" class="table"><h3><span class="title">Table 5. Practice Guidelines for Surveillance of von Hippel-Lindau Syndrome (VHL)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK169222.1/table/CDR0000574548__487/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000574548__487_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Examination/Test </th><th colspan="1" rowspan="1" style="vertical-align:top;">Condition Screened For</th><th colspan="1" rowspan="1" style="vertical-align:top;">Starting Age/Frequency<sup>a</sup></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Ophthalmoscopy </td><td colspan="1" rowspan="1" style="vertical-align:top;">Retinal hemangioblastoma</td><td colspan="1" rowspan="1" style="vertical-align:top;">From infancy; every 6 to 12 mo</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Fluorescein angioscopy </td><td colspan="1" rowspan="1" style="vertical-align:top;">Retinal hemangioblastoma</td><td colspan="1" rowspan="1" style="vertical-align:top;"> If needed (not routinely performed)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Plasma or 24-hour urinary
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catecholamines and metanephrines </td><td colspan="1" rowspan="1" style="vertical-align:top;">Pheochromocytoma</td><td colspan="1" rowspan="1" style="vertical-align:top;">From age 2 y; yearly and as clinically indicated when blood pressure is elevated
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Enhanced MRI of brain/spine<sup>b</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">CNS and peripheral hemangioblastoma</td><td colspan="1" rowspan="1" style="vertical-align:top;">From age 11 y; every 1 to 2 y and
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if symptoms appear</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">CT of abdomen with and without contrast
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(substitute MRI every other year)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Renal, pancreatic, and adrenal neoplasms and cysts</td><td colspan="1" rowspan="1" style="vertical-align:top;">From age 18 y, earlier if indicated; yearly; alternate CT and MRI (reduces radiation)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Ultrasound of abdomen</td><td colspan="1" rowspan="1" style="vertical-align:top;">Renal, pancreatic, and adrenal neoplasms and cysts</td><td colspan="1" rowspan="1" style="vertical-align:top;">Yearly from age 8 to 18 y, earlier if
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indicated; MRI as clinically indicated
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MRI and CT of IACs, audiology, neurology</td><td colspan="1" rowspan="1" style="vertical-align:top;">Endolymphatic sac tumor</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any age for hearing loss, tinnitus, or vertigo</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CNS = central nervous system; CT = computerized tomography; IACs = internal auditory canals; MRI = magnetic resonance imaging. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Frequencies of exams or tests may be increased at organ sites of VHL lesions being monitored. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>Brain MRIs may be used to examine areas of the IACs for signs of endolymphatic sac tumors (ELSTs). If signs or symptoms of ELSTs are present, examine IACs by CT and MRI. </p></div></dd><dt></dt><dd><div><p class="no_margin">Adapted from Pithukpakorn and Glenn [<a class="bk_pop" href="#CDR0000574548_rl_24_7">7</a>]; Choyke et al. [<a class="bk_pop" href="#CDR0000574548_rl_24_2">2</a>]; and Lonser et al.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>]</p></div></dd></dl></div></div></div><p id="CDR0000574548__694"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000526280/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000574548__587"><h5>Surgical interventions</h5><p id="CDR0000574548__720">The management of VHL has changed significantly as clinicians have learned how to best balance the risk of cancer dissemination while minimizing renal morbidity. Some of the initial surgical series focused on performing a bilateral radical nephrectomy for renal tumors followed by a renal transplantation.[<a class="bk_pop" href="#CDR0000574548_rl_24_86">86</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_87">87</a>]
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Nephron-sparing surgery (NSS) for VHL was introduced in the 1980s after several groups demonstrated a low risk of cancer dissemination with a less-radical surgical approach.[<a class="bk_pop" href="#CDR0000574548_rl_24_88">88</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_89">89</a>]
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In 1995, a large, multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_90">90</a>]
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Because of multiple reports of excellent outcomes, when feasible, NSS is now considered the surgical standard of care. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. To avoid the taking of a wide margin, enucleative resection was developed and allows the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.[<a class="bk_pop" href="#CDR0000574548_rl_24_91">91</a>]</p><p id="CDR0000574548__721">Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. To minimize the morbidity of multiple surgical procedures, loss of kidney function, and the risk of distant progression, a specific timing for intervention was questioned. The National Cancer Institute evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated before the largest lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[<a class="bk_pop" href="#CDR0000574548_rl_24_53">53</a>] Later series reinforced that this was an important threshold because 0 of 108 patients with tumors managed at 3 cm or smaller had evidence of distant spread.[<a class="bk_pop" href="#CDR0000574548_rl_24_92">92</a>] For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence.[<a class="bk_pop" href="#CDR0000574548_rl_24_92">92</a>]
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This threshold is now widely used to trigger surgical intervention for VHL-associated ccRCC. When surgery is performed on a patient with VHL, resection of more than a dozen renal tumors may be necessary.[<a class="bk_pop" href="#CDR0000574548_rl_24_93">93</a>]
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The use of intraoperative ultrasound to identify and then remove smaller lesions may delay the need for further surgical interventions.[<a class="bk_pop" href="#CDR0000574548_rl_24_94">94</a>]
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</p><p id="CDR0000574548__722">Many patients with VHL develop new RCCs on an ongoing basis and may require further intervention. Adhesions and perinephric scarring make subsequent surgical procedures more challenging. While a radical nephrectomy could be considered, NSS is still the preferred approach, when feasible. While there may be a higher incidence of complications, repeat and salvage NSS can enable patients to maintain excellent renal functional outcomes and provide promising oncologic outcomes at intermediate follow-up.[<a class="bk_pop" href="#CDR0000574548_rl_24_95">95</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_96">96</a>]
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These surgeries may be best handled at a specialized center with significant experience with this surgical approach.[<a class="bk_pop" href="#CDR0000574548_rl_24_97">97</a>]</p><p id="CDR0000574548__683"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531840/" class="def">Level of evidence: 3di</a></p></div><div id="CDR0000574548__610"><h5>Ablative techniques</h5><div id="CDR0000574548__723"><h5>Radiofrequency ablation (RFA) and cryoablation (CA)</h5><p id="CDR0000574548__724">Thermal ablative techniques utilize either heating or cooling of a mass in an effort to destroy the tumor. Cryoablation (CA) and radiofrequency ablation (RFA) were introduced into the management of small renal masses in the late 1990s.[<a class="bk_pop" href="#CDR0000574548_rl_24_98">98</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_99">99</a>]
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For sporadic renal masses, both thermal ablative techniques have a nearly 90% recurrence-free survival rate, leading the American Urologic Association to consider this as a recommendation in high-risk patients with a small renal mass.[<a class="bk_pop" href="#CDR0000574548_rl_24_100">100</a>] For patients with VHL, the clinical applications of ablative techniques are still not clearly defined, and surgery is still the most-studied intervention. Ablative techniques were first introduced into the management of VHL-associated RCC in a phase II trial investigating the effects of ablation at the time of lesion resection. In this study, 11 tumors were treated, and an intra-operative ultrasound showed complete elimination of blood flow to the tumors; on final pathology, there was evidence of treatment effect on all tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_101">101</a>]
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Since this time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success.[<a class="bk_pop" href="#CDR0000574548_rl_24_102">102</a>] Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function.[<a class="bk_pop" href="#CDR0000574548_rl_24_103">103</a>] Despite limited long-term data, these techniques have been increasingly utilized in the treatment of RCC in patients with VHL. A single-institution study evaluated treatment trends in RCC in 113 patients with VHL. Between 2004 and 2009, 43% of cases were managed with RFA at this center.[<a class="bk_pop" href="#CDR0000574548_rl_24_104">104</a>]</p><p id="CDR0000574548__725">Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. Cryoablation as salvage therapy was evaluated in a series of 14 patients to avoid the morbidity of repeat NSS. There was minimal change in renal function; at a median follow-up of 37 months, there was suspicion for lesion recurrence in only 4 of 33 tumors treated.[<a class="bk_pop" href="#CDR0000574548_rl_24_105">105</a>]
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However, it must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications due to adhesions and scarring, especially along the tract of the ablative probes.[<a class="bk_pop" href="#CDR0000574548_rl_24_106">106</a>-
