Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis

INTRODUCTION — Pediatric soft tissue sarcomas are a heterogeneous group of tumors that are presumed to arise from a primitive mesenchymal cell. These tumors can arise in many anatomic locations and can resemble fat, fibrous tissue, and muscle. Soft tissue sarcomas as a group account for 7 percent of cancers diagnosed in individuals less than 15 years of age; in the United States, they have an estimated incidence of 12.01 per million [1-3].

This topic review will cover the epidemiology, pathology, and pathogenesis of a specific type of pediatric soft tissue sarcoma: rhabdomyosarcoma (RMS). Clinical manifestations, diagnostic evaluation, staging, and risk-adapted therapy for RMS are discussed elsewhere, as are primary tumors of bone and other soft tissue neoplasms arising in children as well as adults. (Refer to appropriate topic reviews.)

EPIDEMIOLOGY — RMS is the most common soft tissue sarcoma of childhood, accounting for one-half of all diagnoses in this age group [4,5]. However, they are rare, representing only 3 to 4 percent of pediatric cancers overall. Approximately 350 new cases are diagnosed in the United States each year, and the annual incidence in children, adolescents, and young adults under the age of 20 is 4.58 cases per one million [4,6].

Two-thirds of cases are diagnosed in children younger than six years of age, and there is a small male predominance (male to female ratio between 1.3 and 1.5). The incidence in Black patients is higher than in White, most notably in those 15 to 19 years [4]. The incidence appears to be lower in Asian (Indian sub-continent and West Indian ethnic origin) when compared with predominantly White populations [7].

Although RMS can arise anywhere in the body, distinct patterns link primary site, histology, and age at diagnosis:

●Head and neck RMS are more common in younger children; when they arise in the orbit, they are almost always of the embryonal type. (See 'Histologic classification' below.)

●Nearly 80 percent of genitourinary tract RMS are embryonal. The botryoid variant (sarcoma botryoides), a unique form of embryonal RMS arising within the wall of the bladder or vagina, is seen almost exclusively in infants. However, it can arise within the nasopharynx in older children.

●Extremity tumors present more commonly in adolescents and are frequently of the alveolar type. (See 'Histologic classification' below.)

Risk factors — As with the majority of childhood cancers, the etiology and specific risk factors for RMS are not known. A few epidemiologic reports suggest a higher incidence of RMS in individuals exposed to radiation in utero, children from families with a low socioeconomic status, those who received antibiotics soon after birth, and those whose parents used recreational drugs during pregnancy [8-13]. However, these associations have not been confirmed by other studies. Additionally, some studies have reported that children with certain birth characteristics, including congenital anomalies [14,15] and a preterm birth [16,17], are more likely to develop RMS compared with those without these characteristics.

Studies evaluating the association between birth weight and RMS have been equivocal [16], with some suggesting low birth weight is positively associated with risk [17], while others demonstrate that children with low birth weight are less likely to develop RMS [13,18]. High birth weight has also been associated with RMS risk [17]. A protective role for higher birth order, immunizations, and immune-related factors (allergies, atopy, daycare attendance, breastfeeding for 12 or more months) has also been suggested, but all of these require confirmation [19-21]. Notably, some studies have indicated that there may be differences in risk factors according to RMS histology. As an example, in one study using data from the Children's Oncology Group and the Utah Population Database [22], investigators found that there was an increased risk of embryonal RMS in children who had a first-degree relative with cancer; this same association was not seen in children with alveolar RMS.

