The Mitosis Marker Anti-Phosphohistone H3 (PHH3) Distinguishes Bizarre Leiomyoma from Leiomyosarcoma and Predicts Behavior in Uterine Smooth Muscle Tumors
KJ Evason, JT Rabban. UCSF, San Francisco, CA
Background: In the uterus, distinction of bizarre leiomyoma from leiomyosarcoma can be challenging because bizarre nuclei may mimic mitoses. Immunohistochemical markers of cell proliferation or cell cycle activity, such as MIB-1, p53, and p16, are of limited value since their expression overlaps in these two entities. Antibodies to the serine-phosphorylated state of histone H3 (PHH3) are specific markers of cells in mitosis and have prognostic value in breast cancer and meningioma. In this study, we hypothesize that PHH3 can distinguish bizarre leiomyoma from leiomyosarcoma. We also evaluate the prognostic significance of PHH3 in a range of uterine smooth muscle tumors.
Design: Fifty cases of uterine smooth muscle tumors, including 11 bizarre leiomyomas, 12 leiomyosarcomas, 7 mitotically active leiomyomas, 15 cellular leiomyomas, and 2 tumors of uncertain malignant potential (STUMP) were evaluated. Slides containing the most atypical appearing nuclei were selected for PHH3 immunohistochemical staining (Upstate Cell Signaling, 1:1200). PHH3 score was defined as the average number of positive tumor cells in 10 high power fields (HPF); 3 separate counts of 10 HPF were performed to determine the average score. Staining was interpreted without knowledge of the pathologic diagnosis. Follow-up data was collected on all patients.
Results: The vast majority of bizarre nuclei in bizarre leiomyoma did not express PHH3. PHH3 score of bizarre leiomyoma (3.3/10 HPF) was significantly lower than the PHH3 score for leiomyosarcoma (34.1/10 HPF) (p<0.001). No significant difference in PHH3 score was observed between bizarre leiomyoma and typical leiomyoma (3.8/10 HPF), mitotically active leiomyoma (6.3/10 HPF), STUMP (9.2/10 HPF), or cellular leiomyoma (4.5/10 HPF). Average follow-up time was 36 months. None of the patients with bizarre leiomyoma or other benign diagnoses developed recurrence, spread, or death, whereas 6 of 12 patients with leiomyosarcoma had recurrence or spread and 3 patients died. Independent of the morphologic diagnosis, PHH3 score predicted outcome: using a threshold PHH3 score of 30 per 10 HPF, sensitivity and specificity for predicting recurrence were 75% and 92%, and for predicting death were 80% and 92%.
Conclusions: PHH3 distinguished bizarre nuclei from atypical mitoses in uterine smooth muscle tumors and reliably distinguished bizarre leiomyoma from leiomyosarcoma. Furthermore, high PHH3 score accurately predicted malignant behavior in uterine smooth muscle tumors, independent of morphologic classification.
Tuesday, March 10, 2009 11:30 AM
Platform Session: Section D, Tuesday Morning