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<a class="bk_pop" href="#CDR0000574548_rl_24_108">108</a>] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[<a class="bk_pop" href="#CDR0000574548_rl_24_97">97</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_109">109</a>]</p><p id="CDR0000574548__711">The clinical applications of ablative techniques in VHL are still not clearly defined, and surgery is still the most-studied intervention. The available clinical evidence suggests that ablative approaches be reserved for small (≤3 cm), solid-enhancing renal masses in older patients with high operative risk, especially in patients facing salvage renal surgery because of a higher complication rate. Young age, tumor size larger than 4 cm, hilar tumors, and cystic lesions can be regarded as relative contraindications. Irreversible coagulopathy is widely accepted as an absolute contraindication.[<a class="bk_pop" href="#CDR0000574548_rl_24_110">110</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_111">111</a>]</p><p id="CDR0000574548__685"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531840/" class="def">Level of evidence: 3di</a></p></div></div><div id="CDR0000574548__578"><h5>Chemotherapy</h5><p id="CDR0000574548__579">A 2011 study evaluated the safety and efficacy of sunitinib in VHL patients.[<a class="bk_pop" href="#CDR0000574548_rl_24_112">112</a>] Fifteen patients with VHL were given 50 mg of sunitinib daily for 28 days, followed by 14 days off for up to four cycles, with a primary endpoint of toxicity. Grade 3 toxicity included fatigue in five patients (33%); dose reductions were made in ten patients (75%). A significant response was observed in RCC but not in hemangioblastoma. Eighteen RCCs and 21 hemangioblastoma lesions were evaluable. Of these, six RCCs (33%) responded partially, versus none of the hemangioblastomas (<i>P</i> = .014). The expression of pFRS2 in hemangioblastoma tissue was also observed to be higher than in RCC, thus raising the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with hemangioblastoma.[<a class="bk_pop" href="#CDR0000574548_rl_24_112">112</a>] </p><p id="CDR0000574548__580">Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[<a class="bk_pop" href="#CDR0000574548_rl_24_113">113</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_115">115</a>] Modest improvement was observed in patients with retinal hemangioblastomas.[<a class="bk_pop" href="#CDR0000574548_rl_24_113">113</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_114">114</a>] In a series of six VHL patients treated with SU5416, stabilization in CNS hemangioblastomas was observed in two patients.[<a class="bk_pop" href="#CDR0000574548_rl_24_115">115</a>] A study of intravitreally administered anti–vascular endothelial growth factor therapy for a patient with retinal hemangioma yielded mixed results.[<a class="bk_pop" href="#CDR0000574548_rl_24_116">116</a>] SU5416 is not licensed for human use.</p><p id="CDR0000574548__686"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531830/" class="def">Level of evidence: 2</a></p></div><div id="CDR0000574548__609"><h5>VHL in pregnancy</h5><p id="CDR0000574548__621">Two studies suggest that pregnancy
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is associated with hemangioblastoma progression in patients with VHL.[<a class="bk_pop" href="#CDR0000574548_rl_24_117">117</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_118">118</a>] One study retrospectively examined the records of 29 patients with VHL from the Netherlands who became pregnant 48 times (49 newborns) between 1966 and 2010 (40% became pregnant before 1990); imaging records were available for 31% of the pregnancies. Researchers reported that 17% of all pregnancies had VHL-related complications, including three patients who had craniospinal hemangioblastoma that significantly (<i>P</i> = .049) changed in progression score before and after pregnancy.[<a class="bk_pop" href="#CDR0000574548_rl_24_117">117</a>] This study's findings are in contrast with a small, prospective investigation.[<a class="bk_pop" href="#CDR0000574548_rl_24_118">118</a>] Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy. </p></div></div><div id="CDR0000574548__290"><h4>Prognosis</h4><p id="CDR0000574548__291">Morbidity and mortality in VHL vary and are influenced by the individual and the family’s VHL phenotype (e.g., Type 1, 2A, 2B, or 2C). (Refer to the <a href="#CDR0000574548__261">VHL familial phenotypes</a> section of this summary for more information.)</p><p id="CDR0000574548__568"> In the past, metastatic RCC has caused about one-third of deaths in patients with VHL, and in some reports, it was the leading cause of death.[<a class="bk_pop" href="#CDR0000574548_rl_24_82">82</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_119">119</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_121">121</a>] With increased surveillance of mutation-positive individuals, the RCC mortality rate is thought to have diminished.</p><p id="CDR0000574548__569">Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem.[<a class="bk_pop" href="#CDR0000574548_rl_24_4">4</a>] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[<a class="bk_pop" href="#CDR0000574548_rl_24_119">119</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_122">122</a>] Hearing and vision may also be decreased or lost as a result of VHL tumors. Periodic screening allows early detection and may prevent advanced disease.</p></div><div id="CDR0000574548__589"><h4>Future directions</h4><p id="CDR0000574548__615">Currently, the renal manifestations of VHL are still generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies. These will include defining the molecular biology and genetics of kidney cancer development, which may result in the development of effective prevention or early intervention therapies. In addition, the evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHL function, identifying new targets, or discovering synthetic lethal strategies that can effectively eradicate RCC. </p></div></div><div id="CDR0000574548__130"><h3>Hereditary Leiomyomatosis and Renal Cell Cancer</h3><div id="CDR0000574548__362"><h4>Introduction</h4><p id="CDR0000574548__594">Hereditary leiomyomatosis and renal cell cancer (HLRCC) (<a href="/entrez/dispomim.cgi?id=605839" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>) is characterized by the presence of one or more of the following: <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000765494/" class="def">cutaneous leiomyomas</a> (or leiomyomata), uterine leiomyomas (fibroids) in females, and RCC. Germline mutations in the <i>fumarate hydratase</i> (<i>FH</i>) gene are responsible for the susceptibility to HLRCC. <i>FH</i> codes for fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle). </p><div id="CDR0000574548__376"><h5>Nomenclature</h5><p id="CDR0000574548__377">Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern.[<a class="bk_pop" href="#CDR0000574548_rl_24_123">123</a>] That report also described a woman aged 20 years with uterine leiomyosarcoma and metastatic RCC. Subsequently, the association of cutaneous and uterine leiomyomas became known as Reed syndrome. However, the clear association of cutaneous leiomyomas and RCC was not described until 2001, when a study reported two Finnish families in whom cutaneous and uterine leiomyomas and papillary type 2 RCC co-segregated.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>] The name hereditary leiomyomatosis and renal cell cancer was then assigned. The term HLRCC is preferred because it is impossible to distinguish between individuals with cutaneous leiomyomas who do or do not have an increased risk of renal cancer.</p></div></div><div id="CDR0000574548__628"><h4>Genetics</h4><div id="CDR0000574548__378"><h5><i>FH </i>Gene</h5><p id="CDR0000574548__643">The <i>FH</i> gene consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. The human <i>FH</i> gene is located on chromosome 1q42.3-43.</p><p id="CDR0000574548__28">HLRCC is an autosomal dominant syndrome; a single mutated <i>FH</i> allele is sufficient to cause the disease.[<a class="bk_pop" href="#CDR0000574548_rl_24_125">125</a>] Inherited biallelic mutations cause fumarate hydratase deficiency (FHD), a disorder characterized by rapidly progressive neonatal neurologic impairment including hypotonia, seizures, and cerebral atrophy. (Refer to the <a href="#CDR0000574548__442">Genetically related disorders</a> section of this summary for more information.)</p><p id="CDR0000574548__380">Germline mutations in <i>FH,</i> plus somatic mutations and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000464169/" class="def">loss of heterozygosity</a> (LOH) in RCC, suggest that loss of function in the fumarate hydratase protein is the basis of tumor formation in HLRCC and, further, that <i>FH</i> functions as a tumor suppressor gene.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_126">126</a>] </p><p id="CDR0000574548__381"> Various mutations in <i>FH</i> have been identified in families with HLRCC. Most are missense mutations, but nonsense, frameshift, and splice-site mutations have been described.[<a class="bk_pop" href="#CDR0000574548_rl_24_126">126</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_129">129</a>] Recently, whole-gene or partial deletions have been identified.</p></div><div id="CDR0000574548__382"><h5>Prevalence</h5><p id="CDR0000574548__646">The prevalence of HLRCC is unknown. It is estimated that more than 100 families with HLRCC have been seen at the National Institutes of Health, but it is likely that HLRCC remains an underrecognized entity (R. Srinivasan, MD, PhD, oral communication, April 2014). </p></div><div id="CDR0000574548__384"><h5>Penetrance of mutations</h5><p id="CDR0000574548__385">Considering the three major clinical manifestations combined, the penetrance of HLRCC is considered to be very high. However, the estimated cumulative incidence of RCC varies widely, from between 2% and 7% to 15%, and perhaps as high as 32%, in families with germline <i>FH</i> mutations, depending on ascertainment method and the imaging modalities used.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_128">128</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_130">130</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_131">131</a>]</p></div><div id="CDR0000574548__386"><h5>Genotype-phenotype correlations</h5><p id="CDR0000574548__387">No genotype-phenotype correlations have been described. Thus, no correlation has been observed between specific <i>FH</i> mutations and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_128">128</a>]</p><p id="CDR0000574548__389">Although smaller studies have suggested the presence of different mutational spectra in FHD and HLRCC,[<a class="bk_pop" href="#CDR0000574548_rl_24_126">126</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>] a study that included a larger cohort of patients indicated that the mutational distribution is fairly similar in these two entities.[<a class="bk_pop" href="#CDR0000574548_rl_24_125">125</a>] The predisposition to HLRCC versus FHD likely results from a difference in gene dosage, rather than the location of the <i>FH</i> mutation as originally suggested.[<a class="bk_pop" href="#CDR0000574548_rl_24_126">126</a>]</p></div><div id="CDR0000574548__556"><h5>Sequence analysis</h5><p id="CDR0000574548__437">Between 80% and 100% of individuals with HLRCC have identifiable, deleterious sequence alterations in <i>FH</i>.[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_128">128</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_132">132</a>]</p></div><div id="CDR0000574548__442"><h5>Genetically related disorders</h5><div id="CDR0000574548__558"><h5>Fumarate hydratase deficiency (fumaric aciduria, FHD)</h5><p id="CDR0000574548__444"> FHD, resulting from inherited biallelic mutations in <i>FH</i>, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline mutations in <i>FH</i> are found in individuals with FHD.[<a class="bk_pop" href="#CDR0000574548_rl_24_133">133</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_134">134</a>] To date, RCC has not been reported in FHD-affected individuals. Most individuals with FHD survive only a few months; very few survive to early adulthood.[<a class="bk_pop" href="#CDR0000574548_rl_24_135">135</a>] However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_126">126</a>]</p></div><div id="CDR0000574548__559"><h5>Somatic mutations</h5><p id="CDR0000574548__446"> LOH around the <i>FH</i> locus has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumor characteristics of the heritable disease.