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Soft Tissue Special Issue: Skeletal Muscle Tumors: A Clinicopathological Review.

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  • 1. Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
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    • Kohashi K 1
    • Kinoshita I 1
    • Oda Y 1
    (3 authors)

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Head and Neck Pathology, 16 Jan 2020, 14(1):12-20
https://doi.org/10.1007/s12105-019-01113-2 PMID: 31950473 PMCID: PMC7021913

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Abstract 

Skeletal muscle tumors are classified into rhabdomyoma and embryonal, alveolar, spindle cell/sclerosing and pleomorphic rhabdomyosarcoma according to WHO classifications of tumors. These tumors arise mostly in the head and neck and, in childhood, represent the largest subset of soft tissue tumors. Although these skeletal muscle tumors show common immunoexpression of two myogenic regulatory factors, MyoD1 and myogenin, their molecular biological backgrounds are quite different. Therefore, treatment regimens vary a great deal depending on the histological subtype. Histopathologically, rhabdomyoma is characterized by well-demarcated lesions with no invasion of the surrounding tissue. Embryonal rhabdomyosarcoma is composed of primitive mesenchymal cells in various stages of myogenesis and shows heterogeneous nuclear staining for myogenin. Alveolar rhabdomyosarcoma, on the other hand, shows a proliferation of uniform primitive round cells arranged in alveolar patterns. The tumor cells at the periphery of alveolar structures adhere in a single layer to the fibrous septa. Diffuse and strong nuclear immunoexpression for myogenin is observed. In genetic backgrounds, almost all alveolar rhabdomyosarcomas contain a characteristic fusion gene such as PAX3/7-FOXO1. Spindle cell/sclerosing rhabdomyosarcoma is characterized by fascicularly arranged spindle-shaped cells or dense hyalinized collagenous matrix. NCOR2- or VGLL2-related gene fusions or MYOD1 (p.L122R) mutation is commonly recognized. Epithelioid rhabdomyosarcoma is a rare variant of rhabdomyosarcoma that shows a proliferation of epithelioid tumor cells having large vesicular nuclei, prominent nucleoli, and amphophilic to eosinophilic cytoplasm arranged in sheets. As these characteristic histological and molecular features are present in each subtype, it is possible to diagnose skeletal muscle tumors accurately.

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Head Neck Pathol. 2020 Mar; 14(1): 12–20.
Published online 2020 Jan 16. https://doi.org/10.1007/s12105-019-01113-2
PMCID: PMC7021913
PMID: 31950473

Soft Tissue Special Issue: Skeletal Muscle Tumors: A Clinicopathological Review

Kenichi Kohashi, Izumi Kinoshita, and Yoshinao Odacorresponding author
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Abstract

Skeletal muscle tumors are classified into rhabdomyoma and embryonal, alveolar, spindle cell/sclerosing and pleomorphic rhabdomyosarcoma according to WHO classifications of tumors. These tumors arise mostly in the head and neck and, in childhood, represent the largest subset of soft tissue tumors. Although these skeletal muscle tumors show common immunoexpression of two myogenic regulatory factors, MyoD1 and myogenin, their molecular biological backgrounds are quite different. Therefore, treatment regimens vary a great deal depending on the histological subtype. Histopathologically, rhabdomyoma is characterized by well-demarcated lesions with no invasion of the surrounding tissue. Embryonal rhabdomyosarcoma is composed of primitive mesenchymal cells in various stages of myogenesis and shows heterogeneous nuclear staining for myogenin. Alveolar rhabdomyosarcoma, on the other hand, shows a proliferation of uniform primitive round cells arranged in alveolar patterns. The tumor cells at the periphery of alveolar structures adhere in a single layer to the fibrous septa. Diffuse and strong nuclear immunoexpression for myogenin is observed. In genetic backgrounds, almost all alveolar rhabdomyosarcomas contain a characteristic fusion gene such as PAX3/7-FOXO1. Spindle cell/sclerosing rhabdomyosarcoma is characterized by fascicularly arranged spindle-shaped cells or dense hyalinized collagenous matrix. NCOR2- or VGLL2-related gene fusions or MYOD1 (p.L122R) mutation is commonly recognized. Epithelioid rhabdomyosarcoma is a rare variant of rhabdomyosarcoma that shows a proliferation of epithelioid tumor cells having large vesicular nuclei, prominent nucleoli, and amphophilic to eosinophilic cytoplasm arranged in sheets. As these characteristic histological and molecular features are present in each subtype, it is possible to diagnose skeletal muscle tumors accurately.

