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Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors

  • Translational Research and Biomarkers
  • Published:
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgment

The Loeffler Family and other generous patients provided philanthropic support for this study. Matteo Ligorio is the recipient of American-Italian Cancer Foundation Post-Doctoral Fellowship. Vincenzo Villani is the recipient of a Research Fellowship from the Centro per la Comunicazione e la Ricerca of the Collegio Ghislieri of Pavia.

Conflicts of interest

There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Vincenzo Villani MD, Matteo Ligorio MD, PhD, Carlos Fernández-del Castillo MD, Francesco Sabbatino MD, PhD, Soldano Ferrone MD, PhD, Andrew L. Warshaw MD, Keith D. Lillemoe MD & Cristina R. Ferrone MD

  2. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Krishnan K. Mahadevan MD & Vikram Deshpande MD

  3. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David T. Ting MD

  4. Department of Medicine and Surgery, University of Salerno, Salerno, Italy

    Francesco Sabbatino MD, PhD

  5. Doctor of Medicine Program, Harvard Medical School, Boston, MA, USA

    Irene Zhang MS

  6. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Mark Vangel PhD

  7. Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jennifer Wargo MD

Authors
  1. Vincenzo Villani MD
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  2. Krishnan K. Mahadevan MD
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  3. Matteo Ligorio MD, PhD
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  4. Carlos Fernández-del Castillo MD
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  10. Andrew L. Warshaw MD
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  11. Keith D. Lillemoe MD
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  12. Jennifer Wargo MD
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  13. Vikram Deshpande MD
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  14. Cristina R. Ferrone MD
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Corresponding author

Correspondence to Cristina R. Ferrone MD.

Additional information

Vincenzo Villani, Krishnan K. Mahadevan, Matteo Ligorio—shared first authorship. Vikram Deshpande and Cristina R. Ferrone—shared last authorship.

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Villani, V., Mahadevan, K.K., Ligorio, M. et al. Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors. Ann Surg Oncol 23 (Suppl 5), 609–617 (2016). https://doi.org/10.1245/s10434-016-5171-x

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  • DOI: https://doi.org/10.1245/s10434-016-5171-x

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