Skeletal Muscle Tumors

2023-01-20 David Papke, MD Affiliation

1.Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Classification

Definition

There are a heterogeneous group of neoplasms that show skeletal muscle ("rhabdomyoblastic") differentiation.^1-5 "Rhabdomyosarcoma" (RMS) refers to malignant rhabdomyoblastic tumors, which account for the majority of tumors in this group, while "rhabdomyoma" refers to benign rhabdomyoblastic tumors. In addition to the rhabdomyoblastic tumor types discussed in this chapter, rhabdomyoblastic differentiation can also be seen in other tumor types including dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, and melanoma.^6,7

Embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) are the two most common RMS subtypes, both of which occur predominantly in children and young adults. ARMS harbors PAX3 or PAX7 gene fusions in most cases, while ERMS does not harbor these fusions.⁸ Additional subtypes include spindle cell/sclerosing RMS (SSRMS),³ pleomorphic rhabdomyosarcoma,⁹ and rare/emerging tumors types including epithelioid RMS,¹⁰ inflammatory rhabdomyoblastic tumor,¹¹ and epithelioid and spindle cell rhabdomyosarcoma.¹²

Skeletal muscle tumours	Genetic event(s)
Rhadomyoma	Extracardiac rhabdomyomas are a heterogeneous group of tumor types, including adult, fetal, and genital rhabdomyomas. Activating alterations in the hedgehog signalling pathway, including PTCH1 and SUFO mutations, have been identified in fetal- and adult-type rhabodmyomas in both the sporadic and syndromic settings.^13,14 Genital rhabdomyomas instead harbor recurrent H3C2 K37I mutations.¹⁵
	Genetic predisposition syndromes associated rhabdomyomas include basal cell nevus syndrome OMIM:109400 and Birt-Hogg-Dubé syndrome OMIM:135150
Embryonal rhabdomyosarcoma (RMS)	Sporadic ERMS characteristically shows aneuploidy,¹⁶ most commonly including polysomy in chromosome 8.¹⁷ Other recurrent alterations include gains in chromosomes 2, 7, 11, 12, 13, 17, 18, 19, and 20.^17-19 Monosomy 9, 10, 14, 15, and 16 are also recurrent, as is loss of 1p.^18-20 There are no specific or recurrent gene fusions in ERMS.¹⁹
	ERMS shows consistent loss of heterozygosity at 11p15.5, including IGF2, H19 and CDKN1C.²¹
	ERMS harbors recurrent mutations in NF1, BCOR and, in the anaplastic variant, TP53.^16,19 RAS pathway alterations are also common.
	ERMS is associated with genetic predisposition syndromes, including Costello syndrome OMIM:218040, Neurofibromatosis type 1 OMIM:162200, Noonan syndrome OMIM:163950 germline genetic variants activating RAS–MAPK pathways,²² Beckwith-Wiedemann syndrome OMIM:130650, DICER1 syndrome OMIM:606241, and Li-Fraumeni syndrome.OMIM:151623
Alveolar rhabdomyosarcoma (ARMS)	ARMS harbors recurrent FOXO1 fusions, including 70-90% with t(2;13)(q35;q14) associated with PAX3::FOXO1 and 10-30% with t(1;13)(p36;q14) associated with PAX7::FOXO1.^20,23 The PAX7::FOXO1 fusion gene is frequnetly amplified.^24,25 There has been research in developing therapy to target FOXO1.²⁶
	ARMS with PAX3::FOXO1 fusion has a worse prognosis than ARMS with PAX7::FOXO1 fusion.²⁷ Age ≥10 years and tumor size > 5 cm are also independent adverse prognostic factors for event-free-survival among tumor with FOXO1 fusion.²⁸ Variant PAX3 fusions have been reported, with partners including FOXO4, NCOA1, NCOA2, and INO8OD.^17,19,29,30 FOXO1:: FGFR1 has also been reported.³¹ Fusion-negative ARMS have outcomes similar to those of ERMS.¹⁷
	ARMS with PAX3 or PAX7 fusions usually show a low mutational burden, and they commonly show whole genome duplication and focal amplification of MYCN or CDK4.¹⁹ FOXO1-fusion negative cases harbor alterations similar to those in ERMS, including RAS pathway alterations and mutations in BCOR, NF1, and TP53.
Pleomorphic rhabdomyosarcoma (RMS)	Pleomorphic RMS is a disease that occurs almost exclusively in adults. It shows complex karyotypes with copy number alterations and unbalanced structural alterations; like most other pleomorphic sarcomas, pleomorphic RMS does not harbor recurrent fusions.³²
	Pleomorphic RMS can occur in the setting of Li-Fraumeni syndrome.
Spindle cell/sclerosing rhabdomyosarcoma (RMS)	Three molecular subgroups have been identified so far - congenital spindle cell RMS, MYOD1-mutant spindle cell/sclerosing RMS, and intraosseous spindle cell RMS. The prognoses of these subtypes are divergent as detailed below.
	Congenital/infantile lesions most commonly occur in paratesticular soft tissue and the head and neck, and they harbor recurrent rearrangements involving VGLL2, NCOA2, and CITED2.^33,34 These tumors are indolent with long-term follow up.^33,34
	MYOD1-mutant spindle cell/sclerosing RMS occurs across a wide age range, with a peak incidence in adolescdents and young adults, and it is characterized by MYOD1 p.L122R and an aggressive clinical course.^35-37
	Intraosseous spindle cell RMS, also described as "epithelioid and spindle cell rhabdomyosarcoma", has a predilection for the craniofascial skeleton and occurs across a wide age range.¹² Uncommonly, this tumor type arises in soft tissue.³⁸ This RMS variant harbors recurrent FUS::TFCP2, EWSR1::TFCP2, and MEIS1::NCOA2 fusions,^12,39,40 and it is associated with a dismal prognosis. ALK expression is common, in the absence of underlying ALK rearrangements.³⁸
	Other gene fusion have been described in rare cases, including EP300::VGLL3 and EWSR1::UBP1.^41,42
Ectomesenchymoma	Ectomesenchymoma is a very rare tumor type showing regions resembling ERMS as well as regions with neuronal or neuroblastic differentiation. Cytogenetic findings are similar to thse of embryonal rhabdomyosarcoma, with polysomy of chromosomes 2, 8, and 11.⁴³
	Recurrent HRAS mutations have been identified, again similar to alterations of embryonal rhabdomyosarcoma.⁴⁴

