Embryonal Rhabdomyosarcoma

Rhabdomyosarcoma may be staged based on site of origin using the American Joint Committee on Cancer (AJCC) / Union for International Cancer Control (UICC) system for soft tissue sarcomas, with the exception of head and neck tumors, which are excluded from this system. In children, a modified TNM staging system is used (the Intergroup Rhabdomyosarcoma Study Group [IRSG] grouping system). This system is heavily reliant on site of origin, with risk stratification based on favorable site (e.g., bile ducts, orbit, head and neck, or genitourinary [excluding bladder, prostate, and parameningeal]) or unfavorable (other) site. The IRSG grouping system is used for surgicopathological evaluation, including assessment of margins and residual disease.

Sporadic cases of ERMS are aneuploid with whole-chromosome gains including polysomy 8, followed by extra copies of chromosomes 2, 11, 12, 13, and/or 20. Whole-chromosome losses include monosomy 10 and 15. In most ERMSs, a genomic event such as chromosome loss, deletion, or uniparental disomy results in loss of one of the two alleles at many chromosome 11 loci. This loss of heterozygosity involves chromosomal region 11p15.5, which contains imprinted genes that encode a growth factor (IGF2) and growth suppressors (H19 and CDKN1C). Genomic amplification in the form of double minutes or ascertained by comparative genomic hybridization is frequent in ERMS with anaplasia.

Genomic studies of ERMS have identified somatic driver mutations involving the RAS pathway (NRAS, KRAS, HRAS, NF1, FGFR4), involving effectors of PI3K (PTEN, PIK3CA), or in genes that control the cell cycle (FBXW7, CTNNB1). Mutation of a RAS isoform occurs in one-third of ERMSs, and mutation of a RAS pathway member has been found in < 50% of ERMSs. Within this group, HRAS mutations are enriched in the infant population (70% of infants aged < 1 year had HRAS or KRAS mutations), and NRAS mutations are enriched in adolescents. NF1 mutations occur in 10% of cases. Epigenetic modifications may also play a role, and BCOR point mutations or focal homozygous deletions are described in 15% of ERMSs. Mutations in TP53 occur in approximately 10% of ERMSs and may be associated with anaplasia. About 30% of ERMSs harbor more than one driver mutation, whereas one quarter have no driver mutation identified. Expression studies have identified markers that distinguish FOXO1 fusion–negative rhabdomyosarcoma (HMGA2 and EGFR [HER1] overexpression) from FOXO1 fusion–positive rhabdomyosarcoma (AP-2β and P-cadherin overexpression).

ERMS forms poorly circumscribed, fleshy, pale-tan masses that impinge upon neighboring structures. Botryoid tumors have a characteristic polypoid appearance with clusters of small, sessile or pedunculated nodules that abut an epithelial surface.

Analogous to embryonic skeletal muscle, ERMS contains primitive mesenchymal cells in various stages of myogenesis. Stellate cells with sparse, amphophilic cytoplasm represent the most primitive end of this spectrum. Differentiating rhabdomyoblasts acquire more cytoplasmic eosinophilia and elongation, manifested by tadpole or spider cells. Terminal differentiation with cross-striations or myotube formation may be evident. Differentiation often becomes more evident after therapy. Typical ERMSs are composed of variably differentiated rhabdomyoblasts within a loose, myxoid mesenchyme, with alternating areas of dense and loose cellularity. The relative amount of myxoid matrix and spindled cells is highly variable. Occasional poorly differentiated ERMSs consist largely of primitive round cells, simulating ARMS (so-called dense pattern).

Botryoid ERMS contains linear aggregates of tumor cells (the cambium layer) that tightly abut an epithelial surface, along with hypocellular polypoid nodules that may appear deceptively benign. ERMS may also have prominent spindle cell morphology, particularly in paratesticular tumors, although small foci of more-typical ERMS are usually present as well. Very rare tumors display mixed embryonal and alveolar morphologies; however, these cases typically lack the FOXO1 gene rearrangements. Heterologous cartilaginous differentiation is occasionally present.

Anaplastic ERMS is defined by the presence of markedly enlarged, atypical cells with hyperchromatic nuclei, often with bizarre, multipolar mitotic figures. Anaplastic features may be focal or diffuse.
By immunohistochemistry, ERMSs are essentially always positive for desmin, although the extent of immunoreactivity is variable. The skeletal muscle–specific nuclear regulatory proteins myogenin (MYF4) and MYOD1 are also positive in essentially all cases, although the number of positive nuclei may be highly variable. MSA and SMA are frequently positive. Aberrant expression of keratins, S100, and NFP may be seen.

Cytological preparations demonstrate primitive round, spindled and stellate cells with scattered rhabdomyoblasts.

Age and tumor stage are the most important risk factors in ERMS. Patients aged 1–9 years have better outcomes than infants or adolescents. Similarly, children have a better outcome than adults.

Lack of FOXO1 gene fusion distinguishes ERMS from ARMS.

Essential: primitive round and spindle cell morphology with scattered differentiated rhabdomyoblasts; positivity for desmin and heterogeneous nuclear staining for myogenin and/or MYOD1.

Desirable (in selected cases): lack of FOXO1 gene rearrangements to distinguish poorly differentiated ERMS from solid ARMS.