Keywords: Rhabdomyoma, Embryonal rhabdomyosarcoma, Alveolar rhabdomyosarcoma, Spindle cell/sclerosing rhabdomyosarcoma, Head and neck

Introduction

Six types of tumors showing skeletal muscle differentiation (rhabdomyoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and ectomesenchymoma) have been described in the latest WHO classifications of tumors, soft tissue and bone. Although these tumors are very rare, they represent the largest subset of soft tissue tumors in childhood [1, 2]. They differ widely in treatment strategy, because their molecular biological backgrounds differ from each other [2]. Therefore, we need to make an accurate pathological diagnosis and prove a tumor’s molecular biological background. In this review article, we introduce the histopathological and molecular features of skeletal muscle tumors such as rhabdomyoma; embryonal, alveolar, spindle-cell/sclerosing rhabdomyosarcoma; and epithelioid rhabdomyosarcoma, and discuss the differential diagnosis specific for tumors that arise in the head and neck.

Rhabdomyoma

Clinical Features

Rhabdomyomas are classified into three groups: adult, fetal, and genital rhabdomyoma. Both adult and fetal rhabdomyoma cases arise mostly in the head and neck, such as in the parapharyngeal space, salivary glands, larynx, mouth, and soft tissue of the neck [3–5]. Uncommon locations in adult or fetal rhabdomyoma include the mediastinum or the chest, abdomen, and extremities, respectively [5]. By definition, genital rhabdomyoma arises from the female or male genital tract [5].

Adult and fetal rhabdomyomas usually present as slowly growing, but some grow rapidly. These growing masses may cause hoarseness, airway obstruction, dysphagia, and decreased vision. The mean age of patients with adult rhabdomyomas is 60 years; the male-to-female ratio is 3:1 [6]. The median age of patients with fetal rhabdomyomas is 2.1 years at the time of diagnosis, and the male-to-female ratio is 5:3 [7]. About 25% of cases are congenital [4]. Meanwhile, clinical symptoms of genital rhabdomyomas include symptomless masses, menorrhagia, postmenopausal uterine bleeding, and scrotal swelling. Genital rhabdomyomas have been described in young to middle-aged adults [8].

Histopathology

Adult rhabdomyomas show a proliferation of large polygonal tumor cells having small round vesicular nuclei, abundant deeply acidophilic and fine granular cytoplasm, and prominent nucleoli with well-defined cellular borders. The cytoplasm may be vacuolated (“spider cells”), or contain rod-like or “jack-straw”-like crystalline structures or cross striations (Fig. 1).

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Adult rhabdomyoma (69-year-old man; hypopharynx). Tumor cells exhibit small rounded nuclei and eosinophilic cytoplasm occasionally with intracytoplasmic vacuoles

Fetal rhabdomyomas of the classic type (myxoid type) are composed of primitive oval or spindle-shaped immature skeletal muscle fibers with abundant myxoid backgrounds. Those of the intermediate (juvenile) type show numerous differentiated skeletal muscle fibers and a less myxoid matrix. Those of the cellular type are characterized by more uniform populations of differentiating myoblasts.

Mitotic figures in the adult type are rare and those in the fetal type are frequent, but nuclear atypia, infiltrative margins, atypical mitoses, and tumor necrosis are not evident.

Genital rhabdomyomas in females are composed of scattered and immature or mature skeletal muscle fibers with loose fibro-collagenous tissue. Therefore, some degree of cytological atypia may be present, but mitotic figures are rarely observed. Those in males show histological features of both the adult and fetal types.

Differential Diagnosis

Granular cell tumor having granular cytoplasm and hibernoma having multivacuolated brown fat cells is histologically similar to adult rhabdomyoma. Immunohistochemically, these tumor cells are positive for S-100 protein, but skeletal muscle differentiation is not observed.