[<a class="bk_pop" href="#CDR0000574548_rl_24_136">136</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_137">137</a>] All three tumors displayed biallelic inactivation of <i>FH</i>. In sporadic forms of kidney cancer, there have been no somatic mutations identified in <i>FH</i> to date.[<a class="bk_pop" href="#CDR0000574548_rl_24_136">136</a>]</p></div></div></div><div id="CDR0000574548__629"><h4>Molecular biology</h4><p id="CDR0000574548__647">The mechanisms by which alterations in <i>FH</i> lead to HLRCC are still being elucidated. Biallelic inactivation of <i>FH</i> has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Blockage of the Krebs cycle at <i>FH</i> results in increased levels of intracellular fumarate, inhibiting HIF prolyl hydroxylases. Inactivating mutations of <i>FH</i> also appear to result in the generation of reactive oxygen species, further contributing to the stabilization of HIF.[<a class="bk_pop" href="#CDR0000574548_rl_24_138">138</a>] This upregulation of the HIF pathway leads to a pseudohypoxic state and upregulation of a transcriptional program contributing to aggressive tumor biology.[<a class="bk_pop" href="#CDR0000574548_rl_24_139">139</a>] Others have demonstrated upregulation of the antioxidant response pathway due to posttranslational modification of <i>KEAP1</i>. The resultant NRF-2 dysregulation leads to upregulation of antioxidant response element–controlled genes such as <i>aldo-keto reductase family 1 member, B10</i> (<i>AKR1B10</i>), possibly contributing to the neoplastic process.[<a class="bk_pop" href="#CDR0000574548_rl_24_140">140</a>]</p></div><div id="CDR0000574548__630"><h4>Clinical manifestations</h4><p id="CDR0000574548__364">The clinical characteristics of HLRCC include cutaneous leiomyomas, uterine leiomyomas (fibroids), and RCC. Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; an RCC that is typically solitary, or no renal tumors; and/or uterine leiomyomas. Disease severity shows significant intrafamilial and interfamilial variation.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_128">128</a>]</p><div id="CDR0000574548__542"><h5>Cutaneous leiomyomas</h5><p id="CDR0000574548__366">Cutaneous leiomyomas present as firm pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 years) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful. Pain is correlated with severity of cutaneous involvement.[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>] The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup; a solitary leiomyoma requires careful analysis of family history. (Refer to the <a href="#CDR0000574548__453">Clinical diagnosis</a> and <a href="#CDR0000574548__458">Differential diagnosis</a> sections below for more information.)</p></div><div id="CDR0000574548__543"><h5>Uterine leiomyomas</h5><p id="CDR0000574548__368">The onset of uterine leiomyomas in women with HLRCC occurs at a younger age than in women in the general population. The age at diagnosis ranges from 18 to 52 years (mean age, 30 years). Uterine leiomyomas are usually large and numerous. Most women experience symptoms including irregular or heavy menstruation and pelvic pain, thus requiring treatment at a younger age than females with leiomyomas in the general population. Women with HLRCC and uterine leiomyomas undergo hysterectomy or myomectomy for symptomatic uterine leiomyomas at a younger age (<30 years) than do women in the general population (median age, 45 years).[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_132">132</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_141">141</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_142">142</a>]</p></div><div id="CDR0000574548__544"><h5>RCCs</h5><p id="CDR0000574548__370">The symptoms of RCC may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with RCC are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop RCC. Most RCCs are unilateral and solitary; in a few individuals, they are multifocal. Approximately 10% to 32% of individuals with HLRCC who presented with multiple cutaneous leiomyomas had RCC at the time that renal imaging was performed.[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_132">132</a>] The median age at detection of RCC was 37 years,[<a class="bk_pop" href="#CDR0000574548_rl_24_143">143</a>] although some cases have been reported to occur as early as age 10 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_144">144</a>] In contrast with other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[<a class="bk_pop" href="#CDR0000574548_rl_24_145">145</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_146">146</a>] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>]</p></div><div id="CDR0000574548__545"><h5>Uterine leiomyosarcoma</h5><p id="CDR0000574548__373">Whether all women with HLRCC have a higher risk of developing uterine leiomyosarcomas than expected among women of similar age in the general population is unclear. In the original description of HLRCC, it was reported that 2 of 11 women with uterine leiomyomas also had uterine leiomyosarcoma, a cancer that may be clinically aggressive if not detected and treated at an early stage.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>] To date, germline mutations in <i>FH</i> have been reported in six women with uterine leiomyosarcoma.[<a class="bk_pop" href="#CDR0000574548_rl_24_147">147</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_148">148</a>] It seems that most <i>FH</i> mutation–positive families are not highly predisposed to uterine cancer, but a few individuals and families appear to be at high risk. In North American studies, no uterine leiomyosarcomas in HLRCC individuals or families have been reported.[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>] Therefore, the risk of uterine leiomyosarcoma in women with HLRCC is uncertain. This is a question in urgent need of a definitive answer.</p></div><div id="CDR0000574548__546"><h5>Other</h5><p id="CDR0000574548__375">Four <i>FH</i>-positive individuals with breast cancer, one case of bladder cancer, and one case of bilateral macronodular adrenocortical disease with Cushing syndrome have been reported. A series from the National Cancer Institute (NCI) found that 20 of 255 patients (7.8%) with HLRCC had adrenal nodules, some of which did not appear to be adenomas on the basis of imaging characteristics. Because many of these lesions were fluorodeoxyglucose avid, resections were performed and all showed evidence of both micronodular and macronodular adrenal hyperplasia, suggesting that adrenal nodules could be an additional manifestation of HLRCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_149">149</a>] It remains to be determined whether these manifestations are truly part of the HLRCC phenotype.[<a class="bk_pop" href="#CDR0000574548_rl_24_132">132</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_147">147</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_150">150</a>]</p></div></div><div id="CDR0000574548__577"><h4>Histopathology</h4><div id="CDR0000574548__651"><h5>Cutaneous leiomyomas</h5><p id="CDR0000574548__652">Cutaneous leiomyomas are believed to arise from the arrectores pilorum muscles attached to the hair follicles. Histologically, these are dermal tumors that spare the epidermis. Morphologically, these tumors have interlacing smooth muscle fibers interspersed with collagen fibers.[<a class="bk_pop" href="#CDR0000574548_rl_24_151">151</a>]</p></div><div id="CDR0000574548__649"><h5>Uterine leiomyomas</h5><p id="CDR0000574548__650">A review of NCI's experience with HLRCC-associated uterine leiomyomas reported that the majority of these cases were well-circumscribed fascicular tumors with occasional cases showing increased cellularity and atypia. The hallmark features of these cases were similar to those observed in HLRCC kidney cancer: the presence of orangiophilic, prominent nucleoli that are surrounded by a perinuclear halo. While some cases had atypical features, no cases had tumor necrosis or atypical mitosis suggestive of malignancy or leiomyosarcoma.[<a class="bk_pop" href="#CDR0000574548_rl_24_152">152</a>]</p></div><div id="CDR0000574548__648"><h5>RCC</h5><p id="CDR0000574548__371">The RCCs associated with HLRCC have unique histologic features, including the presence of cells with abundant amphophilic cytoplasm and large nuclei with large inclusion-like eosinophilic nucleoli. These cytologic features were attributed to type 2 papillary tumors in the original description.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>] However, early studies reported that HLRCC is associated with a spectrum of renal tumors ranging from type 2 papillary to tubulopapillary to collecting-duct carcinoma.[<a class="bk_pop" href="#CDR0000574548_rl_24_128">128</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_153">153</a>] RCC associated with HLRCC may constitute a new renal pathologic entity or a unique HLRCC type. Two studies reported the morphologic spectrum of RCC in HLRCC syndrome after histologic examinations of 40 RCCs from 38 patients with germline <i>FH</i> mutations and HLRCC family histories.[<a class="bk_pop" href="#CDR0000574548_rl_24_153">153</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_154">154</a>] A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.[<a class="bk_pop" href="#CDR0000574548_rl_24_153">153</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_154">154</a>] </p></div></div><div id="CDR0000574548__632"><h4>Management</h4><div id="CDR0000574548__504"><h5>Diagnosis and testing</h5><p id="CDR0000574548__505">Molecular genetic testing for the <i>FH</i> gene is clinically available and performed by CLIA-certified laboratories. <i>FH</i> currently is the only gene known to be associated with HLRCC. The majority of patients with HLRCC have a germline mutation in <i>FH</i>.</p><p id="CDR0000574548__654">Because the genetic analysis of HLRCC is complex, any interpretation of a variant of unknown significance results needs to be performed with consultation by clinical cancer geneticists, ideally in a center that has significant experience with this disease.</p><div id="CDR0000574548__453"><h5>Clinical diagnosis</h5><p id="CDR0000574548__454">There is no current consensus on the diagnostic criteria for HLRCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_155">155</a>] </p><p id="CDR0000574548__455">Some experts suggest that a clinical dermatologic diagnosis of HLRCC requires <b>one</b> of the following:</p><ul id="CDR0000574548__456"><li class="half_rhythm"><div>Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma.</div></li><li class="half_rhythm"><div>A single leiomyoma in the presence of a positive family history of HLRCC.</div></li></ul><p id="CDR0000574548__655">More recent comprehensive criteria for diagnosis have been suggested and are often used by experts in the field. Suggested criteria include dermatologic manifestations or a combination of two of the following manifestations: surgical treatment for symptomatic uterine leiomyomas before age 40 years, type 2 papillary RCC before age 40 years, or a first-degree relative who meets one of these criteria.[<a class="bk_pop" href="#CDR0000574548_rl_24_156">156</a>]
|
|
Collecting duct RCC before age 40 years has been suggested as an additional criterion.[<a class="bk_pop" href="#CDR0000574548_rl_24_157">157</a>]
|
|
