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

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.

• Authors: Vincenzo Villani, Krishnan K Mahadevan, Matteo Ligorio, Carlos Fernández-Del Castillo, David T Ting, Francesco Sabbatino, Irene Zhang, Mark Vangel, Soldano Ferrone, Andrew L Warshaw, Keith D Lillemoe, Jennifer Wargo, Vikram Deshpande, Cristina R Ferrone
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 23 Issue Suppl 5 Pg. 609-617 (12 2016) ISSN: 1534-4681 [Electronic] United States
• PMID: 27020585 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Coloring Agents
• Histones
• Ki-67 Antigen
• Eosine Yellowish-(YS)
• Hematoxylin

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (metabolism)
• Cell Proliferation
• Coloring Agents
• Disease-Free Survival
• Eosine Yellowish-(YS)
• Female
• Hematoxylin
• Histones (metabolism)
• Humans
• Kaplan-Meier Estimate
• Ki-67 Antigen (metabolism)
• Male
• Middle Aged
• Mitotic Index (methods)
• Neuroendocrine Tumors (metabolism, pathology)
• Pancreatic Neoplasms (metabolism, pathology)
• Phosphorylation
• Proportional Hazards Models
• ROC Curve
• Survival Rate
• Time Factors
• Young Adult