Recent advances in the molecular pathology of soft tissue sarcoma: implications for diagnosis, patient prognosis, and molecular target therapy in the future

Abstract

In the present paper, recent advances in the molecular pathology of soft tissue sarcomas (STS) and the implications for their prognostic value are reviewed, and the potential targets of molecular therapy are discussed. According to the molecular genetic aspect, STS are divided into two groups: chromosome translocation-associated sarcomas and sarcomas without specific translocation. In the former group,specific fusion transcripts, such as SS18–SSX, EWS–FLI1, and PAX3–FKHR, could be detected in synovial sarcoma, Ewing's sarcoma and primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma,respectively. The direct or indirect interactions between these fusion transcripts and cell cycle regulators have been elucidated by several investigators. Therefore, these fusion transcripts are promising candidates as molecular targets. As evaluated in carcinomas,alterations of several tumor-suppressor genes and adhesion molecules and overexpression of growth factors and their receptors have been extensively assessed in STS. In mixed-type STS, epidermal growth factor receptor overexpression was associated with decreased overall survival, suggesting the beneficial role of epidermal growth factor receptor inhibitors in STS. In malignant rhabdoid tumor and epithelioid sarcoma, frequent alteration of the SMARCB1/INI1 tumor-suppressor gene and the loss of its protein have been demonstrated, indicating that this molecule could be an effective target of these sarcomas. In sarcomas with epithelioid differentiation,such as synovial sarcoma and epithelioid sarcoma, overexpression of dysadherin, which downregulates E-cadherin expression, was a poor prognostic factor. In conclusion, further studies are necessary to search for effective and specific molecules for the inhibition of tumor growth in each type of STS, especially in sarcomas without specific translocation.

Figure 1

Myxoid/round cell liposarcoma (MRCLS) arising in the buttock of a 36‐year‐old man. (a) The tumor mainly consists of oval to fusiform cells with abundant myxoid matrix and arborizing vasculature, accompanied by a large number of mature lipoblasta (left: myxoid area). The tumor is partially composed of cellular proliferation of undifferentiated round cells with occasional multivacuolated lipoblasts (right: round cell component). (b) Cytogenetic study disclosed reciprocal chromosomal translocation between chromosome 12 and chromosome 16 in this case. (c) The reverse transcription–polymerase chain reaction method detected specific fusion transcripts for MRCLS, FUS–DDIT3 type 2 (arrow). Direct sequencing of the polymerase chain reaction product confirmed the break point between FUS exon 5 and DDIT3 exon 2. P, positive control; S, sample.

Figure 2

Interactions between the fusion transcripts SS18–SSX1, EWS–FLI1, and PAX3–FKHR, and G₁–S checkpoint cell cycle regulators. Molecular alterations in malignant peripheral nerve sheath tumor and dedifferentiated liposarcoma are also demonstrated. ––, direct stimulatory modification; ‐ ‐ ‐, tentative stimulatory modification; ––|, direct inhibitory modification; ⋆, gene alterations.