ArticleJournal of neuroendocrinology2026
Phosphohistone H3 and Ki-67 as prognostic markers in metastatic small intestinal neuroendocrine tumours: A comparative, retrospective cohort study.
Article in Journal of neuroendocrinology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Ki-67 index and mitotic count form the basis of grading of small intestinal neuroendocrine tumours (siNET). We hypothesized that the mitosis-specific marker phosphohistone H3 (PHH3) might better correlate with cancer-specific survival (CSS) and with response to treatment. We evaluated the association between Ki-67 index, PHH3-estimated mitotic count, and survival outcomes in a retrospective cohort of 73 consecutive patients with metastatic siNET. Additionally, we estimated the optimal cut-off for PHH3 and cross-validated the outcome. Both markers adequately distinguished CCS when comparing lower and higher proliferation groups (Ki-67: 128 vs. 95 m; PHH3: 149 vs. 88 m). They were strongly associated with CSS as continuous (HR 1.18 [1.08-1.28] and 1.16 [1.09-1.25]), and dichotomous variables (HR 2.96 [1.31-6.67] and 3.11 [1.50-6.46]). The Cox model based on PHH3 displayed slightly better optimism-corrected Harrell's c-index (0.71 vs. 0.68) and Akaike information criterion (219 vs. 223). Additionally, PHH3 showed significant association with PFS after treatment with somatostatin analogues (HR 1.12 [1.03-1.21]), and borderline significant association with PFS after treatment with peptide receptor radionuclide therapy (HR 1.11 [1.00-1.24]). A cut-off of >2 mitoses per 10 high-power fields estimated by PHH3 seemed to have better discrimination power compared to the standard WHO cut-off (<2). Mitotic count based on PHH3 is associated with CSS and with PFS after treatment with first-line SSA and possibly with PRRT for metastatic siNET. It may be an alternative to Ki-67 for estimation of proliferation and grading. A cut-off of >2 mitoses per 10 HPF might better distinguish G1 and G2 tumours.
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