Inherited syndromes — Most cases of RMS appear to be sporadic, but an estimated 5 to 10 percent of cases may be due to pathogenic or likely pathogenic variants in cancer predisposition genes associated with inherited syndromes. These syndromes include neurofibromatosis, Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, DICER1 syndrome, and Costello syndrome [23-30]. As an example, a large-scale sequencing study of 615 children with newly diagnosed RMS indicated that 7 percent (n = 45) had a pathogenic or likely pathogenic variant in a cancer predisposition gene [30]. There were differences by age at diagnosis and RMS subtype. Individuals with cancer predisposition variants were generally younger at diagnosis, although 40 percent were >3 years of age, suggesting genetic testing should not be limited to those ≤3 years of age as previously recommended. Additionally, cancer predisposition variants were most frequent among those with embryonal RMS. Syndromes implicated in this study include the following:

●Li-Fraumeni syndrome is an inherited condition in which members of affected families are predisposed to a spectrum of cancers, including soft tissue sarcomas, osteosarcomas, adrenocortical and brain tumors, leukemias, and breast cancer in adult relatives [31,32]. Many of these families have germline inactivating variants of the p53 tumor suppressor gene, whose normal function involves cell cycle regulation and the maintenance of genomic integrity. (See "Li-Fraumeni syndrome".)

Despite this association, the likelihood that an individual RMS is attributable to Li-Fraumeni syndrome is small and may be greatest among younger children. This was illustrated in a series of 33 RMS cases in which evidence for a germline p53 mutation was found in 3 of 13 children under three years of age compared with none of 20 children over the age of three [33]. These provocative findings suggest that children who develop RMS at a young age might be at higher risk for a hereditary predisposition syndrome; therefore, screening for germline TP53 variants in children younger than three years should be considered. Furthermore, if a germline TP53 variant is identified, it raises the issue of whether the treatment protocol should be modified to reduce exposure to ionizing radiation and/or chemotherapeutic agents, which may be associated with an increased risk for secondary malignancies [34]. However, there are no standard guidelines, and the approach to such patients is variable.

Presence of anaplasia or anaplastic histology has been associated with Li-Fraumeni syndrome [35,36]. (See 'Anaplasia in RMS' below and "Li-Fraumeni syndrome", section on 'Sarcomas'.)

●Beckwith-Wiedemann syndrome is a fetal overgrowth condition that is associated with an increased incidence of several solid tumors of childhood, including RMS, Wilms tumor, hepatoblastoma, and adrenocortical carcinoma. The genetic abnormalities found in these tumors affect the same chromosomal region (11p15, the locus for the IGF-2 gene) that has been implicated in the etiology of Beckwith-Wiedemann syndrome [37]. (See 'Molecular pathogenesis and molecular diagnostic testing' below and "Presentation, diagnosis, and staging of Wilms tumor", section on 'Beckwith-Wiedemann syndrome' and "Microduplication syndromes", section on '11p15 duplications in Beckwith-Wiedemann syndrome'.)

●Costello syndrome, also called faciocutaneoskeletal syndrome, is characterized by postnatal growth retardation, macrocephaly, coarse facies, loose skin, nonprogressive cardiomyopathy, developmental delay, and papillomata (particularly in the perioral, nasal, and anal regions) [27,38]. Patients with Costello syndrome have a predisposition to develop several malignancies, including RMS, epithelioma, bladder carcinoma, and vestibular schwannoma [28,39-41]. The increased susceptibility to tumors is thought to be related to the presence of a pathogenic variant in the HRAS protooncogene [42,43].

●Patients with neurofibromatosis have a 20-fold increased risk of RMS compared with the general population [44]. Other studies have documented an increased risk of congenital malformations of the central nervous, genitourinary, gastrointestinal, and cardiovascular systems in patients with RMS (32 versus 3 percent in the general population) [14]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

●In patients with familial predisposition to pleuropulmonary blastoma who have a germline DICER1 pathogenic variant (DICER1 syndrome, an autosomal dominant pleiotropic tumor predisposition disorder), there is an increased risk for uterine, cervical, and bladder embryonal RMS [45-47]. (See "Congenital pulmonary airway malformation", section on 'Pleuropulmonary blastoma'.)

