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Archives of Pathology & Laboratory... Aug 2022Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar... (Review)
Review
CONTEXT.—
Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma, based on recent molecular genetic knowledge and morphologic features.
OBJECTIVE.—
To highlight the most recent advances of molecular genetic alterations, and to familiarize pathologists with most recent genotype and phenotype correlation in rhabdomyosarcoma.
DATA SOURCES.—
Data were derived from the World Health Organization Classification of Soft Tissue and Bone Tumors, fifth edition, recently published literature (PubMed), and clinical practice experience.
CONCLUSIONS.—
Current classification has been significantly impacted by genotype and phenotype correlation, especially with PAX-FOXO1 fusion-positive rhabdomyosarcoma versus fusion-negative rhabdomyosarcoma, and with the emergence of 3 distinct new subtypes of spindle cell/sclerosing rhabdomyosarcoma. Although all rhabdomyosarcomas were considered a single diagnostic entity in the past, they are now considered to be a group of histologically similar but biologically diverse entities because their clinical behavior and underlying molecular alterations dramatically differ. This review outlines recent molecular genetic developments, corresponding morphologic features, and current challenges faced by pathologists in daily practice.
Topics: Humans; Mutation; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Soft Tissue Neoplasms; World Health Organization
PubMed: 35051261
DOI: 10.5858/arpa.2021-0183-RA -
JCO Precision Oncology Jun 2023Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and...
PURPOSE
Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades.
PATIENTS AND METHODS
The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had fusion-positive alveolar RMS (ARMS), with 70% having a transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel.
RESULTS
One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [ = .004], 2.78 [ = .010] and 2.26 [ .034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). ARMS had worse prognosis and afflicted older children compared with (HR = 3.45, .016). The most common events in the ARMS group included alterations, amplifications, and deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS ( = .02).
CONCLUSION
Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS.
Topics: Child; Humans; Adolescent; Genomics; Rhabdomyosarcoma; Extremities; Oncogenes; Risk Assessment
PubMed: 37315267
DOI: 10.1200/PO.22.00705 -
Cold Spring Harbor Molecular Case... Feb 2021Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar...
Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar rhabdomyosarcoma is the most aggressive subtype with an 8% 5-yr disease-free survival rate when a chromosomal fusion is present and a 29% 5-yr disease-free survival rate when negative for a fusion event. The underlying biology of -fusion-negative alveolar rhabdomyosarcoma remains largely unexplored and is exceedingly rare in Li-Fraumeni syndrome patients. Here, we present the case of an 11-yr-old male with fusion-negative alveolar rhabdomyosarcoma studied at end of life with a comprehensive functional genomics characterization, resulting in identification of potential therapeutic targets for broader investigation.
Topics: Antineoplastic Agents; Child; Drug Screening Assays, Antitumor; Germ Cells; Humans; Male; Rhabdomyosarcoma, Alveolar; Tumor Suppressor Protein p53; Exome Sequencing
PubMed: 33436392
DOI: 10.1101/mcs.a005983 -
Histopathology May 2021Mucin 4 (MUC4) is a transmembrane glycoprotein normally expressed by several human epithelial surfaces, including those of the colon, vagina, and respiratory tract....
AIMS
Mucin 4 (MUC4) is a transmembrane glycoprotein normally expressed by several human epithelial surfaces, including those of the colon, vagina, and respiratory tract. Although MUC4 overexpression is seen in various carcinomas, its expression among mesenchymal neoplasms is fairly specific to low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma. Having observed unanticipated anti-MUC4 immunoreactivity in rhabdomyosarcoma, we aimed to further characterise its expression.
METHODS AND RESULTS
Expression of MUC4 was assessed by immunohistochemistry in a total of 97 rhabdomyosarcomas using formalin-fixed paraffin-embedded tissue sections. MUC4 was expressed by 21 of 26 PAX3/7-FOXO1 fusion-positive cases, wherein immunoreactivity, varying from weak to strong, was present in 20-100% of neoplastic cells. With the exception of one sclerosing rhabdomyosarcoma showing immunoreactivity in 20% of cells, MUC4 was not expressed by embryonal (n = 28), sclerosing (n = 20), or pleomorphic (n = 23) rhabdomyosarcomas. Analysing published gene expression microarray data from a separate cohort of 33 fusion-positive and 25 fusion-negative rhabdomyosarcomas, we found on average a 11.4-fold increased expression in fusion-positive tumours (P = 0.0004).
CONCLUSIONS
MUC4 is expressed to a variable extent in the majority of PAX3/7-FOXO1 fusion-positive (alveolar) rhabdomyosarcomas, while expression in other rhabdomyosarcoma subtypes is rare.
