Coexpression of erythropoietin and its receptor in endolymphatic sac tumors

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Object. Von Hippel—Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease. Data from previous studies of VHL disease—associated hemangioblastomas (HBs) and renal cell carcinomas (RCCs) have indicated that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth.

Methods. The authors studied ELSTs from five patients with VHL germline mutations. Analysis of the five ELST samples revealed loss of the wild-type allele, consistent with Knudson's two-hit hypothesis for tumorigenesis. All five ELST specimens were characterized microscopically and by immunohistochemical analysis. Coexpression of Epo and Epo-R was found in all five tumors on immunohistochemical studies and confirmed through reverse transcription—polymerase chain reaction and Western blot analysis.

Conclusions. Expression of Epo appears to be a result of VHL gene deficiency, whereas the simultaneous coexpression of Epo-R may reflect a developmental mechanism of tumorigenesis. Coexpression of Epo and Epo-R in ELSTs together with the morphological and genetic similarities of these lesions with other VHL disease—associated tumors indicates that VHL disease—associated tumors in different organs share common pathogenetic pathways.

Article Information

Address reprint requests to: Zhengping Zhuang, M.D., Ph.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D-37, Bethesda, Maryland 20892. email: zhuangp@ninds.nih.gov.

© AANS, except where prohibited by US copyright law.

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Figures

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    Imaging characteristics of an ELST in a 33-year-old man with VHL and right-sided hearing loss. A: Axial T1-weighted postcontrast magnetic resonance image revealing a large heterogeneously enhancing ELST in the right mastoid region (arrowheads). B: Axial computerized tomography scan through the same region demonstrating the bone erosion of the posterior petrous region, which is frequently seen with ELSTs (arrowheads).

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    Results of fluorescence in situ hybridization (upper) demonstrating allelic deletion of the VHL gene in ELST cells. Tumor cells show the loss of one copy of the VHL gene, whereas two copies of the VHL gene reside in the surrounding fibrous tissue. Photomicrographs showing the morphological similarity between an ELST (center left) and an early RCC (center right); both tumors are cystic and composed of clear cells intermixed with numerous small vessels. Photomicrographs obtained following immunohistochemical analysis with CD34, depicting intense vascularization in both the ELST (lower left) and HB (lower right). H & E, original magnification × 200 (center left and right), × 400 (lower left and right).

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    Photomicrographs obtained following immunohistochemical analysis, demonstrating Epo (left) and Epo-R (right) in ELSTs.

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    A: Gel blots showing expression of Epo and Epo-R mRNA in VHL disease—associated ELSTs. Lanes 1 to 4, VHL disease—associated ELSTs; Lane 5, healthy kidney from patient with VHL; and left, molecular weight marker. The Epo mRNA is expressed in the ELST and healthy kidney. The Epo-R mRNA is expressed in VHL disease—associated ELSTs but not in healthy kidney. B: Gel blots for Epo and Epo-R protein showing VHL-associated HB (Lane 1), healthy kidney from patient with VHL (Lane 2), and VHL-associated ELST (Lane 3). Expression of Epo (18 kD) is detected in VHL-associated HB, ELST, and healthy kidney from patient with VHL. Expression of Epo-R (49 kD) is detected in VHL-associated HB and ELST but not in healthy kidney from patient with VHL. Molecular weight markers are also shown (left).

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    Transmission electron micrograph demonstrating a developing murine embryo with vascular sinuses in proximity to the developing ELS (labeled ES). Nucleated erythroblasts can be found both within the vascular lumen and the surrounding mesodermal tissue. Reprinted with permission from Hultcrantz M, Bagger-Sjöbäck D: Embryonic and postnatal development of endolymphatic sac blood vessels. Am J Otol 11 (2):90–94, 1990.

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