HISTOLOGY — Morphologically, the appearance of RMS is similar to that of other small round blue cell tumors of childhood that involve bone and soft tissue, such as lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, and the Ewing sarcoma family of tumors (EFT). As a group, these tumors often pose difficult diagnostic problems, and advanced immunohistochemical (IHC), molecular, genetic, or ultrastructural techniques may be needed to definitively establish the diagnosis. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)

Tissue diagnosis — Adequate tissue for routine light microscopic, IHC, cytogenetic, and molecular genetic studies should be obtained at the time of biopsy or initial resection. In general, cytologic material, such as that obtained by fine needle aspiration biopsy, is typically inadequate for diagnosis [48].

If possible, the initial diagnostic biopsy should be performed at a facility with expertise in the evaluation of the child with a soft tissue or bone sarcoma to ensure that the tissue is processed properly and to allow for the special studies that are essential for accurate diagnosis and histologic classification (table 1) [49]. Review of the diagnostic material by a pediatric pathologist with special expertise in this area should be strongly considered because of the profound implications of a precise diagnosis on treatment and outcome.

The classification of a tumor as RMS requires the identification of features of skeletal muscle lineage. Typically, this involves light microscopic identification of rhabdomyoblasts or cross-striations that are characteristic of skeletal muscle. For cases that lack these features, IHC staining or electron microscopy may provide evidence supporting myogenic differentiation.

Immunohistochemistry — IHC, which is widely available, is a useful and reliable method for identifying muscle-specific proteins such as actin, myosin, desmin, myoglobin, Z-band protein, and myogenic differentiation 1 (MyoD1) [50,51]. Over 99 percent of RMS stain for polyclonal desmin, while muscle-specific actin, myogenin, and myoglobin positivity is found in approximately 95, 95, and 78 percent of tumors, respectively. Myogenin is expressed to a greater degree by alveolar as compared with embryonal RMS, is typically present in less-differentiated myogenic tumor cells [52], and has been associated with a poor prognosis independent of histopathologic subtype, tumor site, cytogenetics, and stage [53].

Other IHC stains may be useful in the differential diagnosis of tumors that present as small round blue cell tumors of childhood, although there is some overlap, resulting in several potential diagnostic pitfalls [51]. As examples:

●NKX2.2 and cluster of differentiation 99 (CD99; cell membrane expression) are sensitive markers for EFT. NKX2.2 (nuclear expression) is more specific and sensitive for EFT, and is negative in RMS. Nuclear NKX2.2 expression is more often a characteristic of an EWSR1/FL1 rearrangement resulting from a t(11;22)(q24;q21) translocation. (See 'Molecular pathogenesis and molecular diagnostic testing' below.)

By contrast, CD99 may be positive in approximately 15 percent of RMS cases (ie, it is less specific for EFT), but the staining pattern is usually weak and focal [54]. However, the CD99 staining pattern is distinctly different, with EFT possessing cell membrane staining, whereas RMS has cytoplasmic staining. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Differential diagnosis'.)

●Leukocyte common antigen and pan B lymphocyte antibodies react with rhabdomyoblasts in approximately 6 percent of cases. The presence of these cell surface markers may falsely suggest a B cell neoplasm if tissue is submitted for flow cytometry in an attempt to rule out a leukemic infiltrate or lymphoma. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Immunophenotype'.)

●Despite their origin from mesenchymal rather than epithelial tissue, aberrant expression of epithelial markers, such as cytokeratin, and neuroendocrine markers, such as synaptophysin, is positive in up to 40 percent of RMS [55].

●Markers of neural differentiation (eg, neuron-specific enolase, S-100 protein) are positive in 6 to 19 percent of cases.

Other adjunctive studies — Two other diagnostic methods are less widely available but may be useful in selected cases.

●Ultrastructural examination using transmission electron microscopy (TEM) can be helpful for poorly differentiated or undifferentiated myogenic tumors if the light microscopic and IHC findings are inconclusive [56-58]. TEM features of rhabdomyoblasts include the presence of myofilaments, thick (desmin) and thin (actin) filaments, myotubular intermediate filaments, and rudimentary Z-band material.

