{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T12:41:59Z","timestamp":1772887319552,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2006,7,14]],"date-time":"2006-07-14T00:00:00Z","timestamp":1152835200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2006,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although epididymal cystadenomas (ECAs) are among the most frequent VHL disease\u2010associated tumours, fundamental questions about their pathogenesis have remained unanswered. Classification of ECAs is controversial, and the cell of origin is unknown. It is also unknown whether ECAs\u2014like other VHL disease\u2010associated tumours\u2014arise as a result of <jats:italic>VHL<\/jats:italic> gene inactivation, and whether ECAs exhibit subsequent activation of hypoxia\u2010inducible factor HIF. Moreover, the morphological spectrum of earliest ECA formation is unknown. In a detailed molecular pathological analysis of a series of epididymides collected from VHL patients at autopsy, we found that ECAs are true neoplasms that arise secondary to inactivation of the wild\u2010type copy of the <jats:italic>VHL<\/jats:italic> gene, followed by early and simultaneous activation of HIF1 and HIF2 associated with up\u2010regulation of downstream targets, including CAIX and GLUT\u20101. The observations also indicate that ECA formation evolves from a variety of microscopic epithelial tumourlets, and that these tumourlets are confined to the efferent ductular system. Although genetic and immunohistochemical analysis of precursor structures consistently revealed <jats:italic>VHL<\/jats:italic> gene inactivation and activation of HIF in the precursor lesions, only a small subset appears to progress into frank cystadenoma. Thus, ECA tumorigenesis in VHL disease shares fundamental principles with tumorigenesis in other affected organ systems. Copyright \u00a9 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2029","type":"journal-article","created":{"date-parts":[[2006,7,14]],"date-time":"2006-07-14T08:18:29Z","timestamp":1152865109000},"page":"32-41","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Epididymal cystadenomas and epithelial tumourlets: effects of VHL deficiency on the human epididymis"],"prefix":"10.1002","volume":"210","author":[{"given":"S","family":"Gl\u00e4sker","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MGB","family":"Tran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SB","family":"Shively","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Ikejiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"RR","family":"Lonser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"PH","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"EH","family":"Oldfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AO","family":"Vortmeyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,7,14]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13643-4"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8493574"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/81.14.1097"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0046-8177(97)90075-7"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0594-85"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.2870130303"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.85.12.4568"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/89.13.970-a"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03540420057030"},{"issue":"4","key":"e_1_2_6_11_2","first-page":"951","article-title":"Allelic deletion and mutation of the von Hippel\u2013Lindau (VHL) tumor suppressor gene in pancreatic microcystic adenomas","volume":"151","author":"Vortmeyer AO","year":"1997","journal-title":"Am J Pathol"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2156"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.2.732"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.14.1822"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/20459"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002740200"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/35017054"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.20.10595"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203938"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00071-5"},{"issue":"6","key":"e_1_2_6_21_2","first-page":"2089","article-title":"Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel\u2013Lindau disease patients","volume":"149","author":"Lubensky IA","year":"1996","journal-title":"Am J Pathol"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20090"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1104"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(64)90107-X"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-4295(97)00074-5"},{"issue":"5","key":"e_1_2_6_26_2","first-page":"456","article-title":"Papillary cystadenoma of the epididymis. 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