</p></div><div id="CDR0000574548__458"><h5>Differential diagnosis</h5><div id="CDR0000574548__659"><h5>Cutaneous lesions</h5><p id="CDR0000574548__660">Cutaneous leiomyomas are rare. The detection of multiple lesions is specific for HLRCC. Because leiomyomas are clinically similar to various cutaneous lesions, histologic diagnosis is required to objectively prove the nature of the lesion.</p></div><div id="CDR0000574548__661"><h5>Uterine leiomyomas</h5><p id="CDR0000574548__662">Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. The majority of uterine leiomyomas are sporadic and nonsyndromic.[<a class="bk_pop" href="#CDR0000574548_rl_24_142">142</a>]</p></div><div id="CDR0000574548__663"><h5>RCCs</h5><p id="CDR0000574548__464"> Diagnostic clues of the syndrome may rely on the presence of several phenotypic features in different organs (cutaneous, uterine, and renal). One or more of these characteristic features of the syndrome may be present in the patient or in one or more of their affected biologic relatives.</p><p id="CDR0000574548__571">Although familial RCCs are associated with rather specific renal pathology, the rarity of these syndromes results in few pathologists gaining sufficient experience to recognize their histologic features. </p><p id="CDR0000574548__507">The differential diagnoses may include other rare familial RCC syndromes with specific renal pathology, including:</p><ul id="CDR0000574548__465"><li class="half_rhythm"><div><b>Hereditary papillary renal cancer (HPRC)</b>. Predisposition to type 1 papillary renal cancer occurs. Inheritance is autosomal dominant.[<a class="bk_pop" href="#CDR0000574548_rl_24_6">6</a>]</div></li><li class="half_rhythm"><div><b>Birt-Hogg-Dubé syndrome (BHD)</b>. A spectrum of renal tumors including renal oncocytoma (benign), chromophobe renal cell cancer (malignant), and a combination of both cell types, so-called oncocytic hybrid tumor. Individuals with BHD can present with cutaneous <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000771540/" class="def">fibrofolliculomas</a> and/or with multiple lung cysts and spontaneous pneumothorax. Inheritance is autosomal dominant.[<a class="bk_pop" href="#CDR0000574548_rl_24_146">146</a>]</div></li></ul></div></div><div id="CDR0000574548__636"><h5>Genetic testing</h5><p id="CDR0000574548__481">Molecular genetic testing is used clinically for confirmation of diagnoses or for predictive testing. It is recommended that both pretest and posttest genetic counseling be offered to persons contemplating germline mutation testing.[<a class="bk_pop" href="#CDR0000574548_rl_24_158">158</a>] Laboratories offering genetic testing for use in clinical decision making must be certified under CLIA laws.[<a class="bk_pop" href="#CDR0000574548_rl_24_159">159</a>]</p><div id="CDR0000574548__438"><h5>Testing strategy</h5><p id="CDR0000574548__439">Molecular genetic testing for a germline <i>FH</i> mutation is indicated in all individuals known to have or who are suspected of having HLRCC, with or without a family history of HLRCC, including individuals with cutaneous leiomyomas, as described in the <a href="#CDR0000574548__453">Clinical diagnosis</a> section of this summary, or individuals who have renal tumors with histologic characteristics consistent with HLRCC. (Refer to the <a href="#CDR0000574548__577">Histopathology</a> section of this summary for more information.)</p></div></div><div id="CDR0000574548__410"><h5>Risk to family members</h5><p id="CDR0000574548__142">HLRCC is inherited in an autosomal dominant manner.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>] If a parent of a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460211/" class="def">proband</a> is clinically affected or has a disease-causing mutation, the siblings of the proband have a 50% chance of inheriting the mutation. Each child of an individual with HLRCC has a 50% chance of inheriting the mutation. The degree of clinical severity is not predictable. Prenatal molecular genetic testing may be available in laboratories offering custom prenatal testing for families in which the disease-causing mutation has been identified in an affected family member.</p><h5><span class="title">Parents of a proband</span></h5><ul id="CDR0000574548__412"><li class="half_rhythm"><div>Some individuals diagnosed with HLRCC have an affected parent, while others have unaffected parents, suggesting that some individuals have HLRCC as the result of a de novo gene mutation.</div></li><li class="half_rhythm"><div>The proportion of cases caused by de novo mutations is unknown as subtle manifestations in parents have not been systematically evaluated; not all unaffected parents have undergone <i>FH</i> mutation testing.</div></li><li class="half_rhythm"><div>Evaluation of parents of a proband with a suspected de novo mutation may include molecular genetic testing if the <i>FH</i> disease-causing mutation in the proband has been identified.</div></li></ul><p id="CDR0000574548__413">Although some individuals diagnosed with HLRCC have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the affected parent before the onset of syndrome-related symptoms, or late onset of the disease in the affected parent.[<a class="bk_pop" href="#CDR0000574548_rl_24_160">160</a>]</p><h5><span class="title">Siblings of a proband</span></h5><ul id="CDR0000574548__415"><li class="half_rhythm"><div>The risk to the siblings of the proband depends upon the genetic status of the proband's parents.</div></li><li class="half_rhythm"><div>If a parent of a proband is clinically affected or has a disease-causing mutation, each sibling of the proband is at a 50% risk of inheriting the mutation.</div></li><li class="half_rhythm"><div>If the disease-causing mutation cannot be detected in the DNA of either parent, the risk to siblings is low but greater than that of the general population because of the possibility of germline mosaicism.</div></li></ul><div id="CDR0000574548__417"><h5>Testing of at-risk family members</h5><p id="CDR0000574548__418">Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces costly and stressful screening procedures in at-risk members who have not inherited their family's disease-causing mutation.[<a class="bk_pop" href="#CDR0000574548_rl_24_159">159</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_161">161</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_162">162</a>]</p><p id="CDR0000574548__419">Early recognition of clinical manifestations may allow timely intervention, which could, in theory, improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early RCC detection is reasonable, but additional objective data regarding the impact of screening on syndrome-related mortality are needed.</p></div></div><div id="CDR0000574548__420"><h5>Related genetic counseling issues</h5><div id="CDR0000574548__551"><h5>Predicting the phenotype in individuals who have inherited a disease-causing mutation</h5><p id="CDR0000574548__422">It is not possible to predict whether HLRCC-related symptoms will occur or, if they do, what the age at onset, type, severity, or rate of disease progression will be in individuals who have a disease-causing mutation. In an in-depth characterization of clinical and genetic features analyzed within 21 new families, the phenotypes displayed a wide range of clinical presentations and no apparent genotype-phenotype correlations were found.[<a class="bk_pop" href="#CDR0000574548_rl_24_128">128</a>]</p><p id="CDR0000574548__423">When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or undisclosed adoption could also be explored. Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued, lifelong, clinical surveillance. Interpretation of the mutation test result is most accurate when a disease-causing mutation has been identified in an affected family member. Those who have a disease-causing mutation are recommended to undergo lifelong, periodic surveillance. Meanwhile, family members who have not inherited the mutation and their offspring are thought to have RCC risks similar to those in the general population. No special management is recommended for mutation-negative members of mutation-positive families.</p></div><div id="CDR0000574548__552"><h5>Early detection of at-risk individuals affects medical management</h5><p id="CDR0000574548__425">More information is needed on the childhood incidence of RCC in HLRCC-affected individuals. One study reported a 17-year-old male who presented with cervical adenopathy and a palpable left flank mass. His father had died of metastatic RCC at age 40 years, and others in the family had skin and uterine leiomyomas. The patient agreed to DNA banking until a genetic test for HLRCC became available, and subsequently gene sequencing revealed a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460200/" class="def">novel mutation</a> (1164delA) in <i>FH</i>, permitting surviving family members to be tested.[<a class="bk_pop" href="#CDR0000574548_rl_24_160">160</a>] Because of the early onset of disease manifestations, earlier genetic testing could provide valuable guidance for these families. </p></div></div></div><div id="CDR0000574548__391"><h5>Surveillance</h5><p id="CDR0000574548__392">There is no consensus on what comprises appropriate clinical surveillance.</p><p id="CDR0000574548__393">It has been suggested that individuals with the clinical diagnosis of HLRCC, individuals with heterozygous mutations in <i>FH</i> without clinical manifestations, and at-risk family members who have not undergone molecular genetic testing undertake the following regular surveillance, performed by physicians familiar with the clinical manifestations of HLRCC.</p><ul id="CDR0000574548__394"><li class="half_rhythm"><div class="half_rhythm"><b>Skin.</b> There are some published recommendations to perform skin exams on a regular basis, but there is no consensus regarding frequency of skin exams, and recommendations have not been prospectively validated.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Uterus.</b> For women with an intact uterus, annual gynecologic consultation is recommended, accompanied by magnetic resonance imaging (MRI) of the pelvis to assess severity of uterine leiomyomas and to search for changes suggestive of developing leiomyosarcoma.[<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_142">142</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Renal.</b> In view of the aggressive nature of this disease, annual imaging with either computerized tomography (CT) scan with contrast or MRI with gadolinium is warranted even if the initial (baseline) evaluation reveals normal kidneys. The age to initiate renal screening is uncertain, however, because HLRCC has been described in children as young as 10 years. The HLRCC Family Alliance recommends annual imaging beginning at age 8 years in children at risk of HLRCC and those with HLRCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_155">155</a>]</div><div class="half_rhythm">Any suspicious renal lesion (indeterminate, questionable, or complex cysts) at a previous examination should be closely followed with periodic CT scan or MRI. Additional use of renal ultrasound examination is helpful in the characterization of cystic lesions. It should be cautioned that ultrasound examination alone is never sufficient. Renal tumors should be evaluated by a urologic oncology surgeon familiar with the HLRCC-related renal cancer.[<a class="bk_pop" href="#CDR0000574548_rl_24_145">145</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_146">146</a>]</div><div class="half_rhythm">Because of the aggressive growth of these tumors, patients warrant regular surveillance with a low threshold for early surgical intervention for solid renal lesions. This strategy differs from that described for several other hereditary kidney cancer syndromes, in which the tumor behavior is more indolent, and for which observation may be a viable option.