Molecular Genetics of Pediatric Soft Tissue Tumors

Abstract

The application of molecular genetics to pediatric soft tissue tumors has grown tremendously over the last decade. It has resulted in the identification of novel genes that have provided us with an increased understanding of oncogenesis. Furthermore, these findings have identified diagnostic and potentially prognostic factors for patient management. Molecular diagnostic techniques, such as reverse transcription PCR (RT-PCR) and fluorescence in situ hybridization (FISH), have become important tools for evaluating pediatric soft tissue tumors. By detecting characteristic fusion genes, these techniques have greatly increased the diagnostic accuracy of histopathological classification. One of the exciting promises of the development of these molecular techniques is their ability to detect micrometastasis and minimal residual disease. Monitoring of minimal residual disease in pediatric soft tissue tumors by quantitative RT-PCR may provide important prognostic information. Furthermore, the potential development of targeted therapy based on the understanding of the molecular pathology of a specific soft tissue tumor may complement existing treatments and improve disease outcome.

TLE1 as a Diagnostic Immunohistochemical Marker for Synovial Sarcoma Emerging From Gene Expression Profiling Studies

“…Demonstration in an appropriate histologic context of t(X;18) by cytogenetics, fluorescence in situ hybridization (FISH) or reverse-transcriptase polymerase chain reaction is considered the gold standard for the diagnosis of synovial sarcoma; however, several practical issues, including cost and the need for specialized equipment and personnel have limited the use of such diagnostic tests. 5,8 Correct diagnosis of synovial sarcoma on the basis of histology alone can be challenging especially in small biopsies, as monophasic synovial sarcomas can appear similar to other spindle cell tumors [including malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma, and hemangiopericytoma], and poorly differentiated synovial sarcomas can resemble several tumor types including Ewing sarcoma. Immunoreactivity for epithelial markers such as cytokeratin and epithelial membrane antigen (EMA) is frequently used to aid in differentiating synovial sarcoma from other spindle cell neoplasms; however, these markers not only lack specificity, 12,27 but also are limited in sensitivity because such epithelial markers are only focally expressed in many synovial sarcomas and are completely negative in a subset of monophasic cases.…”

Gene Translocations in Musculoskeletal Neoplasms

“…Because detection of specific translocations or chimeric gene fusion products can be used reliably as disease-specific markers in diagnosing soft tissue tumors, an increasing number of practicing surgical pathologists or even treating physicians rely on molecular diagnostic validation [18,70]. When evaluating the need to perform molecular evaluation for diagnosis, it is important to proceed along a practical algorithmic pathway before determining the need for molecular diagnostic tests.…”

“…Many existing pathologic techniques may be sufficient to establish a diagnosis without loss of accuracy and specificity. A practical diagnostic approach of integrating morphology, immunohistochemistry, and molecular genetics has been proposed by Chang and Shidham [18]. Initially, the specimens are evaluated for adequacy during fine-needle aspiration biopsy (FNAB) and/ or core biopsy by immediate morphologic interpretation of the cytology smear or frozen section.…”

“…Another distinction that should be made is between rhabdomyosarcoma and Ewing's sarcoma/PNET. Rhabdomyosarcoma and Ewing's sarcoma/PNET share two immunohistochemical markers, CD99 and MyoD, but can be distinguished through molecular translocations (Table 2) [18]. Even desmin positivity, once believed to represent a marker for rhabdomyosarcoma, is present in DRCT and in rare cases of Ewing's sarcoma [33].…”

“…The study of prognostic molecular markers, in particular, the type of fusion gene for determining prognosis in soft tissue sarcomas, has been addressed in four major types of sarcoma: (1) alveolar rhabdomyosarcoma [33]; (2) synovial sarcoma [34]; (3) Ewing's/peripheral neuroectodermal family of tumors [18]; and (4) myxoid liposarcoma [78].…”