title: Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway.
abstract: Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, Maryland 21287, USA. tabel1@jhmi.edu
authors.forename: Ty W
authors.initials: TW
authors.lastname: Abel
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Fraser
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: James S
authors.initials: JS
authors.lastname: Nelson
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Yachnis
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Bouffard
authors.forename: Hernando
authors.initials: H
authors.lastname: Mena
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
mesh_terms: D000293:Adolescent; D000328:Adult; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005729:Ganglioneuroma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006223:Hamartoma Syndrome, Multiple / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D013959:Thyroid Diseases / Q000378:metabolism / Q000503:physiopathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human