[<a class="bk_pop" href="#CDR0000574548_rl_24_131">131</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_145">145</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_146">146</a>]</div></li></ul><p id="CDR0000574548__687"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000526280/" class="def">Level of evidence (skin surveillance): 5</a></p><p id="CDR0000574548__688"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531827/" class="def">Level of evidence (uterine surveillance): 4</a></p><p id="CDR0000574548__689"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531827/" class="def">Level of evidence (renal surveillance): 4</a></p></div><div id="CDR0000574548__397"><h5>Treatment of manifestations</h5><div id="CDR0000574548__547"><h5>Cutaneous lesions</h5><p id="CDR0000574548__399">Cutaneous leiomyomas are most appropriately examined by a dermatologist. Treatment of cutaneous leiomyomas is difficult. Surgical excision may be performed for a solitary painful lesion. Lesions can be treated by cryoablation and/or lasers. Several medications, including calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and antiepileptic drugs, reportedly reduce leiomyoma-related pain.[<a class="bk_pop" href="#CDR0000574548_rl_24_163">163</a>] Results are pending from a randomized clinical trial (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=694464" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">09-C-0072</a> [<a href="https://clinicaltrials.gov/show/NCT00971620" title="Study NCT00971620" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT00971620</a>]) that used botulinum toxin A (Botox) for the treatment of pain associated with cutaneous leiomyomas.</p><p id="CDR0000574548__690"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531846/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000574548__548"><h5>Uterine leiomyomas</h5><p id="CDR0000574548__401">Uterine leiomyomas are best evaluated by a gynecologist. The uterine leiomyomas of HLRCC are treated in the same manner as sporadic leiomyomas. However, because of the multiplicity, size, and potential rapid growth observed in HLRCC-related uterine leiomyomas, most such women may require medical and/or surgical intervention earlier and more often than would be expected in the general population. Medical therapy (currently including gonadotropin-releasing hormone agonists, anti-hormonal medications, and pain relievers) may be used to initially treat uterine leiomyomas, both to decrease their size in preparation for surgical removal and to provide temporary relief from leiomyoma-related pain. When possible, myomectomy to remove leiomyomas while preserving the uterus is the treatment of choice. Hysterectomy should be performed only when necessary.[<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_142">142</a>]</p><p id="CDR0000574548__691"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531845/" class="def">Level of evidence: 4</a></p></div><div id="CDR0000574548__549"><h5>RCCs</h5><p id="CDR0000574548__403">Because of their biological aggressiveness, efforts aimed at early detection of HLRCC-related RCC is prudent, although it must be acknowledged that there currently is no proof that early detection in this context is clearly associated with improved survival. Surgical excision of these malignancies appears to require earlier and more extensive surgery than that required for other hereditary kidney cancers. Further studies may demonstrate that even small tumors are of a high histologic grade upon pathologic review. Total nephrectomy or partial nephrectomy with a wide margin should be considered in individuals with a detectable renal mass, including small, subcentimetric tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_131">131</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_145">145</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_146">146</a>]</p><p id="CDR0000574548__692"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531845/" class="def">Level of evidence: 4</a></p></div><div id="CDR0000574548__550"><h5>Therapies under investigation</h5><p id="CDR0000574548__405">Recent studies suggest that HIF overexpression is involved in HLRCC tumorigenesis.[<a class="bk_pop" href="#CDR0000574548_rl_24_164">164</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_165">165</a>] Therefore, potential targeted therapies for HLRCC-associated tumors may include, for example, anti-HIF therapies, such as <a href="/nuccore/830644" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">R59949</a>, that regulate prolyl hydroxylase activity, thus preventing HIF accumulation.</p><p id="CDR0000574548__478">Other investigations [<a class="bk_pop" href="#CDR0000574548_rl_24_166">166</a>] that targeted the <i>FH</i> pathway in HLRCC kidney cancer have confirmed very high expression of NAD(P)H dehydrogenase quinine 1 (NQO1) in HLRCC kidney tumors, when compared with two other types of hereditary RCC, including ccRCC from VHL disease, and type 1 papillary RCC from HPRC families. High NQO1 expression predicts enhanced sensitivity to 17-allyl-aminodemethoxy-geldanamycin (AAG), [<a class="bk_pop" href="#CDR0000574548_rl_24_167">167</a>] a heat-shock protein inhibitor, resulting in greatly improved anti-tumor activity.[<a class="bk_pop" href="#CDR0000574548_rl_24_168">168</a>] It is expected that HLRCC kidney tumors will be especially sensitive to 17-AAG. Animal xenograft studies are in progress to test this hypothesis.[<a class="bk_pop" href="#CDR0000574548_rl_24_166">166</a>]</p><p id="CDR0000574548__656">Loss of oxidative phosphorylation resulting from biallelic inactivation of <i>FH</i> renders HLRCC tumors almost entirely reliant on aerobic glycolysis for meeting cellular adenosine triphosphate and other bioenergetics requirements. Consequently, aerobic glycolysis is being explored as a therapeutic strategy.[<a class="bk_pop" href="#CDR0000574548_rl_24_169">169</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_170">170</a>] A phase II study (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=674631" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">10-C-0114</a> [<a href="https://clinicaltrials.gov/show/NCT01130519" title="Study NCT01130519" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT01130519</a>]) examining the combination of bevacizumab and erlotinib for the treatment of advanced HLRCC is ongoing and is based partly on the premise that this combination might inhibit effective glucose delivery to tumor cells.[<a class="bk_pop" href="#CDR0000574548_rl_24_171">171</a>]</p><p id="CDR0000574548__570">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div></div><div id="CDR0000574548__633"><h4>Prognosis</h4><p id="CDR0000574548__644">Prognosis is quite good for cutaneous and uterine manifestations of HLRCC. Local management of cutaneous manifestations, when required, and hysterectomy, where indicated, will address these sites fairly effectively and with minimal long-term consequences or sequelae. The incidence of uterine leiomyosarcomas is likely quite low and is unlikely to substantively affect median survival at a cohort level. RCC in the context of HLRCC is a considerably more ominous manifestation, and the 10% to 32% of HLRCC patients who develop RCC [<a class="bk_pop" href="#CDR0000574548_rl_24_124">124</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_127">127</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_132">132</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_143">143</a>] are at high risk of developing metastatic disease.[<a class="bk_pop" href="#CDR0000574548_rl_24_145">145</a>] Metastatic RCC associated with HLRCC is characterized by an aggressive clinical course and is uniformly fatal in the absence of effective intervention. We do not currently have sufficiently large patient cohorts or databases to provide a precise estimate of survival in this patient subgroup. </p></div><div id="CDR0000574548__634"><h4>Future directions</h4><p id="CDR0000574548__645">There are two major unmet needs in the management of patients with HLRCC. The first is the ability to detect RCC earlier and with a higher degree of precision. Development of blood-based or imaging tools that permit cost-effective surveillance of the kidneys of patients with HLRCC will have a major positive effect on the outcomes of these individuals. The second major unmet need is a more accurate determination of the genotype-phenotype correlations with the various genetic lesions found in the <i>FH</i> gene. New polymorphisms in the <i>FH</i> gene are frequently of uncertain significance, and considerable effort needs to be expended to determine their clinical significance. Devising in silico prediction tools and linking these to robust patient databases and registries will assist in expanding our understanding of the consequences of specific <i>FH</i> gene variants. </p></div></div><div id="CDR0000574548__94"><h3>Birt-Hogg-Dubé Syndrome</h3><div id="CDR0000574548__322"><h4>Introduction</h4><p id="CDR0000574548__95">Birt-Hogg-Dubé syndrome (BHD) (<a href="/entrez/dispomim.cgi?id=135150" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>) is an autosomal dominant inherited hamartomatous disorder caused by germline mutations in the <i>folliculin</i> (<i>FLCN</i>) gene.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>] First described by Birt in 1977, BHD often causes cutaneous hamartomas such as fibrofolliculomas and trichodiscomas.[<a class="bk_pop" href="#CDR0000574548_rl_24_173">173</a>] The clinical characteristics of BHD include not only cutaneous manifestations (fibrofolliculomas, trichodiscomas), but also pulmonary cysts/history of spontaneous pneumothorax, and various histology types of renal tumors. Acrochordons can be found in BHD but are a common finding in the general population and are not specific.[<a class="bk_pop" href="#CDR0000574548_rl_24_174">174</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_176">176</a>] Disease severity can vary significantly. Skin lesions typically appear during the third or fourth decade of life and increase in size and number with age. Lung cysts are mainly bilateral and multifocal; most individuals are asymptomatic but have a high risk of spontaneous pneumothorax. Approximately 15% to 30% of individuals with BHD develop renal tumors, which are typically bilateral, multifocal, and slow growing; the median age at tumor diagnosis is 46 to 48 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_177">177</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_178">178</a>] The most common tumors are hybrid oncocytic tumors (a mixture of oncocytoma and chromophobe histologic cell types) (50%), chromophobe RCC (30%), and oncocytomas (9%). Clear cell and papillary tumors have been described but make up less than 10% of BHD renal tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_177">177</a>] Some families present with renal tumors and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.[<a class="bk_pop" href="#CDR0000574548_rl_24_179">179</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_180">180</a>]</p><div id="CDR0000574548__323"><h5>Natural history</h5><p id="CDR0000574548__324">The clinical characteristics of BHD include cutaneous hamartomas of the skin, including fibrofolliculomas (specific cutaneous lesions), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly among family members and between families. To date, there is no evidence of increased risk of skin cancer or malignant transformation of these hamartomatous lesions. In 2001, a family-based study showed that patients with the clinical diagnosis of BHD were seven times more likely than clinically unaffected family members to develop renal tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_181">181</a>] It also demonstrated that patients with the clinical diagnosis of BHD were 50 times more likely than clinically-unaffected family members to develop a spontaneous pneumothorax. That study confirmed that renal tumors and spontaneous pneumothorax are both major manifestations of BHD. To date, there is no evidence of increased overall mortality or decreased pulmonary function in BHD patients. Renal tumors associated with BHD are relatively indolent. Most appropriately managed patients will require no more than one partial nephrectomy during their lifetimes. Metastatic disease, although described, is rare.[<a class="bk_pop" href="#CDR0000574548_rl_24_182">182</a>]</p></div></div><div id="CDR0000574548__675"><h4>Genetics</h4><div id="CDR0000574548__336"><h5><i>FLCN</i> Gene</h5><p id="CDR0000574548__492">
