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Pancreatic neuroendocrine tumors (PNET) are being diagnosed with greater frequency and have a widely variable natural history. Recent advances in staging for PNET incorporate the mitotic rate for tumors identified on hematoxylin and eosin stains (H&E), dividing lesions into low grade, intermediate grade, and high grade based on mitotic rate. This staging system can help with prognostic information, and may also guide adjuvant treatment, but is reliant on an accurate assessment of mitotic count. By H&E, mitotic figures can be difficult to identify and require an experienced histopathologist for accurate enumeration. Proliferative index, as measured by Ki-67, is also used in PNET but may over-represent actual mitotic figures since this also captures the G1 phase. More recently, staining with phosphohistone H3 (PHH3) has been described for use in identifying mitotic figures in malignancies such as melanoma and glioblastoma. PHH3 is exclusively expressed in the mitotic phase of the cell cycle thus yields a much more accurate representation of mitotic rate in tumors. Our hypothesis was that an anti-PHH3 antibody can more accurately identify mitotic rates in pancreatic neuroendocrine tumors (PNET) than traditional H&E staining. This will result in more accurate staging and will improve patient management.
Histologic sections from 77 patients with PNET were stained with both H&E and anti-PHH3 antibodies and were reviewed by a blinded histopathologist to assess total mitotic count. Tumors were graded by number of mitoses and correlated with clinical outcome.
The results demonstrate a significantly higher number of mitoses identified using the PHH3 stain compared to H&E (p< 0.05). In this patient population, traditional H&E staining did not correlate with survival, but PHH3 staining for <2 mitoses was highly sensitive for clinical outcome. (p<0.05, mean follow-up > 36 months)
Taken together, these results suggest that PHH3 may provide a more accurate assessment of mitotic rate in PNET. Additional studies are currently underway to expand this cohort to assess mitotic rate determined by PHH3 stain compared to Ki-67 with several different observers.

Pancreatic neuroendocrine tumor stained with anti-phosphohistone3 (PHH3) antibody highlighting mitotic figures

Pancreatic neuroendocrine tumor stained with anti-phosphohistone3 (PHH3) antibody highlighting mitotic figures

Correlation with clinical outcome with mitotic rate as determined by H&E and PHH3.