Utility of phosphohistone H3 in uterine smooth muscle tumors: an Outcome-Based Assessment

Abstract

BACKGROUND: In the absence of tumor cell necrosis, the distinction between uterine leiomyoma with bizarre nuclei (LBN) and leiomyosarcoma (LMS) is dependent on the mitotic count. Most LBNs have <2 mitotic figures (MF)/10 high power fields (HPF) while LMS have >10 MFs/10 HPFs. Mitosis-counting is not always accurate because of potential confusion between true MFs and karyorrhectic nuclei. Also, behavior of tumors with ambiguous morphologies (significant nuclear atypia, >2 to <10 MFs, indeterminate necrosis, or combinations thereof) is variable and uncertain. Phosphohistone H3 (PHH3), a mitosis-specific immunomarker, has been shown to be useful in the diagnosis of uterine smooth muscle tumors (USMT) but assessment methods have not been standardized. DESIGN: PHH3 immunohistochemistry was done on 48 LMS, 23 smooth muscle tumors of uncertain malignant potential (STUMP) and 23 leiomyomas (LM) (including 11 LBN). Result was expressed as highest count/10 HPFs and listed according to histologic types. In order to test the discriminating power of PHH3 in distinguishing benign USMT with ambiguous morphologies from malignant tumors, 2 biologic patient groups were further delineated. Those in Group 1 all had a benign outcome (11 LBN, 9 STUMP with no recurrence) while in Group 2, patients had either a recurrence or death (2 STUMP with recurrence, and 29 LMS). RESULTS: Median follow-up of LMS, STUMP and LM patients were respectively 28, 71 and 62 months. 52.1% (25/48) with LMS died while 8.7% (2/23) with STUMP had a recurrence, both at 14 months. All with LM/LBN were alive and with no tumors. The respective median PHH3 scores for LMS, STUMP and LM were 17, 3 and 2/10HPF (p<0.05). The corresponding H&E mitotic counts were 12, 3 and 1/10 HPF. Median ages for Group 1 and 2 patients were 44 and 53 years, respectively, and median follow-up were 69 (range 5-156) and 7 (range 1-96) months. PHH3 scores for Groups 1 and 2 were 3 and 24/10 HPF, respectively. Using ROC analysis, a PHH3 score of ≥6/10 HPF was highly compatible with malignancy with sensitivity of 80.6%, specificity of 93.7%, and positive and negative predictive values of 92.5% and 83.3%, respectively. For malignant USMT, multivariate analysis showed that a PHH3 score of ≥29/10 HPFs was independently associated with a poor outcome. CONCLUSIONS: In USMT with ambiguous morphologies, a PHH3 score of ≥6/10 HPF is highly predictive of malignancy. PHH3 score may also be a useful prognostic indicator for malignant USMT.