Clinicopathologic markers of uterine leiomyosarcoma originating from smooth muscle tumors of low malignancy

Abstract

The aims of the study were (1) to increase the limited knowledge on molecular markers contributing to uterine leiomyosarcoma (LMS) tumorigenesis and (2) to test the ability to predict the clinical course of smooth muscle tumors of low malignancy (SMTLM). Retrospectively, 2,360 uterine smooth muscle tumors were classified according to the Stanford criteria. After central review, the clinical course of the SMTLM was traced, and immunohistochemical stainings for p53, p16, p21, Rb, estrogen receptor, progesterone receptor (PR), cyclin A, cyclin D1, vascular endothelial growth factor, WT-1, and Ki-67 were performed on paraffin-embedded tissue of the primary tumor and recurrences. On the same tissues, fluorescence in situ hybridization (FISH) analysis was performed to determine differences in HMGA2, p53, Rb, and 1p36 loci involvement. Five SMTLM were identified, of which two relapsed after 2 and 3 years, respectively. Recurrence tumors were surgically resected, and 3 years later, both patients are alive and there is no evidence for progression of disease. The age at diagnosis in the group with benign course was lower (39, 40, 43 years) than that in the group that recurred (48, 53 years). Both recurrent SMTLMs expressed less PR and, only quantitatively, more p53. One case expressed more cyclin D1 when compared to its primary. p16 level was reduced in one recurrent SMTLM. FISH of both SMTLMs that recurred revealed homozygous deletion of p53 and Rb loci in one of each primary and recurrent tumor. Loss of 1p36 loci was found in both recurrent SMTLMs, and in one case, this genetic imbalance was already present in the primary tumor. The current data provide evidence that the age at diagnosis of SMTLM is a prognostic factor and that LMS originating from SMTLM carries an overall better prognosis than primary LMS. Recurrent tumors showed decreased PR levels. Accumulation of genetic losses, including p53, Rb, and 1p36 loci, may identify a subgroup of SMTLMs with a higher potential towards malignancy.