Embryonal Rhabdomyosarcoma

Clinical Features

Embryonal rhabdomyosarcomas mostly affect children under 5 years of age, with a smaller peak in adolescence [1]. The male-to-female ratio is 1.5:1 [1]. Embryonal rhabdomyosarcomas commonly arise in the head and neck and in the genitourinary systems [9, 10]. Uncommon locations include the biliary tract, retroperitoneum, and soft tissue of the extremities. They produce a variety of clinical symptoms related to mass effects and obstruction, such as proptosis, diplopia, sinusitis, unilateral deafness, urinary retention, and jaundice.

Histopathology

Embryonal rhabdomyosarcomas contain primitive mesenchymal cells in various stages of embryogenesis of skeletal muscles. These primitive mesenchymal cells, having hyperchromatic round to spindle-shaped nuclei and scant to abundant eosinophilic cytoplasm, proliferate in patternless sheets with myxoid and collagenous stroma (Fig. 2). Varying numbers of rhabdomyoblasts with abundant eosinophilic cytoplasm and deeply fibrillar materials are seen around the nucleus. The botryoid type of embryonal rhabdomyosarcoma is characterized by a “cambium layer”, a submucosal zone of markedly increased cellularity. Heterologous cartilaginous differentiation is occasionally recognized. In some tumors, anaplasia defined using the Wilms tumor definition of large, lobate, hyperchromatic nuclei (at least three times the size of neighboring nuclei) may be focally or diffusely observed.

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Embryonal rhabdomyosarcoma (4-year-old boy; paratestis). Tumor is composed of various myogenic differentiated cells with myxoid stroma

Immunohistochemically, these tumor cells are varyingly positive for desmin, myogenin, and myoD1 (Table ​(Table1)1) [11]. Aberrant expression of cytokeratin, S-100 protein, and neurofilament may also be observed.

Table 1

Histological points in rhabdomyosarcomas

Embryonal rhabdomyosarcoma
 Primitive mesenchymal tumor cells in various stages of embryogenesis of skeletal muscles
 Varyingly positive for myogenin
Alveolar rhabdomyosarcoma
 Uniformed small rounded tumor cells
 Tumor cells adhered in a single layer to the alveolar fibrous septa
 Diffusely and strongly positive for myogenin
Spindle cell/sclerosing rhabdomyosarcoma
 Spindle-shaped tumor cells arranged in intralacing fascicles
 Prominent hyalinization or sclerosis with tumor cells arranged in trabecular or microalveolar patterns

Genetics

Embryonal rhabdomyosarcoma is characterized by a consistent loss of heterozygosity at 11p15.5, and gains of chromosomes 2, 8, 12, 13, and/or 20 [12–14]. Mutations of the FGFR4/RAS/AKT pathway including FUFR4, PTPN11, GAB1, PIK3CA, PTEN, KRAS, NRAS, and NF1 (16/35, 46%) are detected, as are those of TP53 (6/35, 17%), BCOR (4/35, 11%) and ARID1A (4/35, 11%) [14]. An extremely high frequency of PTEN hypermethylation is also observed (Table ​(Table2)2) [15].

Table 2

Genetic backgrounds in rhabdomyosarcomas

Embryonal rhabdomyosarcoma
 Mutations of FGFR4/RAS/AKT pathway
 PTEN hypermethylation
Alveolar rhabdomyosarcoma
 PAX3/7-FOXO1 fusion gene
Spindle cell/sclerosing rhabdomyosarcoma
 NCOR2 or VGLL2-related fusion gene
 MYOD1 (p.L122R) mutation

Differential Diagnosis

Fetal rhabdomyomas are generally well-circumscribed, but infiltrative growth is not observed. Neither atypical mitoses nor tumor necrosis are also evident. In some cases, there is mild cellular pleomorphism, but marked cellular atypia is not a feature of this tumor, as it is with embryonal rhabdomyosarcoma.

Ectomesenchymomas consist of embryonal rhabdomyosarcoma with variable neuronal/neuroblastic components. Histologically, the latter covers the entire spectrum of neuroblastic tumors such as neuroblastoma, ganglioneuroblastoma and ganglioneuroma. Neuroblasts are immunopositive for TH, PHOX2B and HuC/D, and schwann-like cells and ganglion cells are respectively immunopositive for S-100 protein and HuC/D [16, 17].

