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Chariton Safonov
Chariton Safonov

Alveolar Rhabdomyosarcoma

Most rhabdomyosarcomas develop in children and teens, but they can also occur in adults. Adults are more likely to have faster-growing types of RMS and to have them in parts of the body that are harder to treat. Because of this, RMS in adults is often harder to treat effectively.

alveolar rhabdomyosarcoma

Okcu MF, Hicks J. Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis. UpToDate. Accessed at www.uptodate.com/contents/rhabdomyosarcoma-in-childhood-and-adolescence-epidemiology-pathology-and-molecular-pathogenesis on May 21, 2018.

Because rhabdomyosarcoma is so rare, many people with the disease are treated as part of clinical trials. Clinical trials are studies that test the newest, most promising treatments. Ask your healthcare team about clinical trials and whether your child is eligible to join.

Childhood rhabdomyosarcoma is, fortunately, very rare. Your healthcare team can confirm whether your child has this type of cancer and if so, determine what stage it is. The team will work with you to plan a treatment strategy and offer support to help your family cope.

Treatment for a child, teen, or young adult with alveolar rhabdomyosarcoma is based on the size and stage of the tumor, where the tumor is located on the body, and whether or not the tumor has spread to other parts of the body. The combination of these factors helps doctors decide whether the cancer is low risk, intermediate risk, or high risk.

Right now, I am studying tumor samples from cancer patients to understand how rhabdomyosarcoma cells might be using DNA methylation to form and grow. I hope this line of research will open exciting new areas for treatment and provide valuable biomarkers for cancer detection, diagnosis, and risk assessment.

Alveolar rhabdomyosarcoma (ARMS) is a subtype of the rhabdomyosarcoma soft tissue cancer family whose lineage is from mesenchymal cells and are related to skeletal muscle cells.[1] ARMS tumors resemble the alveolar tissue in the lungs.[1] Tumor location varies from patient to patient, but is commonly found in the head and neck region, male and female urogenital tracts, the torso, and extremities.[2] Two fusion proteins can be associated with ARMS, but are not necessary, PAX3-FKHR (now known as FOXO1).[3][4] and PAX7-FKHR.[5][6] In children and adolescents ARMS accounts for about 1 percent of all malignancies, has an incidence rate of 1 per million, and most cases occur sporadically with no genetic predisposition.[1] PAX3-FOXO1 is now known to drive cancer-promoting gene expression programs through creation of distant genetic elements called super enhancers.[7]

ARMS cells are often small with little cytoplasm. The nuclei of the cells are round with normal, dull, chromatin structures.[1] The ARMS cells often clump together and have fibrovascular septae that interrupts the aggregates. The fibrovascular septae that disrupts the aggregates often give the tumor the physiology of the alveoli found in the lungs.[1] In a few cases, there may not be any fibrovascular septae and this gives the tumor a more solid phenotype and no alveoli physiology.[1] Immunostaining for myogenin and for MyoD can be used to determine ARMS from other rhabdomyosarcoma tumors and immunostaining for AP2β and p-cadherin can distinguish fusion positive ARMS from fusion negative.[1]

ARMS usually occurs in the skeletal muscles and is postulated to be derived from precursor cells within the muscle tissue.[1] During embryonic development ARMS occurs in the mesoderm which is the precursor for the skeletal muscle tissue.[1] ARMS accounts for roughly 20 to 30 percent of all rhabdomyosarcoma tumors and therefore accounts for roughly 1 percent of malignancies found in children and adolescents.[1] There is an age determination on which PAX proteins fuse together with the FOXO1 transcription factor. PAX3-FOXO1 positive subset of ARMS occurs mostly in older children and young adults, while PAX7-FOXO1 positive subset of ARMS and fusion negative subsets occur most often in younger children.[1]

Purpose: To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene.

Patients and methods: The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets.

Conclusion: The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.

Rhabdomyosarcoma is a rare sarcoma that develops in the muscles and can cause pain and swelling. The different types and grades of rhabdomyosarcoma require different treatment approaches. At MSK Kids, we use precision genetic testing to assess rhabdomyosarcomas. Our doctors were the first to identify a genetic mutation found in some people with the embryonal form of the disease. Our rhabdomyosarcoma experts have seen more patients with this tumor than most healthcare professionals.