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<i>FLCN</i> encodes a transcript of 5.5 kb containing 14 exons. In BHD patients, <i>FLCN</i> mutations have been identified in all translated exons, except for exons 8 and 10.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>] <i>FLCN</i> encodes a 64-kDa protein, folliculin (FLCN), which is highly conserved among species.</p></div><div id="CDR0000574548__337"><h5>Prevalence</h5><p id="CDR0000574548__338">More than 100 affected families from various populations have been described in various countries, including the United States, United Kingdom, Japan, Denmark, Spain, Italy, Australia, Canada, and the Netherlands.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_184">184</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_185">185</a>]</p></div><div id="CDR0000574548__339"><h5>Genotype-phenotype correlations</h5><p id="CDR0000574548__340">No correlation has been established between specific <i>FLCN</i> mutations and renal, pulmonary, and cutaneous manifestations. However, it was reported that individuals who have a deletion in the polycytosine tract of exon 11 may have a lower risk of developing renal cancers than individuals with other mutations,[<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>] but the sample size was small and this observation was not replicated in a subsequent study.[<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>] On the basis of three major clinical manifestations, penetrance of BHD is considered to be very high. Anticipation is not known to occur in BHD.</p></div></div><div id="CDR0000574548__676"><h4>Molecular biology</h4><p id="CDR0000574548__726">The identification of a somatic "second hit" in most BHD-associated tumors strongly suggests that <i>FLCN</i> functions as a tumor suppressor. Both somatic point mutations in the wild-type <i>FLCN</i> allele and loss of heterozygosity have been identified, although the former appears to be the more common mechanism of inactivation of the second allele.[<a class="bk_pop" href="#CDR0000574548_rl_24_186">186</a>] The precise mechanisms by which inactivation of <i>FLCN</i> leads to tumorigenesis remain to be elucidated. However, folliculin, the protein product of <i>FLCN</i>, has been implicated as a component of the cellular energy–sensing system. Both folliculin and two recently identified folliculin interacting proteins, FNIP1 and FNIP2, appear to interact with 5’-AMP activated protein kinase (AMPK).[<a class="bk_pop" href="#CDR0000574548_rl_24_184">184</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_187">187</a>]
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AMPK is a major cellular energy and nutrient sensor and regulates activity of mTOR in response to these stimuli.[<a class="bk_pop" href="#CDR0000574548_rl_24_188">188</a>] Additionally, both folliculin and FNIP1 are phosphorylated by AMPK, although the significance of this posttranslational modification is not clearly understood. </p><p id="CDR0000574548__727">The effects of folliculin loss on mTOR activity have been studied by several groups. Tissue-specific activation of both mTORC1 and mTORC2 was demonstrated in two independently generated kidney-specific <i>FLCN</i> knockout mouse models, suggesting that mTOR may play a role in the development of BHD-related tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_189">189</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_190">190</a>]
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More recent work suggests that aerobic glycolysis is upregulated as a consequence of <i>FLCN</i> inactivation. This glycolytic shift appears to be a consequence of constitutive AMPK activation in <i>FLCN</i>-null cells. AMPK activation has been shown to upregulate HIF1 and is well studied as a transcriptional activator of several genes necessary for aerobic glycolysis.[<a class="bk_pop" href="#CDR0000574548_rl_24_191">191</a>]</p></div><div id="CDR0000574548__677"><h4>Clinical manifestations</h4><p id="CDR0000574548__678">The three major features of BHD include cutaneous lesions, pulmonary cysts and spontaneous pneumothorax, and renal tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>]</p><div id="CDR0000574548__325"><h5>Cutaneous lesions</h5><p id="CDR0000574548__326">Individuals with BHD usually present with multiple, small, skin-colored, dome-shaped papules distributed over the face, neck, and upper trunk. The characteristic dermatologic manifestations include fibrofolliculomas (hamartomas of the hair follicle) and trichodiscomas.[<a class="bk_pop" href="#CDR0000574548_rl_24_173">173</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_192">192</a>] The age at diagnosis of cutaneous lesions ranges from 20 to 72 years (median age, 54 years). Only a very small percentage of <i>FLCN</i> mutation carriers lack cutaneous manifestations,[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_179">179</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_180">180</a>] suggesting that <i>FLCN</i> is highly penetrant for this syndromic phenotype. Approximately 84% of patients in whom skin lesions are biopsied are found to have fibrofolliculomas, which are pathognomonic for BHD.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>] Histologically, fibrofolliculomas are characterized by multiple anastamosing epithelial strands emanating from a central follicle. Mucin-rich or thick connective tissue stroma may encapsulate the epithelial component. The molecular biology of fibrofolliculoma is being elucidated.[<a class="bk_pop" href="#CDR0000574548_rl_24_193">193</a>] Some describe these as lesions that emanate from the sebaceous mantle of the hair follicle. The underlying molecular mechanism, which stems from <i>FLCN</i> loss and drives the development of fibrofolliculomas, is unclear but is possibly the result of increased WNT signaling.[<a class="bk_pop" href="#CDR0000574548_rl_24_193">193</a>] Fibrofolliculomas and trichodiscomas are different stages of a single pathologic process. Trichodiscomas consist of a round or elliptical well-demarcated proliferation of thick fibrous and vascular stroma in the reticular dermis. Trichodiscomas are also associated with BHD, but they are not specific to this disorder.</p></div><div id="CDR0000574548__327"><h5>Pulmonary cysts and spontaneous pneumothorax</h5><p id="CDR0000574548__328">Lung cysts are present in 89% of BHD patients when CT imaging is performed. These cysts are often bilateral and multifocal and are located predominantly within the lower lobes of the lung. Most BHD-related lung cysts are asymptomatic; however, they have an increased risk of developing spontaneous pneumothorax. Patients with a mutation in <i>FLCN</i> and a family history of spontaneous pneumothorax had a statistically significant increased risk of spontaneous pneumothorax compared with BHD patients without a family history of spontaneous pneumothorax (<i>P</i> = .011).[<a class="bk_pop" href="#CDR0000574548_rl_24_194">194</a>]</p><p id="CDR0000574548__488">The occurrence of spontaneous pneumothorax is similar among men (20%) and women (29%). Patients with BHD who suffer spontaneous pneumothorax do so at an early age, typically before the fifth decade. Although spontaneous pneumothorax typically occurs before age 22 years, the oldest reported age at occurrence is 71 years. The probability of having the first spontaneous pneumothorax by age 30 years is 6% (95% CI, 3–10%), and by age 50 years is 75% (95% CI, 19–32%).[<a class="bk_pop" href="#CDR0000574548_rl_24_194">194</a>]</p><p id="CDR0000574548__489">The clinical presentation of spontaneous pneumothorax ranges from asymptomatic to dyspnea and chest pain. Clinical findings include tachypnea or decreased to absent breath sounds. Radiographic investigation may require a high-resolution chest CT to confirm the diagnosis because a chest x-ray may not be sensitive enough to detect a loculated pneumothorax. Up to 75% of patients with a history of spontaneous pneumothorax experience a second one. Differences in reported spontaneous pneumothorax recurrence may reflect the efficacy of different treatment modalities.</p><p id="CDR0000574548__490"> Histologic findings of pleuro-pulmonary lesions associated with BHD patients include thin-walled pleural and subpleural cysts and bullae, intra-parenchymal air cysts, pleural blebs and changes consistent with spontaneous pneumothorax, and underlying emphysematous changes in lung tissue parenchyma adjacent to the bullae.[<a class="bk_pop" href="#CDR0000574548_rl_24_179">179</a>]</p></div><div id="CDR0000574548__329"><h5>Renal tumors</h5><p id="CDR0000574548__330">Approximately 25% to 35% of individuals with BHD develop renal tumors,[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_173">173</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_177">177</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_181">181</a>] which are multifocal in 65% of cases and often bilateral. The frequency of renal tumors among patients with BHD whose medical records were reviewed was 20%, and the frequency of renal tumors among BHD patients evaluated by CT scan was 29%. Most renal tumors associated with BHD are slow growing. Median age at diagnosis is 48 to 50 years (range, 31–71 years).[<a class="bk_pop" href="#CDR0000574548_rl_24_143">143</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>] Men developed renal tumors more often than did women (27 males; 11 females). Renal tumors associated with BHD seem to occur at a younger age than do sporadic forms of RCC, in which the median age at diagnosis is 64 years.[<a class="bk_pop" href="#CDR0000574548_rl_24_196">196</a>]</p><p id="CDR0000574548__331">The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumors (67%), chromophobe renal cell cancer (23%), and renal oncocytoma (3%). Only renal oncocytoma is considered a benign tumor.[<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>] Other histologic renal tumor subtypes, including clear cell renal cell cancer and papillary renal carcinoma, occur uncommonly in BHD patients.