{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:30:15Z","timestamp":1774330215947,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,9,18]],"date-time":"2006-09-18T00:00:00Z","timestamp":1158537600000},"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":[[2006,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Haemangioblastomas are the key central nervous system manifestation of von Hippel\u2013Lindau (VHL) disease, which is caused by germline mutation of the <jats:italic>VHL<\/jats:italic> gene. We have recently shown that \u2018tumour\u2010free\u2019 spinal cord from patients with VHL disease contains microscopic, poorly differentiated cellular aggregates in nerve root tissue, which we descriptively designated \u2018mesenchymal tumourlets\u2019. Here we have investigated spinal cord tissue affected by multiple tumours. We show that a small subset of mesenchymal tumourlets extends beyond the nerve root to form proliferative VHL\u2010deficient mesenchyme and frank haemangioblastoma. We thus demonstrate that tumourlets present potential, but true precursor material for haemangioblastoma. We further show that intraradicular tumourlets consist of scattered VHL\u2010deficient cells with activation of HIF\u20102\u03b1 and HIF\u2010dependent target proteins including CAIX and VEGF, and are associated with an extensive angiogenic response. In contrast, activation of HIF\u20101\u03b1 was only observed in the later stages of tumour progression. In addition, ultrastructural examination reveals gradual transition from poorly differentiated VHL\u2010deficient cells into vacuolated cells with a \u2018stromal\u2019 cell phenotype. The evolution of frank haemangioblastoma seems to involve multiple steps from a large pool of precursor lesions. Copyright \u00a9 2006 Pathological Society of Great Britain and Ireland. 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