title: Better see to better agree: phosphohistone H3 increases interobserver agreement in mitotic count for meningioma grading and imposes new specific thresholds.
abstract: BACKGROUND
  Mitotic count on hematoxylin and eosin (H&E)-stained slides is a crucial diagnostic criterion in meningioma grading. However, mitosis assessment on H&E slides can be impaired by technical factors and by pathologist's experience. Phosphohistone H3 (PHH3) serine-10 is a mitosis-specific antibody that has proven to facilitate mitotic count in various tumors.
  
  
  METHODS
  A series of 70 meningiomas (15 grade I, 40 grade II, 15 grade III) was used to validate PHH3 intra- and interobserver reproducibility and to identify PHH3-specific mitotic thresholds. Four pathologists with different experience in neuropathology counted mitoses on both H&E- and PHH3-stained slides.
  
  
  RESULTS
  H&E and PHH3 mitotic rates were highly correlated (Pearson's r = 0.92, P < .0001). PHH3 mitotic counts had both a good mean interobserver correlation (R(m) = 0.83) and a good intraclass correlation (0.78), higher than H&E mitotic indices (R(m) = 0.77, intraclass correlation = 0.71). After further stratification of meningiomas according to World Health Organization grade, PHH3 performed better in terms of interobserver concordance (Kendall's W = 0.761) compared with H&E (Kendall's W = 0.697). Referring to the same meningioma groups identified by World Health Organization grade as the gold standard, the volume under the receiver operator characteristic surface was 0.91, indicating a very good diagnostic ability of PHH3 scores in discriminating the 3 meningioma groups. The 2 optimal PHH3-specific cutoff values were 6.61 and 22.02.
  
  
  CONCLUSIONS
  PHH3 staining is a useful diagnostic complementary tool to standard H&E mitotic count, optimizing intra- and interobserver reproducibility. PHH3-specific mitotic thresholds should be adopted to avoid overgrading of meningioma when ancillary methods are employed.
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Eleonora
authors: E
authors: Duregon
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Adele
authors: A
authors: Cassenti
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Alessandra
authors: A
authors: Pittaro
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Laura
authors: L
authors: Ventura
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Rebecca
authors: R
authors: Senetta
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Roberta
authors: R
authors: Rudà
authors: Department of Medical Sciences, University of Torino, Turin, Italy (A.C., A.P., R.S., P.C.); Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Italy (E.D.); Department of Statistical Sciences, University of Padua, Padova, Italy (L.V.); Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy (R.R.).
authors: Paola
authors: P
authors: Cassoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D006657:Histones / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008579:Meningioma / Q000473:pathology*; D008875:Middle Aged; D008938:Mitosis; D008940:Mitotic Index / Q000379:methods*; D060787:Neoplasm Grading; D015588:Observer Variation; D010766:Phosphorylation; D015203:Reproducibility of Results
chemical_list: D000906:Antibodies; D014408:Biomarkers, Tumor; D006657:Histones
keywords: PHH3; cutoff; meningioma; mitotic count
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