Genetic aberrations in soft tissue leiomyosarcoma

Abstract

Leiomyosarcoma is a malignant mesenchymal tumor composed of cells showing smooth muscle differentiation. This tumor usually occurs in middle-aged or older adults, and forms a significant percentage of retroperitoneal, vascular, extremity, and uterine sarcomas. Leiomyosarcomas are most often associated with complex karyotypes with numerous chromosomal gains and losses. Some of these cytogenetic and molecular genetic aberrations correlate with histopathologic features and clinical outcomes. Identification of genetic alterations with specific identification of oncogenes and tumor suppressor genes may lead to additional insights into the tumorigenesis of leiomyosarcoma and the opportunity to confer the benefits of targeted therapy.

Introduction

Bone and soft tissue sarcomas are uncommon neoplasms representing no more than 1% of malignant tumors [1]. Some of these tumors, such as synovial sarcoma, Ewing’s sarcoma, and osteosarcoma, occur most often in adolescents or in young adults; other sarcomas, however, such as leiomyosarcoma or well-differentiated liposarcoma, are more frequent in older individuals. On the basis of histology alone, there are more than 50 distinct types of sarcoma [2]. From the molecular point of view, these neoplasms can be bifurcated into two major groups: (a) sarcomas showing specific, recurrent genetic alterations, and relatively simple karyotypes (such as the EWSR1-FLI1 gene fusion in Ewing’s sarcoma) and (b) sarcomas showing multiple and often variable gene alterations and very complex karyotypes, such as leiomyosarcoma and osteosarcoma [3].

Leiomyosarcoma is a malignant tumor composed of cells showing distinct features of the smooth muscle lineage. It usually occurs in middle-aged or older adults. These tumors arise most commonly in five distinct anatomic sites: (1) retroperitoneum; (2) deep extremity; (3) uterus; (4) blood vessels; and (5) superficial dermis. When confined to the dermis, this latter group has an indolent clinical course and rarely metastasizes. Leiomyosarcoma constitutes a significant percentage of retroperitoneal and pelvic sarcomas. It is comparatively less common at other sites, accounting for at most 10–15% of extremity sarcomas. The deep leiomyosarcomas frequently arise in association with the smooth muscle wall of a vessel or a tubular digestive organ. Uterine leiomyosarcomas arise in the context of the myometrium. Deep leiomyosarcoma is a deadly cancer with significant mortality associated with pulmonary metastases. Risk for local recurrence, metastasis and tumor-specific mortality correlates with the three-tiered histologic grade (low, intermediate and high) assigned under the French sarcoma grading system guidelines [4], though these criteria are not clearly applicable to the uterine and dermal categories.

Leiomyosarcoma is often present as an enlarging mass. Imaging studies demonstrate a nonspecific soft tissue mass, but are helpful in delineating the relationship to adjacent structures, particularly in the retroperitoneum. The typical histologic pattern of leiomyosarcoma is of intersecting, sharply marginated fascicles of spindle cells with abundant eosinophilic cytoplasmic and elongated (cigar-shaped) nuclei. The great majority of leiomyosarcomas are reactive for SMA, desmin, and h-caldesmon on immunohistochemistry, though none of these markers are absolutely specific for smooth muscle differentiation.

Until recent years gastrointestinal stromal tumors (GISTs) were not clearly delineated from leiomyosarcoma. In contrast to GISTs, where >90% of cases are positive for c-kit protein in immunohistochemisty analysis, leiomyosarcoma only rarely expresses c-kit and even then, only at low levels [5], [6]. The signature mutation and overexpression of KIT and PDGFRA genes provide a target for selective therapy with the kinase inhibitor imatinib mesylate (Gleevec) [7]. In contrast, therapeutically relevant targets in leiomyosarcoma have yet to be discerned. Currently, leiomyosarcoma is not amenable or unlikely to be controlled by surgery alone and is treated by conventional cytotoxic chemotherapy at many centers, yet only 50% of patients respond with less than 10% long-term survival [6]. Clearly, efforts are needed to reveal recurrent genetic and molecular changes in leiomyosarcoma that may lead to improved therapeutic interventions.