[<a class="bk_pop" href="#CDR0000574548_rl_24_177">177</a>]</p><p id="CDR0000574548__491"> Of 70 BHD patients with renal tumors and <i>FLCN</i> mutation, five (7%) have reportedly died from metastatic RCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>] The tumor histology in these five patients included clear cell, tubulo-papillary, and/or papillary histologic features, which are known to have a more biologically aggressive natural history. Death related to BHD-related oncocytoma and chromophobe neoplasms is exceedingly uncommon. Similar to VHL and HPRC, the renal parenchyma of BHD patients commonly shows microscopic renal tumors adjacent to renal cell cancers. The presence of microscopic oncocytosis provides histologic evidence that BHD patients are at lifetime risk of developing clinical renal tumors. It has been shown that 70% of BHD-related renal tumors had either a <i>BHD</i> somatic mutation or an LOH involving the second wild-type <i>FLCN</i> allele.[<a class="bk_pop" href="#CDR0000574548_rl_24_186">186</a>] The high frequency of <i>FLCN</i> somatic second hits supports the hypothesis that <i>FLCN</i> functions as a tumor suppressor gene. Acquired somatic <i>FLCN</i> mutations have been only rarely identified in sporadic clear cell renal cell cancer.[<a class="bk_pop" href="#CDR0000574548_rl_24_197">197</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_198">198</a>]</p></div><div id="CDR0000574548__332"><h5>Other manifestations</h5><p id="CDR0000574548__333">Bilateral multifocal parotid oncocytomas [<a class="bk_pop" href="#CDR0000574548_rl_24_199">199</a>] have been reported in eight BHD patients.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_199">199</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_201">201</a>] The bilateral, multifocal presentation of these rare tumors, in combination with recent molecular investigations, suggests they are part of the BHD phenotype. </p><p id="CDR0000574548__508">It should be noted that germline <i>FLCN</i> mutations were also found in patients suspected of having BHD because of their specific renal and pulmonary manifestations, in the absence of cutaneous findings.[<a class="bk_pop" href="#CDR0000574548_rl_24_201">201</a>]</p><p id="CDR0000574548__334">Lipomas, angiolipomas,[<a class="bk_pop" href="#CDR0000574548_rl_24_202">202</a>] collagenomas,[<a class="bk_pop" href="#CDR0000574548_rl_24_173">173</a>] cutaneous neurothekeomas, meningiomas,[<a class="bk_pop" href="#CDR0000574548_rl_24_203">203</a>] multinodular goiters of thyroid,[<a class="bk_pop" href="#CDR0000574548_rl_24_204">204</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_205">205</a>] ovarian cysts,[<a class="bk_pop" href="#CDR0000574548_rl_24_205">205</a>] parathyroid adenomas,[<a class="bk_pop" href="#CDR0000574548_rl_24_202">202</a>] pulmonary histiocytomas,[<a class="bk_pop" href="#CDR0000574548_rl_24_206">206</a>] and chorioretinal lesions [<a class="bk_pop" href="#CDR0000574548_rl_24_205">205</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_207">207</a>] have all been reported in BHD patients. Whether these manifestations are truly associated with BHD remains to be determined.</p><p id="CDR0000574548__335">The evidence associating colonic polyps and neoplasms and BHD is conflicting.[<a class="bk_pop" href="#CDR0000574548_rl_24_181">181</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_198">198</a>]</p></div></div><div id="CDR0000574548__341"><h4>Management</h4><div id="CDR0000574548__348"><h5>Risk assessment for Birt-Hogg-Dubé syndrome</h5><div id="CDR0000574548__349"><h5>Genetic testing</h5><p id="CDR0000574548__350"><i>FLCN</i> (<i>BHD</i>) is the only gene known to be associated with BHD. It is located on chromosome 17p11.2.[<a class="bk_pop" href="#CDR0000574548_rl_24_208">208</a>] Molecular testing is available for clinical applications such as diagnostic testing and prenatal diagnosis. Fifty-three percent (27 of 51) families with BHD were found to have an insertion or deletion in the polycytosine tract in exon 11 (a mutational "hot spot").[<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>] Sequence analysis of all <i>FLCN</i> coding exons (exon 4–14) increases the mutation detection in probands to 84% (51 of 61) and is available on a clinical basis.</p><p id="CDR0000574548__351">Molecular genetic testing performed in a CLIA-certified laboratory is indicated for all individuals known to have or suspected of having BHD, including individuals with the following:</p><ol id="CDR0000574548__352"><li class="half_rhythm"><div>Five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma [<a class="bk_pop" href="#CDR0000574548_rl_24_173">173</a>] with or without family history of BHD.</div></li><li class="half_rhythm"><div>A family history of BHD with a single fibrofolliculoma or a single renal tumor or history of spontaneous pneumothorax.</div></li><li class="half_rhythm"><div>Multiple and bilateral chromophobe, oncocytic, and/or oncocytic hybrid renal tumors.</div></li><li class="half_rhythm"><div>A single oncocytic, chromophobe, or oncocytic-hybrid tumor and a family history of renal cancer with any of above renal cell tumor types.</div></li><li class="half_rhythm"><div>A family history of autosomal dominant primary spontaneous pneumothorax without a history of lung cyst.</div></li></ol></div><div id="CDR0000574548__346"><h5>Genetic counseling</h5><p id="CDR0000574548__347">Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a disease-causing mutation, the siblings of the proband are at 50% risk of inheriting the mutation. The degree of clinical severity is not predictable. Prenatal diagnosis for pregnancies at 50% risk is possible if the disease-causing allele of an affected family member has been identified. (Refer to the <a href="/books/n/pdqcis/CDR0000062865/">Cancer Genetics Risk Assessment and Counseling</a> PDQ summary for more information.)</p></div><div id="CDR0000574548__353"><h5>Clinical diagnosis</h5><p id="CDR0000574548__354">The three major features of BHD include cutaneous lesions, lung cysts and spontaneous pneumothorax, and renal tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_172">172</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>] (Refer to the <a href="#CDR0000574548__677">Clinical manifestations</a> section for more detailed descriptions of these manifestations.)</p><p id="CDR0000574548__730">The dermatologic diagnosis of BHD is made in individuals who have five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma.[<a class="bk_pop" href="#CDR0000574548_rl_24_173">173</a>] An adequate biopsy (typically a punch biopsy) is required to make a diagnosis of fibrofolliculoma. An expert panel has developed the following diagnostic criteria for BHD (patients must fulfill one major or two minor criteria for diagnosis):[<a class="bk_pop" href="#CDR0000574548_rl_24_209">209</a>]</p><ul id="CDR0000574548__740"><li class="half_rhythm"><div><b>Major criteria:</b><ul id="CDR0000574548__741"><li class="half_rhythm"><div>At least five fibrofolliculomas or trichodiscomas, at least one histologically confirmed, of adult onset.</div></li><li class="half_rhythm"><div>Pathogenic <i>FLCN</i> germline mutation.</div></li></ul></div></li><li class="half_rhythm"><div><b>Minor criteria:</b><ul id="CDR0000574548__742"><li class="half_rhythm"><div>Multiple lung cysts: bilateral, basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax.</div></li><li class="half_rhythm"><div>Renal cancer: early-onset (age <50 y) or multifocal or bilateral renal cancer, or renal cancer of mixed chromophobe and oncocytic histology.</div></li><li class="half_rhythm"><div>A first-degree relative with BHD.</div></li></ul></div></li></ul><div id="CDR0000574548__743"><h5>Differential diagnosis</h5><p id="CDR0000574548__361">It is important to distinguish between BHD-associated renal cancer and sporadic RCC because this may have implications for management. Genetic testing for a mutation in <i>FLCN</i>, a family history of BHD, or the presence of extra-renal manifestations associated with BHD are helpful in establishing a diagnosis of this condition. Because a variety of histologic variants of kidney cancer can be seen in association with BHD, it is often necessary to make a histologic diagnosis to help differentiate between the benign tumors (oncocytomas) and those with a malignant potential (chromophobe, clear cell, and papillary RCC).[<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>]</p><p id="CDR0000574548__693">The differential diagnosis of pulmonary cysts includes lymphangioleiomyomatosis (LAM); distinguishing this from BHD can be clinically challenging. One study proposed a set of findings that permit differentiation between BHD and LAM.[<a class="bk_pop" href="#CDR0000574548_rl_24_210">210</a>] These include bibasilar, peripheral, and subpleural distribution for BHD versus diffuse distribution for LAM; elliptical or lentiform shape for BHD-related cysts versus round shape for LAM; and HMB-45 negativity on immunohistochemical staining for BHD versus HMB-45 positivity for LAM. This approach has not been validated; further study is warranted.</p></div></div></div><div id="CDR0000574548__342"><h5>Surveillance</h5><p id="CDR0000574548__343">BHD patients display two main clinical presentations. Most commonly, individuals present with a documented family history of BHD. Other presentations include individuals without a BHD family history or one that is unknown. In the former clinical scenario, if the patient's biological relative has a genetic diagnosis with an identified <i>FLCN</i> mutation, the patient may choose to begin evaluation with genetic counseling and mutation testing.</p><p id="CDR0000574548__471">Clinical surveillance for individuals at risk of BHD includes dermatologic, radiological, and histological examinations to identify characteristic cutaneous lesions, renal tumors, and lung cysts, with or without a history of spontaneous pneumothorax. Not all features are present in each at-risk individual, and some BHD family members may have no discernible phenotypic findings (i.e., they are clinically unaffected carriers of deleterious <i>FLCN</i> mutations). This clinical scenario is being encountered with increasing frequency as the number of syndrome-associated genes for which mutation testing can be offered clinically expands. In most disorders, the natural history of genetically abnormal/clinically normal individuals has not yet been well characterized. These major features of BHD are described in the <a href="#CDR0000574548__353">Clinical diagnosis</a> section.</p><p id="CDR0000574548__472">Decisions regarding the use of lifelong surveillance for hereditary RCC syndromes must consider both risks and benefits. Approximately 15% to 29% of individuals with BHD have renal tumors,[<a class="bk_pop" href="#CDR0000574548_rl_24_181">181</a>,<a class="bk_pop" href="#CDR0000574548_rl_24_183">183</a>] which are commonly bilateral and multifocal and include a number of specific histologies within an individual or family.[<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>] For at-risk individuals who will undergo periodic imaging for many years even when no tumor is present, a surveillance schedule that minimizes the lifetime dose of radiation is advised. </p><p id="CDR0000574548__473">Contrast-enhanced CT or MRI are both useful modalities for the detection of BHD renal tumors.[<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>] Ultrasounds (sonograms) alone may not be sufficient for detecting renal tumors because some tumors are isoechoic with the renal parenchyma,[<a class="bk_pop" href="#CDR0000574548_rl_24_182">182</a>] but they may help identify renal cysts. If a renal tumor is detected, the patient is referred to a urologic oncology surgeon for management, which may include continued monitoring or surgery, depending mainly on tumor size.