Molecular analyses of 6 different types of uterine smooth muscle tumors: Emphasis in atypical leiomyoma

Abstract

BACKGROUND: Uterine smooth muscle tumors (USMTs) constitute a group of histologic, genetic, and clinical heterogeneous tumors that include at least 6 major histologically defined tumor types: leiomyoma (ULM), mitotically active leiomyoma (MALM), cellular leiomyoma (CLM), atypical leiomyoma (ALM), uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Apart from ULM and LMS, the nature of these variants is not well defined. METHODS: A total of 167 cases of different USMT variants were collected, reviewed, and diagnostically confirmed based on the World Health Organization and Stanford schemes. These included 38 cases of LMS, 18 cases of STUMP, 42 cases of ALM, 22 cases of CLM, 7 cases of MALM, and 40 cases of ULM. Molecular analysis included selected microRNAs (miRNAs), oncogenes, and tumor suppressors that are highly relevant to USMT. RESULTS: Overall, 49% (17/35) of LMS cases and 7% (1/14) of STUMP cases died due to their USMT, but no deaths were attributed to ALM. miRNA profiling revealed that ALM and LMS shared similar miRNA signatures. P53 mutations and PTEN deletions were significantly higher in LMS, ALM, and STUMP compared with other USMT variants (P <.01). In contrast, MED12 mutations were extremely common in ULM and MALM (>74%) but were significantly less common (<15%) in CLM, ALM, STUMP, and LMS (P <.01). CONCLUSION: Six types of USMT have different gene mutation fingerprints. ALM shares many molecular alterations with LMS. Our findings suggest that ALM may be a precursor lesion of LMS or have similar genetic changes during its early stage. Cancer 2014;120:3165-77.

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

“…Our findings raise the intriguing possibility that leiomyomas with bizarre nuclei may be a precursor of leiomyosarcomas. Our data and findings from two previous studies 39,51 demonstrate that in contrast to leiomyomas, MED12 mutations in leiomyomas with bizarre nuclei and leiomyosarcomas do not occur frequently, and that these mutations may not act as 'driver' mutations in the development of leiomyomas with bizarre nuclei and leiomyosarcomas. To further explore the concept of tumor progression and to identify biomarkers to differentiate between diagnostically challenging uterine smooth muscle tumors, high-resolution molecular studies are needed to search for recurrent genetic changes in chromosome areas where overlap between leiomyomas, leiomyomas with bizarre nuclei, and leiomyosarcomas occur.…”

“…39,51 Overall, 25% of patients suffering from leiomyosarcomas in our study demonstrated a MED12 codon 44 mutations in the primary tumor. Surprisingly, in a patient (leiomyosarcoma1) with two subsequent leiomyosarcoma metastases that occurred 4 and 7 years after initial diagnosis MED12 mutation was no longer detectable in the metastases indicating that a tumor cell clone lacking MED12 mutation could have metastasized.…”

“…The quality of the DNA was evaluated using a multiplex PCR approach. 38,39 Samples with three or four bands on a 1.5% agarose gel were used for array-CGH analysis.…”

Uterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP): Review of Pathophysiology, Classification, Diagnosis, Treatment, and Surveillance

“…Various cell cycle regulatory proteins and tissue expression may have the potential for diagnostic utility [36,37]. Ki-67 is a non-histone nuclear protein only expressed in G1-M phases of the cell cycle, used as a marker of cellular proliferation.…”

“…Bcl-2 is a protein that regulates and prevents abnormal apoptotic cell death. This regulatory protein also promotes cellular replication by reducing the requirement for growth factors [36,[38][39][40].…”