Rhabdomyosarcoma (RMS) is a mesenchymal tumor of soft tissue in children that originates from a myogenic differentiation defect. Expression of SNAIL transcription factor is elevated in the alveolar subtype of RMS (ARMS), characterized by a low myogenic differentiation status and high aggressiveness. In RMS patients SNAIL level increases with higher stage. Moreover, SNAIL level negatively correlates with MYF5 expression. The differentiation of human ARMS cells diminishes SNAIL level. SNAIL silencing in ARMS cells inhibits proliferation and induces differentiation in vitro, and thereby completely abolishes the growth of human ARMS xenotransplants in vivo. SNAIL silencing induces myogenic differentiation by upregulation of myogenic factors and muscle-specific microRNAs, such as miR-206. SNAIL binds to the MYF5 promoter suppressing its expression. SNAIL displaces MYOD from E-box sequences (CANNTG) that are associated with genes expressed during differentiation and G/C rich in their central dinucleotides. SNAIL silencing allows the re-expression of MYF5 and canonical MYOD binding, promoting ARMS cell myogenic differentiation. In differentiating ARMS cells SNAIL forms repressive complex with histone deacetylates 1 and 2 (HDAC1/2) and regulates their expression. Accordingly, in human myoblasts SNAIL silencing induces differentiation by upregulation of myogenic factors. Our data clearly point to SNAIL as a key regulator of myogenic differentiation and a new promising target for future ARMS therapies.

Rhabdomyosarcoma (RMS) is the most frequently occurring soft tissue sarcoma among children and adolescents, however, rare instances of the disease have been noted in adults. Based on histological analysis of the tumor, two major RMS subtypes may be distinguished: embryonal (ERMS) and alveolar (ARMS). ERMS is usually associated with better survival and typically occurs in the head and neck and urogenital tract. ARMS occurs in the extremities and trunk and generally has a significantly worse prognosis1,2,3. High aggressiveness of ARMS subtype is associated with presence of PAX3-FOXO1 or PAX7-FOXO1 fusion genes and increased levels of MET receptor, a member of tyrosine kinase receptors family (RTK), which is associated with metastatic potential of RMS cells2,4. RMS development is likely connected to a differentiation defect of stem cells or early progenitors, such as mesenchymal stem cells or satellite cells/myoblasts3,5,6.

Myogenic differentiation is regulated by different early and late myogenic factors. These basic helix-loop-helix (bHLH) transcription activators contain a conserved DNA binding domain, that recognizes the enhancer box (E-box) motif[7]. Myogenic factor 5 (MYF5) and myogenic differentiation 1 (MYOD/MYOD1) are responsible for the early stages of differentiation, whereas myogenin (MYOG) and myogenic factor 6 (MRF4) are responsible for terminal differentiation7. Those myogenic factors regulate genes and muscle-specific microRNAs. An interesting example is miR-206, which is induced by MYOD to enhance differentiation and facilitate cell cycle exit8. Aberrations within the regulatory myogenic pathway described above may be one of the crucial causes of the rhabdomyosarcoma development3,4.

A number sign (#) is used with this entry because of evidence that alveolar rhabdomyosarcoma results from fusion of the PAX3 gene (606597) on chromosome 2 with the FKHR gene (FOXO1A; 136533) on chromosome 13 as a result of a translocation t(2;13), or from fusion of the PAX7 gene (167410) on chromosome 1 with the FKHR gene as a result of a translocation t(1;13).

Douglass et al. (1987) found a specific translocation, t(2;13)(q35;q14), in 5 cases of advanced rhabdomyosarcoma. It was identified directly in cells that had metastasized from bone marrow in 1 patient, and in xenografts derived from the tumors of 4 other patients. Wang-Wuu et al. (1988) did chromosomal analysis of 16 rhabdomyosarcomas (4 primary tumors and 12 tumors after nude mouse passage). Of 7 alveolar tumors, 4 had t(2;13)(q37;q14); in 2 of these it was the only structural abnormality. Eight of 9 embryonal tumors had trisomy 2. 041b061a72


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