[<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>] If no renal tumor is detected on initial imaging, experts recommend lifelong surveillance at least once every 36 months because of the risk of developing RCC.[<a class="bk_pop" href="#CDR0000574548_rl_24_182">182</a>]</p><p id="CDR0000574548__757"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000526280/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000574548__344"><h5>Treatment</h5><div id="CDR0000574548__494"><h5>Skin</h5><p id="CDR0000574548__495"> Cryotherapy, electrodessication, surgery, and laser therapy have been used with good cosmetic results, but relapse usually occurs because the cutaneous lesions are a manifestation of an inherited skin condition.[<a class="bk_pop" href="#CDR0000574548_rl_24_211">211</a>-<a class="bk_pop" href="#CDR0000574548_rl_24_213">213</a>] Therefore, patients may require continuous cosmetic care. Some BHD patients are emotionally affected by their dermatologic condition, regardless of the number or extent of cutaneous lesions. Therefore, the psychological state of BHD patients warrants consideration, with skin care recommendations appropriately tailored to individual needs.</p><p id="CDR0000574548__758"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531846/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000574548__497"><h5>Renal</h5><p id="CDR0000574548__498">Partial nephrectomy is the treatment of choice in the management of BHD-related kidney neoplasms, to preserve optimal long-term kidney function in patients at risk of multiple primary renal tumors. However, this renal-sparing surgery depends on the size and location of the tumors found during surgery. It is important to incorporate knowledge of the high cumulative risk of multifocal and bilateral kidney tumors in this syndrome, as surgical management is planned. In general, renal tumors smaller than 3 cm in diameter may be monitored radiologically under close supervision of the urologic oncology surgeon; immediate surgery may not be required.[<a class="bk_pop" href="#CDR0000574548_rl_24_195">195</a>] These are general recommendations, and each case should be evaluated carefully and managed individually. Total nephrectomy may be necessary in some cases. </p><p id="CDR0000574548__345">Surveillance of at-risk individuals and relatives includes abdominal/pelvic CT scans and evaluation of renal tumors by urologic surgeons and radiologists experienced in the management of these complicated patients. Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and eliminates costly and stressful screening procedures in at-risk relatives who have not inherited their family's disease-causing mutation.</p><p id="CDR0000574548__759"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531845/" class="def">Level of evidence: 4</a></p></div><div id="CDR0000574548__499"><h5>Spontaneous pneumothorax</h5><p id="CDR0000574548__500">The management of spontaneous pneumothorax in BHD patients is similar to that employed in the general population.[<a class="bk_pop" href="#CDR0000574548_rl_24_194">194</a>]</p><p id="CDR0000574548__501">The clinical presentation of spontaneous pneumothorax in patients with BHD is variable. Therapy is dictated by the underlying lung condition and general health of the patient. One study reported that of 101 spontaneous pneumothoraces, 78 required medical intervention, and 23 were managed by observation alone.[<a class="bk_pop" href="#CDR0000574548_rl_24_194">194</a>] Thirty-five percent of pneumothoraces were treated with tube thoracostomy (chest tube) only; 14% were treated by open thoracotomy and a second treatment, including mechanical or chemical pleurodesis and lung resection; and approximately 13% were treated with combined tube thoracostomy, thoracotomy, and a third treatment, including mechanical or chemical pleurodesis or lung resection. Patients with BHD—especially those with multiple lung cysts—should be advised to avoid or be cautious with scuba diving, air travel, and mechanical ventilation because each exposure increases the risk of spontaneous pneumothorax.[<a class="bk_pop" href="#CDR0000574548_rl_24_194">194</a>]</p><p id="CDR0000574548__760"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531845/" class="def">Level of evidence: 4</a></p></div></div></div><div id="CDR0000574548__679"><h4>Prognosis</h4><p id="CDR0000574548__728">The major cause of morbidity and mortality in BHD is related to renal lesions. Because of the rarity of BHD, it is difficult to generate robust overall survival data on populations of patients with the syndrome; however, when patients are managed with an appropriate surveillance and intervention strategy, their life expectancy should not be significantly different from that of matched individuals in the general population.</p></div><div id="CDR0000574548__680"><h4>Future directions</h4><p id="CDR0000574548__729">Identification of <i>FLCN</i>, the gene responsible for BHD, in 2001 has led to a number of studies elucidating its function and possible genotype-phenotype correlations. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/11220238" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11220238</span></a>]</div></li></ol></div></div><div id="CDR0000574548__625"><h2 id="_CDR0000574548__625_">Changes to This Summary (07/06/2015)</h2><p id="CDR0000574548__626">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="CDR0000574548__744"><b><a href="#CDR0000574548__24">Major Heritable Renal Cell Cancer (RCC) Syndromes</a></b></p><p id="CDR0000574548__771">Revised <a class="figpopup" href="/books/NBK169222.1/table/CDR0000574548__484/?report=objectonly" target="object" rid-figpopup="figCDR0000574548484" rid-ob="figobCDR0000574548484">Table 1</a>, Hereditary RCC
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Syndromes and Susceptibility Genes, to include cumulative
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RCC risk estimates of 24% to 45% for von Hippel-Lindau
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syndrome, 15% to 30% for Birt-Hogg-Dubé syndrome
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(BHD), and approaching 100% for hereditary papillary renal
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cancer.</p><p id="CDR0000574548__772">Revised <a href="#CDR0000574548__95">text</a> to state that approximately 15% to 30% of
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individuals with BHD develop renal tumors, which are
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typically bilateral, multifocal, and slow growing; the median age
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at tumor diagnosis is 46 to 48 years (cited Benusiglio et al. as reference 178).</p><p id="CDR0000574548__773">Added <a href="#CDR0000574548__326">text</a> to state that trichodiscomas are also associated
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with BHD, but they are not specific to this disorder.</p><p id="CDR0000574548__disclaimerHP_3">This summary is written and maintained by the <a href="http://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="#CDR0000574548__AboutThis_1">About This PDQ Summary</a> and <a href="http://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000574548__AboutThis_1"><h2 id="_CDR0000574548__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000574548__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000574548__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of kidney cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000574548__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000574548__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="http://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="CDR0000574548__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000574548__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="CDR0000574548__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 Genetics of Kidney Cancer (Renal Cell Cancer) are:</p><ul><li class="half_rhythm"><div>Eric Jonasch, MD (University of Texas, M.D. Anderson Cancer Center)</div></li><li class="half_rhythm"><div>Brian Matthew Shuch, MD (Yale University School of Medicine)</div></li><li class="half_rhythm"><div>Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)</div></li></ul><p id="CDR0000574548__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="http://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="CDR0000574548__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000574548__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/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000574548__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000574548__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="CDR0000574548__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000574548__AboutThis_15">National Cancer Institute: PDQ® Genetics of Kidney Cancer (Renal Cell Cancer). Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: <a href="http://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq</a>. Accessed <MM/DD/YYYY>.</p><p id="CDR0000574548__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="http://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="CDR0000574548__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000574548__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="http://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="CDR0000574548__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000574548__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="http://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="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div><div id="CDR0000574548__GetMore_3"><h2 id="_CDR0000574548__GetMore_3_">Get More Information From NCI</h2><p id="CDR0000574548__GetMore_15"><i><b>Call 1-800-4-CANCER</b></i></p><p id="CDR0000574548__GetMore_16">For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.</p><p id="CDR0000574548__GetMore_25"><i><b>Chat online
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK169222.1/?report=reader">PubReader</a></li><li><a href="/books/NBK169222.1/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK169222" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK169222" style="display:none" title="Cite this Page"><div class="bk_tt">PDQ Cancer Genetics Editorial Board. 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class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#CDR0000574548__4" ref="log$=inpage&link_id=inpage">Introduction</a></li><li><a href="#CDR0000574548__24" ref="log$=inpage&link_id=inpage">Major Heritable Renal Cell Cancer Syndromes</a></li><li><a href="#CDR0000574548__625" ref="log$=inpage&link_id=inpage">Changes to This Summary (07/06/2015)</a></li><li><a href="#CDR0000574548__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li><li><a href="#CDR0000574548__GetMore_3" ref="log$=inpage&link_id=inpage">Get More Information From NCI</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div 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<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
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<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK169222&ncbi_domain=pdqcis&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK169222.1/&ncbi_pagename=Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®) - PDQ Cancer Information Summaries - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
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