Article Bibliography

Reference Number	Pubmed ID	Last Year	Title	Authors
1	31696361	2020	The current landscape of rhabdomyosarcomas: an update.	Leiner J et al
2	31950473	2020	Soft Tissue Special Issue: Skeletal Muscle Tumors: A Clinicopathological Review.	Kohashi K et al
3	33183730	2020	Challenges in the Diagnosis of Pediatric Spindle Cell/Sclerosing Rhabdomyosarcoma.	Chen S et al
4	34166060	2021	Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.	Shern JF et al
5	34958505	2022	Evolving classification of rhabdomyosarcoma.	Agaram NP et al
6	25581729	2015	Myogenic differentiation and histologic grading are major prognostic determinants in retroperitoneal liposarcoma.	Gronchi A et al
7	33428337	2021	Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases With Literature Review and Proposal of Diagnostic Criteria.	Agaimy A et al
8	34107813	2021	Rhabdomyosarcoma: How Advanced Molecular Methods Are Shaping the Diagnostic and Therapeutic Paradigm.	Giannikopoulos P et al
9	8333559	1993	Pleomorphic rhabdomyosarcoma in adulthood. Analysis of 11 cases with definition of diagnostic criteria.	Gaffney EF et al
10	21921782	2011	Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16 cases of a morphologically distinct variant of rhabdomyosarcoma.	Jo VY et al
11	33318583	2021	"Inflammatory Leiomyosarcoma" and "Histiocyte-rich Rhabdomyoblastic Tumor": a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as "Inflammatory Rhabdomyoblastic Tumor".	Cloutier JM et al
12	31383960	2020	A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation.	Le Loarer F et al
13	16294371	2006	Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development.	Tostar U et al
14	23780909	2013	Mutations in Hedgehog pathway genes in fetal rhabdomyomas.	Hettmer S et al
15	35842480	2022	Molecular assessment of paratesticular rhabdomyomas demonstrates recurrent findings, including a novel H3C2 p.K37I mutation.	Acosta AM et al
16	30617281	2019	Rhabdomyosarcoma.	Skapek SX et al
17	20351326	2010	Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.	Williamson D et al
18	8764111	1996	Gains, losses, and amplification of genomic material in rhabdomyosarcoma analyzed by comparative genomic hybridization.	Weber-Hall S et al
19	24436047	2014	Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.	Shern JF et al
20	24113309	2013	Classification of rhabdomyosarcoma and its molecular basis.	Parham DM et al
21	26349418	2015	Pediatric Rhabdomyosarcoma.	Shern JF et al
22	31130285	2019	Germline-Activating RRAS2 Mutations Cause Noonan Syndrome.	Niihori T et al
23	28035744	2017	Impact of fusion gene status versus histology on risk-stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials.	Selfe J et al
24	8789435	1996	In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma.	Barr FG et al
25	22447499	2012	Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group.	Duan F et al
26	30373318	2018	Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma.	Nguyen TH et al
27	23526739	2013	PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report.	Skapek SX et al
28	33216382	2021	Survival outcomes of patients with localized FOXO1 fusion-positive rhabdomyosarcoma treated on recent clinical trials: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.	Heske CM et al
29	12183429	2002	Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions.	Barr FG et al
30	19953635	2010	Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family.	Sumegi J et al
31	21666686	2011	FOXO1-FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma.	Liu J et al
32	12550764	2003	Chromosomal imbalances in pleomorphic rhabdomyosarcomas and identification of the alveolar rhabdomyosarcoma-associated PAX3-FOXO1A fusion gene in one case.	Gordon A et al
33	23463663	2013	Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma.	Mosquera JM et al
34	26501226	2016	A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases.	Alaggio R et al
35	27562493	2016	MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes.	Rekhi B et al
36	30181563	2019	MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification.	Agaram NP et al
37	33913590	2021	MYOD1 as a prognostic indicator in rhabdomyosarcoma.	Ahmed AA et al
38	33382123	2021	Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression: a clinicopathological and molecular analysis of 11 cases.	Xu B et al
39	30720533	2019	Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype.	Agaram NP et al
40	32556562	2020	Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases.	Chrisinger JSA et al
41	34184341	2021	Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens.	Montoya-Cerrillo DM et al
42	34877752	2022	Novel EWSR1::UBP1 fusion expands the spectrum of spindle cell rhabdomyosarcomas.	El Zein S et al
43	21803398	2012	Ectomesenchymoma with t(1;12)(p32;p13) evolving from embryonal rhabdomyosarcoma shows no rearrangement of ETV6.	Howley S et al
44	26872011	2016	Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma.	Huang SC et al

External Links

Citation

David Papke, MD

Skeletal Muscle Tumors

Atlas Genet Cytogenet Oncol Haematol. 2023-01-20

Online version: http://atlasgeneticsoncology.org/solid-tumor/209005/skeletal-muscle-tumors

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