Validation of a Mitotic Index Cutoff as a Prognostic Marker in Undifferentiated Uterine Sarcomas

Abstract

Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutoff of 25 mitoses/10 high-power fields (corresponding to 11.16 mitotic figures/mm) could successfully divide tumors into 2 prognostic groups with significantly different overall survival. The goals of the current study were to (1) validate this mitotic index cutoff in an independent, multicenter cohort and (2) explore the prognostic value of the mitotic index groups in relation to other clinicopathologic variables. Cases were included from 3 independent institutions: The Norwegian Radium Hospital, The Mayo Clinic, and Skåne University Hospital. A total of 40 tumors were included after central review. All cases were negative for the YWHAE-FAM22A/B and JAZF1-JJAZ1 translocations. Survival data were available on all patients. In this study, one-third of patients with UUS survived beyond 5 years. The crude (unadjusted) Cox Proportional Hazards model revealed a number of parameters that significantly impacted overall survival, including mitotic index group, patient age, stage, and the presence of tumor necrosis. Classification into the uniform and pleomorphic types was not prognostic. Combining these parameters into an adjusted model revealed that only the mitotic index group and stage were prognostic. On the basis of these findings, it is proposed that UUS be subdivided into "mitogenic" and "not otherwise specified" types.

Localized high grade endometrial stromal sarcoma and localized undifferentiated uterine sarcoma: a retrospective series of the French Sarcoma Group

“…The authors propose that undifferentiated uterine sarcoma should be divided by mitotic index into 'mitogenic' and 'NOS' (ie, tumors with mitotic index below the cut-off). Their study reaffirms that a subgroup of patients with 'NOS' undifferentiated uterine sarcoma can achieve long term survival and that better methods of determining prognosis are needed 10. Mitotic index was not a prognostic factor in the current series.…”

Uterine mesenchymal tumours: recent advances

“…Patients with SMARCA4‐deficient UUS may benefit from enrolment in ongoing clinical trials using tazemetostat, a selective small molecule EZH2 inhibitor or single or combined anti‐PD‐1 therapy using nivolumab and ipilimumab antibodies . Mitotic index appears to have prognostic significance in all UUS, regardless of genotype, with mitotic activity beyond 25/10 HPF (11.16/mm 2 ) having considerably worse survival outcomes …”

“…40,41 Mitotic index appears to have prognostic significance in all UUS, regardless of genotype, with mitotic activity beyond 25/10 HPF (11.16/mm 2 ) having considerably worse survival outcomes. 42 Uterine tumour resembling ovarian sex cord tumour Fusions involving growth regulation by estrogen in breast cancer 1 (GREB1) and estrogen receptor 1 (ESR1) genes have recently been detected in UTROSCT, a mesenchymal tumour of uncertain malignant potential that resembles sex cord stromal tumours of the ovary. [43][44][45][46] Both genes encode key proteins that are involved in the sex hormone pathway.…”

Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes

“…Finally, the selected slides were reviewed again at the Karolinska University Hospital. Mitotic rate and grade of nuclear atypia was determined as described previously (12,13). IHC for estrogen receptor and progesterone receptor was performed locally in clinical labs accredited for this analysis.…”

“…Indeed, smooth-muscle tumors have a distinct biology depending upon whether they arise in the gynecologic tract or not (3,5). Previously, our group has demonstrated that division into mitotic index groups has prognostic significance for overall survival (12,13). Other studies have attempted to use atypia to subdivide UUS into "uniform" and "pleomorphic" types (14,15).…”