Original articleLoss of DNA copy number of 10q is associated with aggressive behavior of leiomyosarcomas: a comparative genomic hybridization study
Introduction
Leiomyosarcoma (LMS) can develop virtually anywhere in the body. Malignant mesenchymal neoplasm displaying smooth muscle differentiation is relatively rare in somatic soft tissue and accounts for 10% of soft tissue sarcomas. The LMS of the GI tract that occur in the body cavities and retroperitoneum have to be distinguished from gastrointestinal stromal tumors (GIST) and their counterparts in the soft tissue. They are categorized into (a) those occurring in skin and subcutaneous tissue, (b) those arising in major vessels, and (c) retroperitoneal tumors [1], [2]. The tumor can also recur locally following excision. Common sites of distant metastases are the lungs and liver.
Uterine leiomyosarcomas (ULMS), which account for 20–30% of uterine sarcomas, appear to arise de novo in the uterus. The malignant transformation of a preexisting leiomyoma is rare [3]. At present, histologic criteria distinguishing malignant from benign smooth muscle tumors are site-specific, and the biological behavior of the tumor is difficult to predict on the basis of morphology alone. A previous study showed differences in expression of estrogen receptor and CD44 in ULMS and extrauterine leiomyosarcomas (EULMS) [4].
Whether chromosomal changes in LMS are site-specific has not been documented, because of insufficient data. This is in part due to technical problems, including difficulties in obtaining adequate metaphase cells for chromosome analysis, poor morphology of banding, complexity of the chromosomal rearrangements, and overgrowth of stromal cells. To date, ∼63 EULMS [5], [6] and 14 ULMS [7], [8], [9], [10], [11], [12], [13], [14] have been analyzed cytogenetically. Numerical and structural abnormalities (either or both) were found in 60% (38 of 63) of the tumors. Although consistent structural chromosomal alterations have not been identified in LMS, common gains or losses of genetic material were detected in multiple cases. Recurrent abnormalities were identified in LMS, including losses of 3p21∼23, 8p21∼pter, 13q12∼13, 13q32∼qter, 1q42∼qter, 2p15∼pter, 18q11, 1p36, 11q23∼qter, and 10q23∼qter, and gains of 1q12∼31. Aberrations involving chromosomes 1, 10, and 17 were common findings in both EULMS and ULMS. Study of LMS with comparative genomic hybridization (CGH) has also been performed. With this technique, ∼81 more EULMS [15], [16], [17], [18], [19] and 65 ULMS [18], [20], [21], [22] have been analyzed. The most frequent losses detected in EULMS and ULMS with CGH were 2p, 10q, 11q, 12p, 13q, and 16q. The most common gains were Xp, 1q, 5p, 8q, and 17p. It appears that the pathogenesis of ULMS and EULMS may follow similar genetic pathways. In the present study, we analyzed 17 EULMS using CGH and karyotyping to provide additional cases to support this hypothesis.
Section snippets
Tumor samples
Eighteen fresh tissues snap-frozen in liquid nitrogen were obtained from 17 patients, following approval by the Institutional Review Board. Tumors ranged in size from 3.5 to 27 cm (Table 1). About 6–12 sections were examined under routine hematoxylin–eosin (H&E) staining and were diagnosed as LMS, using previously established criteria [23]. In addition, 15 out of the 17 cases were analyzed immunohistochemically, using smooth muscle actin, desmin, CD34, c-kit, S-100, and cytokeratins (DAKO,
Immunohistochemistry
The well-differentiated grade 1 and 2 tumors showed strong positivity for desmin or actin in at least 75% of the surface area of the paraffin section. A representative photograph of a well-differentiated LMS with H&E stain and positive immunoreactivity with desmin is shown in Fig. 1. Two high-grade tumors (cases 3 and 9) and one well-differentiated tumor (case 10) were negative for desmin but strongly positive for smooth muscle actin. Two tumors were focally CD34 positive (cases 7 and 8). CD34
Discussion
We studied 17 malignant soft tissue tumors. All the tumors had morphological features of smooth muscle differentiation. Genomic imbalances were present in 88% of the tumors studied. One of the most common genomic alterations in EULMS was loss of chromosome 10 or 10q, which was detected in 59% of tumors. One tumor had a loss of the 10q22 region only. Mutations of the PTEN gene in the nearby region 10q23 had been analyzed in previous studies; however, mutation of PTEN is not a common event in
Conclusion
Genomic alterations were detected in 88% of EULMS. The most common abnormalities were losses of 13q, 10q, 2q, and 16q and gain of 5p. Loss of 10q and gain of 5p in LMS are often associated with high-grade tumors, or with metastases and large tumors; therefore, they may be associated with more aggressive behavior of LMS. Because the same abnormalities were found in both EULMS and ULMS, the findings support the hypothesis that pathogenesis of LMS may follow the same genetic pathway, although
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