Malignant rhabdoid tumors, which were originally described as a rhabdomyosarcomatoid variant of Wilms’ tumors, show a proliferation of rounded to polygonal tumor cells having large, vesicular rounded to bean-shaped nuclei and scant to abundant eosinophilic cytoplasm [18, 19]. A point of differential diagnosis is the complete loss of SMARCB1/INI1 immunoexpression [19–26]. Although tumor cells are occasionally positive for smooth muscle actin, skeletal muscle differentiation is extremely rare (Table ​(Table3)3) [25].

Table 3

Differential diagnosis in rhabdomyosarcomas

DiagnosisHistologyImmunohistochemistryGenetics
Malignant rhabdoid tumorIntracytoplasmic inclusion, round to oval cells with prominent nucleoliSMARCB1(−), Cytokeratin(+ , focal)Homozygous inactivation of SMARCB1
Synovial sarcomaUniformed spindle-shaped dark blue cell, epithelioid cells arranged in tubulesSMARCB1(+ , reduced), EMA( +)SS18-SSX1/2
Ewing sarcomaUniformed small round cells with finely stippled chromatinNKX2.2( +)EWSR1-ETS
CIC sarcomaUniformed round cells with prominent nucleoli, mildly nuclear pleomorphismWT1( +), ETV4( +), NKX2.2(−)CIC gene rearrangement
Sarcomas with BCOR genetic alterationsArborized vasculature, myxoid stromaBCOR( +), STAB2( +)BCOR gene rearrangement, BCOR-ITDa
EctomesenchymomaEmbryonal rhabdomyosarcoma with neuroblastic tumorTH( +), PHOX2B( +), HuC/D( +)–
Neuroendocrine carcinomaSmall round cells having hyperchromatic nuclei and scant cytoplasmCytokeratin( +), synaptophysin/chromgranin A( +)–
Olfactory neuroblastomaUniformed small rounded to ovoid cells, Homer Wright rosettesSynaptophysin/chromogranin A( +)–
Malignant Triton tumorSpindle-shaped tumor cells with nuclear pleomorphismH3K27me3(−), S-100(+ , patchy), Myogenin( +)SUZ12 or EED12 mutation, NF1 mutation

aBCOR-ITD, BCOR-internal tandem duplication

Alveolar Rhabdomyosarcoma

Clinical Features

Alveolar rhabdomyosarcomas often occur in adolescents and young adults, with a peak incidence at 10–25 years of age, and the male-to-female ratio is approximately even [1]. They mostly arise in deep soft tissue of the extremities, head and neck, and paraspinal and perineal regions [27–29]. They produce a variety of clinical symptoms related to mass effects.

Histopathology

Alveolar rhabdomyosarcomas often show a proliferation of small round tumor cells having hyperchromatic nuclei and scant to a few eosinophilic cytoplasm with alveolar patterns. Fibrovascular septa are characteristically lined by a single layer of tumor cells (Fig. 3a). Rhabdomyoblasts and multinucleated giant cells having multiple and peripherally placed nuclei and weakly eosinophilic cytoplasm are also seen (Fig. 3b). The solid variant is composed of sheet arrangements of discohesive tumor cells without fibrovascular septa (Fig. 3c).

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Alveolar rhabdomyosarcoma. a Tumor cells at the periphery of alveolar structures adhere in a single layer to the fibrous septa (6-year-old girl; groin). b Tumor cells at the periphery of alveolar structures adhere in a single layer to the fibrous septa. Multinucleated giant cells show eosinophilic cytoplasm without cross-striations (15-year-old girl; maxillary sinus). c Solid variant of alveolar rhabdomyosarcoma shows sheet arrangement of tumor cells without alveolar patterns (1-month-old girl; orbital fossa)

Immunohistochemically, these tumor cells show skeletal muscle differentiation, and the nuclear expression of myogenin is usually strong and diffuse, in contrast to other rhabdomyosarcoma subtypes (Table ​(Table1)1) [11]. Immunoexpressions of cytokeratin, neuroendocrine markers and INSM1 are occasionally seen [30].