Topics: Adult; Female; Head and Neck Neoplasms; Humans; Mucin-4; Rhabdomyosarcoma, Alveolar; Soft Tissue Neoplasms
PubMed: 33368602
DOI: 10.1111/his.14321 -
Nature Communications Nov 2021Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations...
Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.
Topics: Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Child; Chromatin; DNA Helicases; Epigenomics; Gene Expression Regulation, Neoplastic; Humans; Muscle Development; Muscle, Skeletal; Nuclear Proteins; Oncogene Proteins, Fusion; PAX7 Transcription Factor; Paired Box Transcription Factors; Proteomics; Rhabdomyosarcoma; Transcription Factors; Transcriptional Activation
PubMed: 34836971
DOI: 10.1038/s41467-021-27176-w -
Cancer Medicine May 2023Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.
AIMS
The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.
MATERIALS & METHODS
Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies.
RESULTS
One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02).
DISCUSSION
Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS.
CONCLUSION
These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.
Topics: Humans; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Vinorelbine; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Cyclophosphamide; Chronic Disease
PubMed: 37016270
DOI: 10.1002/cam4.5749 -
Journal of the Korean Association of... Apr 2023This systematic review aimed to analyze the clinicopathological profile and relevant prognostic factors of head and neck rhabdomyosarcoma in pediatric patients. The... (Review)
Review
This systematic review aimed to analyze the clinicopathological profile and relevant prognostic factors of head and neck rhabdomyosarcoma in pediatric patients. The search was carried out in the electronic search portals PubMed, Lilacs, Embase, Scopus, and Web of Science. The search yielded studies that were then analyzed regarding study topic, data extraction, and risk of bias using the STROBE (Strengthening the Reporting of Observational Studies) guidelines. Finally, three studies were included for qualitative analysis. Most of the cases involved embryonic and alveolar rhabdomyosarcoma. Expression of MYOD1 was highly correlated with diagnosis of spindle cell/sclerosing rhabdomyosarcoma, which appears to have a poor prognosis in children. Furthermore, tumor size <5 cm and absence of metastasis accompanied by complete resection and administration of adjuvant therapies such as chemotherapy and radiotherapy favored a better prognosis.
PubMed: 37114443
DOI: 10.5125/jkaoms.2023.49.2.61 -
Cells Jul 2021Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a... (Review)
Review
Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation with driving activity on tumor growth. HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.
Topics: Cell Differentiation; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Protein-Tyrosine Kinases; Rhabdomyosarcoma; Translocation, Genetic
PubMed: 34359977
DOI: 10.3390/cells10071808 -
International Journal of Molecular... Feb 2024Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic... (Review)
Review
Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, or . ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-β). This overexpression of TGF-β1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes epithelial to mesenchymal transition (EMT). Overexpression of TGF-β also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-β in this tumor type. We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.
Topics: Humans; Rhabdomyosarcoma, Alveolar; Transforming Growth Factor beta; Transforming Growth Factor beta1; Paired Box Transcription Factors; Epithelial-Mesenchymal Transition; Rhabdomyosarcoma; Oncogene Proteins, Fusion
PubMed: 38474036
DOI: 10.3390/ijms25052791 -
Andes Pediatrica : Revista Chilena de... Jun 2021Rhabdomyosarcoma (RMS) is a malignant solid tumor of mesenchymal origin. It is the most com mon soft-tissue sarcoma in childhood and adolescence. 65% of cases are...
INTRODUCTION
Rhabdomyosarcoma (RMS) is a malignant solid tumor of mesenchymal origin. It is the most com mon soft-tissue sarcoma in childhood and adolescence. 65% of cases are diagnosed before the age of 6. Histological subtypes include embryonal, alveolar, pleomorphic, and fused-cell RMS. The embryo nal subtype is more frequent in children, while the alveolar one is more frequent in adolescents and adults.
OBJECTIVE
To describe the clinical presentation of primary alveolar rhabdomyosarcoma in a schoolgirl.
CLINICAL CASE
7-year-old schoolgirl with one-month history of progressive pain in her left thigh. X-ray shows a lytic lesion in the left femur diaphysis. A study was performed with 2 biopsies, immunohistochemistry, and PAX-FOXO1 studies which were compatible with alveolar RMS. Con clusion: Primary alveolar rhabdomyosarcoma of the bone is rare, but it should be considered within the differential diagnosis of primary small-round-blue cell bone tumors. Despite presenting a poor prognosis cytogenetic, this type of tumor seems to have better biological behavior, which for a successful treatment makes necessary to have a high index of suspicion in order to install a multimodal therapy in the context of a national protocol.
Topics: Child; Female; Femoral Neoplasms; Humans; Rhabdomyosarcoma, Alveolar
PubMed: 34479252
DOI: 10.32641/andespediatr.v92i3.2613