●Molecular studies such as reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescent in situ hybridization (FISH) may be helpful to identify characteristic fusion proteins in some cases (eg, alveolar RMS (table 2)). In general, FISH for FOXO1 is utilized to a greater extent to identify alveolar RMS than is RT-PCR. (See 'Alveolar RMS and chromosome translocations' below.)

Histologic classification — The WHO classification of soft tissue tumors categorizes rhabdomyosarcoma into four major histologic subtypes [59,60]:

●Embryonal RMS, which is associated with an intermediate prognosis. (See 'Embryonal RMS' below.)

●Alveolar RMS, as defined by FOXO1 rearrangement by FISH or RT-PCR (both the classic and solid variants), with a relatively poorer prognosis. (See 'Alveolar RMS and chromosome translocations' below.)

●Pleomorphic RMS, which is mostly seen in adult population.

●Spindle cell/sclerosing RMS with various molecular subtypes and varying prognostic groups

●Separate categories have been established for "sarcoma, not otherwise specified (NOS)," which is used to designate tumors that could not be classified into a specific subtype, and for diffusely anaplastic sarcomas, which were previously included as pleomorphic sarcomas in older classifications and are associated with a poor prognosis [61].

The embryonal subtype is the most common, accounting for 59 percent of all RMS cases. Most (50 percent) are of the classic subtype, and the botryoid and spindle cell variants comprise 6 and 3 percent, respectively. Alveolar RMS represents 21 percent of all cases, while the remainder are classified as undifferentiated (8 percent), pleomorphic (1 percent), or sarcoma NOS (11 percent).

The morphologic appearance of the tumor cells of both alveolar and embryonal RMS is nonspecific. The cells have scant cytoplasm and a centrally placed, round nucleus that occupies the majority of the cell. It is the organizational architecture of the tumor that distinguishes alveolar from embryonal subtype.

Embryonal RMS — Classic embryonal RMS (picture 1) is composed of typical rhabdomyoblasts arranged in sheets and large nests, with infrequent intermixed fusiform cells and no suggestion of an alveolar architectural pattern. The typical rhabdomyoblast has moderate to deeply eosinophilic cytoplasm, representing poorly formed myofilaments. Myofilaments with cross-striations are usually present only in the well-differentiated spindle cell subtype, which is so named because the cells have a characteristic elongated spindle-like appearance. This spindle cell version often presents in a paratesticular location and does not have the molecular changes seen with the spindle cell/sclerosing RMS subtype. (See 'Spindle cell/sclerosing RMS' below.)

A subset of embryonal RMS, the spindle cell RMS variant occurs in neonates and infants less than one year of age. This subset may be confused with congenital/infantile fibrosarcoma, and IHC for desmin, myogenin, and MyoD1 should be performed in these cases. The embryonal subset of sclerosing RMS more typically occurs in children greater than one year of age, and it is also seen in adults.

The botryoid variant of embryonal RMS takes its name from the "grape-like" gross appearance of the tumor. The polypoid mass grows beneath an epithelial surface, and dense subepithelial aggregates of rhabdomyoblasts (the so-called "cambrium" layer) are characteristic (picture 2). the botryoid variant typically arises within the wall of the bladder or vagina (picture 3 and picture 4) and is seen almost exclusively in infants.

Alveolar RMS — The typical appearance of alveolar RMS is that of fibrovascular septae that are lined with densely packed ovoid to round tumor cells and separated by pseudo-alveolar spaces, which vaguely resemble pulmonary alveoli (picture 5). Frequently, the "loosely adherent" rhabdomyoblasts are shed into these pseudo-alveolar spaces. Less well-differentiated alveolar RMS may feature only a suggestion of fine fissuring or micro-alveoli; molecular techniques may aid in the diagnosis of such cases [62].

Previously, the presence of any alveolar architectural pattern was sufficient to categorize a tumor as alveolar RMS. However, in treatment protocols, the Soft Tissue Sarcoma Committee of the Children's Oncology Group has recommended that the tumor must have a predominant (>50 percent) alveolar component and possess a FOX01 rearrangement, t(1;13) or t(2;13), by FISH or RT-PCR to be subtyped and classified as alveolar (ie, "fusion positive") (table 2). In fact, treatment protocols are designed to emphasize fusion status by excluding patients with alveolar histology who are fusion negative in the intermediate risk group. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Alveolar rhabdomyosarcoma'.)

Anaplastic (pleomorphic) RMS — Pleomorphic RMS is defined by the presence of large hyperchromatic nuclei with atypical, bizarre mitotic figures. The nuclear size is threefold larger than that of adjacent "typical" tumor cells. This form is almost entirely seen in adults in their sixth and seventh decades of life and has a very poor prognosis.

Spindle cell/sclerosing RMS — The spindle cell/sclerosing RMS subtype is one of the major histology groups associated with molecular changes, based on the WHO 2022 classification system. This subtype was previously described as part of the embryonal histology. Spindle cell/sclerosing RMS has been divided into three further subtypes:

●Congenital spindle cell RMS with VGLL2/NCOA2/CITED2 rearrangements

●MyoD1-mutant spindle cell/sclerosing RMS

●Intraosseous spindle cell RMS with TFCP2/NCOA2 rearrangements

Anaplasia in RMS — Anaplasia can be seen in any histologic subtype of RMS; it is seen in a very small fraction of patients. This finding is seen most often in patients with Li-Fraumeni syndrome and is typically associated with a poor prognosis [35,36]. (See "Li-Fraumeni syndrome", section on 'Sarcomas'.)

MOLECULAR PATHOGENESIS AND MOLECULAR DIAGNOSTIC TESTING — Over the last decade, much has been learned about the molecular genetic alterations that characterize RMS. Two major histologic subtypes, alveolar and embryonal RMS, reflect distinct clinical and molecular entities that may arise through distinct biologic mechanisms. The characteristic genetic alterations are presumed to play some role in their pathogenesis. The diagnosis of a RMS is usually based upon both histology and molecular studies. A consensus opinion on diagnostic studies for RMS is available from the combined Children's Oncology Group (COG), European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe [63].

Alveolar RMS and chromosome translocations — Alveolar RMS presents throughout childhood in the trunk and extremities, and harbors distinguishing chromosomal translocations, as occurs with several other sarcomas (table 2). The most common translocation occurs between the long arms of chromosome 2 and 13, t(2;13)(q35;q14), and fuses the PAX3 gene (which normally functions as a transcription regulator during early neuromuscular development) with the FOXO1 gene, a transcription factor [64,65]. A less common translocation, t(1;13)(p36;q14), fuses a different gene, the PAX7 gene located on chromosome 1, with FOXO1 [66]. It is hypothesized that these unique fusion genes in some way activate the transcription of other genes that contribute to the transformed phenotype, although the mechanisms by which this occurs are just beginning to be elucidated [67]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Alveolar rhabdomyosarcoma'.)

Reverse transcriptase polymerase chain reaction (RT-PCR) assays are available that detect the presence of either of these fusion genes, which may be used to support the diagnosis of alveolar RMS. Fluorescence in situ hybridization (FISH) using a FOXO1 probe is a fast and accurate test to identify both translocations as well. In one COG study, PAX3-FOXO1 and PAX7-FOXO1 fusion transcripts were identified in 55 and 22 percent of alveolar RMS, respectively, while 23 percent were fusion negative [68]. Identification of the fusion gene may be particularly helpful for tumors with equivocal or nondiagnostic light microscopic and immunohistochemical (IHC) findings.

The type of fusion gene is of clinical relevance. Patients with a PAX7-FOXO1 translocation tend to be younger and more likely to present with an extremity lesion, and may have a better outcome compared with those with the PAX3-FOXO1 translocation [68,69].

With COG protocols, diagnosis is based upon fusion gene status rather than histology alone. Assessment for FOXO1 rearrangement by FISH or RT-PCR is required to provide a diagnosis of alveolar RMS for risk stratification purposes, regardless of the histomorphologic features. Therefore, FISH or RT-PCR for FOXO1 rearrangement is performed on all RMS tumors. (See 'Molecular classification and risk stratification' below.)

There are additional rare translocations and genetic abnormalities that have been described in alveolar RMS. The relatively rare novel translocations include PAX3/FOXO4, PAX3/NCOA1, PAX3/NCOA2, FOXO1/FGFR1, FUS/TFCP2, and EWSR1/TFCP2. In addition, CDK4 amplification, mutations in TP53, CDKN2A, CDKN2B, and FGFR4, and ALK copy gains have been identified. Both tumor suppressor mutations (RASSF, HIC1, CASP8) and DNA methylation play a role in the pathogenesis of alveolar RMS.

Embryonal type — Embryonal RMS typically occurs in young children, mainly in the head, neck, and genitourinary sites. While specific translocations have not been identified, most embryonal RMS have loss of heterozygosity (LOH) at the 11p15 locus, the site of the IGF-2 gene. IGF-2 is an imprinted gene, meaning that only the paternal allele is transcriptionally active. It is thought that 11p LOH leads to loss of maternal genetic information with duplication of paternal genetic information (paternal disomy) [70,71].

Embryonal RMS overproduce insulin-like growth factor 2 (IGF-2), a factor that stimulates the growth of these tumors in vitro and whose inhibition is accompanied by growth repression [72,73]. Alveolar RMS also overexpress IGF-2, at least the subset with the PAX3-FOXO1 translocation [74]. Taken together, these data suggest that upregulated IGF-2 expression plays an important role in the growth of RMS, regardless of histology.

The mechanism responsible for IGF-2 overexpression in embryonal RMS is unclear. One possibility is a loss of imprinting at this locus, with re-expression of the normally silent maternal IGF-2 allele [75]. Loss of imprinting with biallelic expression (ie, expression of both maternal and paternal alleles) and 11p LOH with paternal disomy could both lead to a double-gene dose effect, potentially resulting in IGF-2 overexpression.

Of note, the 11p15.5 locus harbors important genes that may be altered in embryonal RMS, including H19, CDKN1C, and HOTS in addition to IGF-2. Certain mutations (pRb, TP53, GLI, CDKN2A, CDKN2B, RAS, FGFR4, PIK3CA, CTNNB1 [beta-catenin], MyoD1) and a deletion in the NF1 gene may be present.

Additional genetic abnormalities may include ALK copy gain and DNA methylation aberrations.

Spindle cell/sclerosing type — Rearrangements of VGLL2 and NCOA2 are characteristic of the spindle cell/sclerosing type variant in neonates and infants less than one year of age, and has a favorable outcome. The gene fusions include VGLL2-CITED2, VGLL2-NC0A2, TEAD1-NCOA2, PAX3-NCOA2, PAX3-NCOA2, and SRF-NCOA2.

By contrast, spindle cell/sclerosing RMS in children older than one year of age tend to have an aggressive course and unfavorable outcome. These subsets of embryonal RMS are defined by mutations in MyoD1 and PIK3CA, and in some cases, mutations in both these genes.

Other pathways — Abnormalities in a variety of other molecular pathways have been described in RMS (eg, TP53 [30], RAS [76], RB1, and PTCH gene mutations, MDM2, CDK4, and MYCN amplification, abnormalities in the basic helix-loop-helix myogenic differentiation family of proteins). The interactions between these molecular changes, PAX/FOXO1 translocations, and 11p LOH are areas of active investigation. It remains unclear how any of these molecular abnormalities lead to the failure of terminal myogenic differentiation, and/or malignant transformation in RMS. A complete discussion of this subject is beyond the scope of this review, and several contemporary references are available [77-80].

