Phosphohistone H3 Immunohistochemical Labeling: a Potentially Useful Tool for Risk Stratification and Prognostic Analysis in Gastrointestinal Stromal Tumors.

Abstract BackgroundIt is well recognized that risk stratification of gastrointestinal stromal tumors (GISTs) is closely related to tumor size, mitotic index (MI), and primary location. Among these three parameters, tumor size and primary location are easily established, while MI is subjective and its repeatability is poor. It is thus necessary to identify a biomarker to represent the true MI. Expression status and biological or prognostic significance of mitotic marker phosphohistone H3 (PHH3) and cell proliferation marker Ki67 in GIST have not been clearly understood until now. MethodsAn immunohistochemistry experiment was performed to detect the expression status of PHH3 and Ki67 in 125 paraffin-embedded GIST samples. All of the patients were followed up until September 30, 2019. ResultsThe MI determined using stained hematoxylin and eosin (H&E) sections (MI-H&E) and immunohistochemically positive PHH3 index (PHH3-IHC) was compared among groups of different genders, ages, primary locations, and histological subtypes, showing that the difference was not statistically significant (P>0.05). MI-H&E and the immunohistochemically positive Ki67 index were positively correlated (r=0.273, P=0.001), but the correlation was lower than that with the PHH3-positive index (r=0.705, P=0.000). The PHH3-positive index was also positively correlated with the Ki67 index (r=0.224, P=0.006). MI-H&E were positively correlated with MI quantified using immunohistochemically stained PHH3 sections (MI-PHH3) (P<0.05). After using PHH3 to perform MI quantification, the risk stratification of five GIST cases was changed, where two cases were given a higher risk grade and three cases were given a lower risk grade. Follow-up data were obtained from 98 cases (98/125, 78.4%), including two cases of metastasis and one death. Both metastatic and death cases had high MI-H&E. One metastatic case and one death case had high PHH3-positive indexes, while the remaining metastatic case had a low PHH3-positive index. ConclusionImmunohistochemical PHH3 labeling is a potentially useful tool for risk stratification and prognostic analysis in GIST. Using immunohistochemical PHH3 labeling makes it more convenient for pathologists to determine the MI for GIST. MI quantification with immunohistochemical PHH3 sections can be used as an adjunct tool for risk stratification and prognostic analysis of GIST, but cannot completely replace MI quantification using stained H&E sections. The Ki67 index is positively correlated with MI-H&E, although the efficiency of tumor risk stratification is lower than that of PHH3.