Alveolar Rhabdomyosarcoma

See section Embryonal rhabdomyosarcoma.

A t(2;13)(q36;q14) translocation is found in the majority of ARMSs, and a t(1;13)(p36;q14) is seen in a smaller subset. These translocations juxtapose PAX3 (at 2q36.1) or PAX7 (at 1p36.13) with the FOXO1 gene at 13q14.11, to generate chimeric genes that encode PAX3-FOXO1 and PAX7-FOXO1 fusion proteins. PAX3 and PAX7 represent transcription factors that play essential roles in myogenesis. The PAX-FOXO1 fusion proteins function as oncoproteins affecting growth, survival, differentiation, and other pathways through activation of numerous downstream target genes such as MET, ALK, FGFR4, MYCN, IGF1R, and MYOD1. Less common fusion gene variants include the fusion of PAX3 to FOXO4, NCOA1, or INO80D and the fusion of FOXO1 to FGFR1.

Amplification of genomic regions 2p24 (containing the MYCN oncogene) and 12q13-q14 (including CDK4) occur most often in PAX3-FOXO1 ARMSs, and amplification of regions 1p36 (which encompasses the PAX7 locus) and 13q31 (which includes MIR17HG) are associated specifically with PAX7-FOXO1 tumors. Analyses of individual genes in sporadic ARMS have implicated several important oncogenetic pathways. Inactivating mutations of TP53 and CDKN2A/CDKN2B and activating mutations of FGFR4 are present in a small subset. ALK gene copy-number gain and cytoplasmic overexpression of ALK protein occur in the vast majority of ARMSs; however, targeting this kinase in vivo does not yield therapeutic efficacy. The presence of recurrent somatic mutations (fusion-positive ARMSs have few to none) and distinct gene expression and DNA methylation profiles characterize fusion-positive and fusion-negative rhabdomyosarcomas (fusion-negative ARMS profiles are similar to those of ERMS).

ARMS is soft, fleshy, and gray, with variable amounts of fibrous tissue and occasional necrotic areas and hemorrhage. Deep-seated tumors involving the musculature commonly infiltrate surrounding tissues.

ARMS is highly cellular and composed of primitive round cells with scant cytoplasm and hyperchromatic nuclei. Tumor cells are arranged in nests separated by fibrovascular septa, which frequently exhibit loss of cellular cohesion in the center, conferring a pattern of irregular alveolar spaces and a varying degree of cystic change. The solid subtype of ARMS is composed of sheets of neoplastic cells that have cytomorphological features of ARMS but lack septa or discohesion. Mitotic activity is often brisk. Occasionally, recognizable rhabdomyoblastic differentiation can be discerned. Multinucleated tumor giant cells are a common feature of ARMS. Rare cases may show clear cell morphology, with pale-staining and glycogen-containing cytoplasm. Tumors with mixed embryonal and alveolar features were previously considered to be a subtype of ARMS, but most such cases lack PAX-FOXO1 fusions, thus appearing to be clinically and biologically more akin to ERMS. However, fusion genes have been detected in rare cases of so-called mixed ERMS/ARMS, which therefore represent examples of ARMS.

Rhabdomyoblastic differentiation of ARMS is shown immunohistochemically with positive reactions to desmin, myogenin, and MYOD1. The nuclear expression of myogenin is strong and diffuse, unlike in ERMS and other rhabdomyosarcoma subtypes in which the staining pattern is focal. MYOD1 expression may be focal. Occasional expression of keratin or neuroendocrine markers (CD56, synaptophysin, and chromogranin) may also be observed.

Fine-needle biopsies are highly cellular and consist of uniform round cells with scant cytoplasm and variable rhabdomyoblastic differentiation. Wreath-like multinucleated giant cells are a common feature.

Risk stratification predictive of outcome has been addressed with surgicopathological staging and fusion-based classification (the Intergroup Rhabdomyosarcoma Study Group [IRSG] grouping system). The prognosis for patients with fusion-positive ARMS is worse than for those with fusion-negative rhabdomyosarcoma and ERMS, and the prognosis for patients with PAX3-FOXO1 ARMS is inferior to that for patients with PAX7-FOXO1 ARMS. Amplification of MYCN, CDK4, and MIR17HG has also been correlated with poor outcomes.

Approximately 85% of histologically diagnosed ARMSs contain characteristic fusion genes. In fusion-positive ARMSs, PAX3-FOXO1 and PAX7-FOXO1 account for about 70–90% and 10–30% of the fusions, respectively. Rare cases show alternative novel gene fusions (see Pathogenesis, above), which can be detected by various molecular strategies. The absence of one of these gene fusions suggests a diagnosis of ERMS with a primitive phenotype (formerly known as fusion-negative ARMS or mixed ERMS–ARMS).

Essential: uniform primitive round cell morphology with features of arrested myogenesis; an alveolar growth pattern is common but not required; strong, homogeneous nuclear immunoexpression for myogenin; heterogeneous staining for desmin and/or MYOD1; detection of PAX3/7-FOXO1 fusion genes by molecular analysis.