title: Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors.
abstract: The staging of pancreatic neuroendocrine tumors (PNETs) is continuously evolving. Mitotic count, as measured by hematoxylin and eosin (H&E) or Ki67 labeling index (Ki67LI), is the best predictor of disease biology. However, both of these methods have several limitations. Phosphorylated histone H3 (PHH3), a novel mitotic marker, is potentially more accurate and easier to evaluate. This study aimed to evaluate the prognostic impact of PHH3 on patients with PNETs.
  
  
  
  Clinicopathologic data and paraffin-embedded tissue were evaluated for 100 of the 247 PNET patients whose tumors were resected between 1998 and 2010. Mitotic counts were analyzed on H&E-, Ki67-, and PHH3-stained slides by two independent pathologists. Kaplan-Meier curves, log-rank tests, Cox regression models, and time-dependent receiver operative characteristics (ROC) curves were used to evaluate the prognostic power of these markers. An internal data cross-validation was performed to select the best cutoff.
  
  
  
  Of the 100 PNET patients resected, 53 were men. The median age of the patients was 59 years (range 19-96 years). The median follow-up period was 68 months (range 3-186 months). The median time for evaluation of an H&E- or PHH3-stained slide was 3 min, relative to 15 min for Ki67. The findings showed H&E, Ki67, and PHH3 all to be excellent predictors of disease-specific survival (DSS). However, PHH3 was superior to H&E and Ki67 in predicting both disease-free survival (DFS) (p = 0.006) and DSS (p = 0.001). Evaluation of the PHH3 mitotic count showed 7 mitoses per 10 high-power fields (HPFs) to be the optimal cutoff for differentiating between low- and high-risk PNET patients.
  
  
  
  PHH3 is a better predictor of both DFS and DSS than H&E or Ki67 in PNET. In addition, PHH3 appears to be both easier to interpret and more accurate when compared to current prognostic markers.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Villani
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Krishnan K
authors.initials: KK
authors.lastname: Mahadevan
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ligorio
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Del Castillo
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sabbatino
authors.affiliation: Doctor of Medicine Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Vangel
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Warshaw
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lillemoe
authors.affiliation: Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wargo
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. cferrone@mgh.harvard.edu.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D004396:Coloring Agents; D018572:Disease-Free Survival; D004801:Eosine Yellowish-(YS); D005260:Female; D006416:Hematoxylin; D006657:Histones / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index / Q000379:methods*; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016016:Proportional Hazards Models; D012372:ROC Curve; D015996:Survival Rate; D013997:Time Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004396:Coloring Agents; D006657:Histones; D019394:Ki-67 Antigen; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin