title: Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas.
abstract: OBJECTIVE
  The aim of this study was to evaluate the role of certain cell-cycle regulatory proteins in the recurrence of atypical meningiomas. These proteins were analyzed with immunohistochemical staining to identify predisposing factors for the recurrence of atypical meningiomas.
  
  
  METHODS
  The authors retrospectively reviewed the medical records of patients with atypical meningiomas diagnosed in the period from January 2000 to June 2012 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center. Clinical data included patient sex and age at the time of surgery, presenting symptoms at diagnosis, location and size of tumor, extent of surgery, use of postoperative radiotherapy, duration of follow-up, and recurrence. Immunohistochemical staining for cell-cycle regulatory proteins (p16, p15, p21, p27, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1) and proliferative markers (MIB-1 antigen, mitosis, and p53) was performed on archived paraffin-embedded tissues obtained during resection. The recurrence rate and time to recurrence were assessed using Kaplan-Meier analysis.
  
  
  RESULTS
  Of the 67 atypical meningiomas eligible for analysis, 26 (38.8%) recurred during the follow-up period (mean duration 47.7 months, range 8.4-132.1 months). Immunohistochemically, there was overstaining for p16 in 44 samples (65.7%), for p15 in 21 samples (31.3%), for p21 in 25 samples (37.3%), for p27 in 32 samples (47.8%), for CDK4 in 38 samples (56.7%), for CDK6 in 26 samples (38.8%), for pRB protein in 42 samples (62.7%), and for cyclin D1 in 49 samples (73.1%). Multivariate analysis using the Cox proportional-hazards regression model showed that incomplete resection (HR 4.513, p < 0.001); immunohistochemical understaining for p16 (HR 3.214, p < 0.001); immunohistochemical overstaining for CDK6 (HR 3.427, p < 0.001), pRB protein (HR 2.854, p = 0.008), and p53 (HR 2.296, p = 0.040); and increased MIB-1 labeling index (HR 2.665, p = 0.013) and mitotic index (HR 2.438, p = 0.024) predicted the recurrence of atypical meningiomas after resection.
  
  
  CONCLUSIONS
  Findings in this study indicated that p16, CDK6, and pRB protein were associated with the recurrence of atypical meningiomas.
authors.affiliation: Department of Neurosurgery and Division of Neurooncology, and.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Kyu Hong
authors.initials: KH
authors.lastname: Kim
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Lee
authors.forename: Young Min
authors.initials: YM
authors.lastname: Lee
authors.forename: Sung-Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyung Dong
authors.initials: HD
authors.lastname: Kim
authors.forename: Young Zoon
authors.initials: YZ
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008579:Meningioma / Q000473:pathology*; D008875:Middle Aged; D008938:Mitosis / Q000502:physiology; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D018797:Cell Cycle Proteins
keywords: CDK = cyclin-dependent kinase; CDK6; GTR = gross-total resection; NF2 = neurofibromatosis Type 2; RB protein; RFS = recurrence-free survival; ROC = receiver operating characteristic; atypical meningioma; immunohistochemistry; oncology; p16; p16 = p16INK4A; pRB = phosphorylated retinoblastoma; recurrence