Molecular classification and risk stratification — Treatment of RMS is selected according to a risk-based algorithm, which historically has combined histologic classification (embryonal versus alveolar) with presurgical stage and postsurgical clinical group. However, histologic classification is not always straightforward. RMS is defined as showing at least minimal evidence of skeletal muscle differentiation by IHC or transmission electron microscopy, but in a large proportion of cases, morphologic evidence of muscle differentiation is limited to a small percentage of tumor cells or may be extremely difficult to detect. Furthermore, although molecular detection of the chimeric transcription factors PAX3-FOXO1 or PAX7-FOXO1, which are found exclusively in alveolar RMS, was initially thought to provide an objective basis for distinguishing between the two major forms of the disease (alveolar versus embryonal), up to 45 percent of RMS with alveolar morphology lack FOXO1 rearrangement or another unique gene fusion [81]. (See 'Alveolar RMS and chromosome translocations' above.)

Data suggest that these fusion-negative alveolar tumors behave more like embryonal RMS (with a more favorable outcome overall) than fusion-positive alveolar RMS, at least for low and intermediate-risk tumors [82-85]. Clinical practice has evolved away from using histology alone to classify these tumors, and this has been replaced by an assessment of the presence or absence of the characteristic fusion gene. For patients with fusion-negative tumors, practice is evolving toward molecular classification based upon gene expression, which may offer a more clinically relevant diagnostic scheme, improving patient management and therapeutic RMS outcomes [82,86-89].

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SUMMARY

●Epidemiology – Rhabdomyosarcoma (RMS) is rare overall, but it is the most common soft tissue tumor of childhood and is responsible for approximately one-half of all soft tissue sarcomas in this age group. Two-thirds of cases are diagnosed in children under the age of six. The etiology and risk factors are largely unknown. (See 'Epidemiology' above.)

●RMS and inherited syndromes – Most cases of RMS appear to be sporadic, but the disease has been associated with cancer predisposition syndromes (neurofibromatosis and Li-Fraumeni, Beckwith-Wiedemann, DICER1, and Costello syndromes). (See 'Inherited syndromes' above.)

●Histopathology – Morphologically, the appearance of RMS is similar to that of other small round blue cell tumors of childhood that involve bone and soft tissue, such as lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, and the Ewing sarcoma family of tumors. Advanced immunohistochemical, molecular, genetic, or ultrastructural techniques may be needed to definitively establish the diagnosis. (See 'Histology' above.)

●Histologic classification – Several major histologic subtypes of RMS are identified, a distinction that is important for both treatment and prognosis. The embryonal and alveolar subtypes are most common. (See 'Histologic classification' above.)

•Embryonal RMS – While specific translocations have not been identified in typical embryonal RMS, most embryonal RMS have loss of heterozygosity at the 11p15 locus, the site of the IGF-2 gene.

•Alveolar RMS – Alveolar RMS typically harbor distinguishing chromosomal translocations, specifically a FOX01 rearrangement. The fusion gene products of these translocations can be identified by reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH), which must be used to support the diagnosis of this subtype. (See 'Alveolar RMS and chromosome translocations' above.)

•Spindle cell/sclerosing RMS - The congenital/infantile spindle cell variant RMS is identified with tumor-defining translocations involving NCOA2 and VGLL2 genes. It occurs in neonates and infants less than one year of age, and has a favorable outcome. With children older than one year of age, spindle cell/sclerosing RMS with MyoD1 and PIK3CA gene mutations occur. These tumors tend to be aggressive with a poor prognosis. (See 'Spindle cell/sclerosing RMS' above.)

●Molecular classification and risk stratification – Traditionally, treatment of RMS has been selected according to a risk-based algorithm that combines histologic classification with presurgical stage and postsurgical clinical group. Histologic classification is not always straightforward, and clinical practice has evolved to include information on the presence or absence of the characteristic fusion genes. FISH or RT-PCR for FOXO1 rearrangement is performed on all RMS tumors. Assessment for FOXO1 rearrangement by FISH or RT-PCR is required to provide a diagnosis of alveolar RMS for risk stratification purposes, regardless of the histomorphologic features. (See 'Molecular classification and risk stratification' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Marc Horowitz, MD, and Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.