Alveolar rhabdomyosarcoma is a definitionally high-grade, aggressive tumor type that shows skeletal muscle differentiation, round cell cytomorphology, and, often, nested architecture. 

Alveolar rhabdomyosarcoma occurs across a wide age range, with a peak incidence in late adolescence and with some examples occurring in children and older adults.¹ There is no sex predominance.² 

Alveolar rhabdomyosarcoma occurs most commonly in the head and neck, extremities, and pelvis.^1,3 It usually presents as an enlarging, painless mass, although some cases present due to mass effect on adjacent structures.⁴ There are rare but well-documented cases of a so-called leukemic presentation, in which patients present with diffuse bone marrow involvement and, sometimes, rhabdomyoblasts in peripheral blood smears.^5,6

Alveolar rhabdomyoma is a round cell neoplasm with scant cytoplasm and primitive, somewhat irregular nuclei, and it most commonly shows nested growth. In a subset of cases, tumor nests are centrally discohesive, imparting the alveolar appearance for which this tumor type is named. The cells exhibit larger, more irregular nuclei than other round cell neoplasms, a useful diagnostic clue. Some cases show diffuse, sheet-like growth, which render them harder to recognize.

Neoplastic cells express desmin, and, consistent with their immature differentiation state, they often express myogenin more diffusely than myoD1.^7,8 Recent work has demonstrated that immunohistochemistry for FOXO1 is diffusely expressed in alveolar rhabdomyosarcomas harboring FOXO1 fusions; this marker is sensitive and specific among other differential diagnostic considerations.⁹ Tumors in the head and neck region frequently express keratins and neuroendocrine markers, presenting a pitfall for the misdiagnosis of poorly differentiated neuroendocrine carcinoma.¹⁰

Alveolar rhabdomyosarcoma is an aggressive malignancy, with a 5-year overall survival of about 30%.¹ About 20-25% of patients present with metastatic disease.¹¹ Fusion-negative alveolar rhabdomyosarcoma shows better outcomes than fusion-positive alveolar rhabdomyosarcoma.^12,13

• PAX3::FOXO1 fusions, corresponding to t(2;13)(q36;q14, are present in about 70% of alveolar rhabdomyosarcoma (Fig.1).^14-17 The resulting gene fusion generates a chimeric protein that functions as an oncogenic transcription factor, with downstream target genes including ALK,¹⁸ FGFR4,¹⁸ MET,¹⁹ MYCN,²⁰ MYF5,¹⁸ and MYOD1.¹⁸

Figure 1. Alveolar rhabdomyosarcoma with t(2;13)(q36;q14), associated with FOXO1 rearrangement

• PAX7::FOXO1 fusions, corresponding to t(1;13)(p36;q14), are present in about 15% of {alveolar rhabdomyosarcoma) and are associated with a relatively better prognosis than PAX3::FOXO1 fusions.^17,21,22 Amplification of 1p36, including the PAX7 locus, is associated with this fusion and is likely important in driving expression of the chimeric transcript.^23,24 The fusion gene, including the 3' aspect of FOXO1, is co-amplified in these cases (Fig. 2).

Figure 2. Amplification of the 3' FOXO1 is common in PAX7::FOXO1-rearranged alveolar rhabdomyosarcoma, associated with t(1;13)(p36;q14).

• Amplification of 13q31, including the MIR17HG micro-RNA cluster, is also associated with PAX7::FOXO1 fusion.^25,26

• Rare fusions in alveolar rhabdomyosarcoma include PAX3::FOXO4,²⁷ PAX3::NCOA1 corresponding to t(2;2)(q35;p23),^28,29 PAX3::INO80D,³⁰ and FOXO1::FGFR1.³¹ A reported case of FOXO1::FGFR1 fusion demonstrated a three-way, t(8;13;9)(p11.2;q14;9q32) translocation.³¹

• About 15% of alveolar rhabdomyosarcoma are not associated with fusions and overlap with embryonal rhabdomyosarcoma in gene expression profiling studies.^17,27,32 Fusion-negative alveolar rhabdomyosarcoma has a relatively better prognosis, comparable to that of embryonal rhabdomyosarcoma, and there is a movement to reclassify such examples as embryonal rhabdomyosarcoma with a primitive phenotype.^12,22

• Amplification of chromosome 12q13, including MDM2, CDK4, and GLI1, occurs as a secondary genetic event in approximately 30% of alveolar rhabdomyosarcoma, including tumors driven by FOXO1 fusions.²⁵ This amplification is associated with worse overall survival, independent of fusion status.³³

• Amplification of 2p24, including MYCN, is identified in approximately 30% of alveolar rhabdomyosarcoma and is associated with with PAX3::FOXO1 fusion.^25,33,34 MYCN amplification is associated with poor outcome.³⁴

• Other, uncommon secondary alterations include mutations in CDKN2A/CDKN2B (10-15%),^35,36 TP53 (~5%),³⁷ and FGFR4 (rare,