Genetics

Approximately 85% of alveolar rhabdomyosarcomas are associated with fusion genes. PAX3-FOXO1 and PAX7-FOXO1 respectively account for about 70–90% and 10–30% of fusion-positive alveolar rhabdomyosarcomas [31, 32]. In a few alveolar rhabdomyosarcomas, variant rearrangements generate fusions such as PAX3 fused to FOXO4, NCOA1, or NCOR2 or FOXO1 fused to FGFR (Table ​(Table2)2) [33–36]. The gene fusion subtype seems to affect the prognosis, with fusion types PAX3-FOXO1 having worse prognoses than PAX7-FOXO1 fusions [31, 32, 37]. Fusion-negative alveolar rhabdomyosarcomas have outcomes similar to those of embryonal rhabdomyosarcomas [32, 33].

Differential Diagnosis

Various small round cell tumors such as poorly differentiated synovial sarcoma, Ewing sarcoma, round cell sarcoma with EWSR1-non ETS fusions, CIC sarcoma, and sarcomas with BCOR genetic alterations are included in differential diagnosis. However, these round cell sarcomas show no immunoexpression for myogenin [38–41]. Although neuroendocrine carcinomas and olfactory neuroblastomas are positive for neuroendocrine makers, skeletal muscle differentiation is not observed (Table ​(Table33).

Spindle Cell/Sclerosing Rhabdomyosarcoma

Clinical Features

Spindle cell/sclerosing rhabdomyosarcomas are a rare subtype of rhabdomyosarcoma and account for 3–10% of rhabdomyosarcomas [42–44]. They affect various ages, from childhood to adulthood. Although in adults they arise mostly in the head and neck, in children the paratesticular region is the most common site of involvement, followed by the head and neck [42–44].

Histopathology

Spindle cell rhabdomyosarcomas show a cellular proliferation of spindle-shaped tumor cells having hyperchromatic nuclei and pale eosinophilic cytoplasm arranged in intersecting or herringbone patterns (Fig. 4a). Meanwhile, sclerosing rhabdomyosarcomas are characterized by prominent hyalinization or sclerosis with tumor cells arranged in cord, nested, trabecular, or microalveolar patterns (Fig. 5, Table ​Table11).

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Spindle cell rhabdomyosarcoma (31-year-old woman; pharynx). a Spindle-shaped tumor cells are arranged in interlacing fascicles. b A few myogenin-positive immunoreactive cells. c Tumor cells are diffusely positive for MyoD1

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Sclerosing rhabdomyosarcoma (30-year-old man; elbow). Abundant hyalinized stroma with micro-alveolar patterns are observed

Immunohistochemically, their tumor cells are positive for desmin, myogenin, and myoD1. Some cases show only very limited immunopositivity for desmin and myogenin but are often strongly positive for MyoD1 (Fig. 4b, c).

Genetics

Spindle cell/sclerosing rhabdomyosarcomas are classified into three groups based on genetic background: an NCOR2- or VGLL2-related gene fusions subset commonly associated with infantile spindle cell rhabdomyosarcoma, an MYOD1 (p.L122R)-mutant subset, and a subset lacking recurrent genetic abnormalities [45, 46]. The MYOD1-mutant subset occasionally shows a PIK3CA mutation (Table ​(Table2)2) [46–48]. It has also been reported that rare intraosseous spindle cell rhabdomyosarcomas harbor a gene fusion of EWSR1/FUS-TFCP2 and MEIS1-NCOA2 [49, 50].

Differential Diagnosis

Malignant Triton tumors (malignant peripheral nerve sheath tumor with skeletal-muscle differentiation) show both neural and skeletal muscle differentiation. More than half of cases occur in conjunction with neurofibromatosis type 1. They show variable proportions of immunoreactive cells for desmin and myogenin. A point of differential diagnosis is the complete loss of H3K27me3 immunoexpression in malignant Triton tumor cells (Table ​(Table3)3) [51–55].

Epithelioid Rhabdomyosarcoma

Epithelioid rhabdomyosarcomas, not listed in the WHO classification, were reported by Jo et al. as a rare definitive rhabdomyosarcoma variant [56]. The median patient age is 65 years (range, 6–78 years); the male-to-female ratio is 2:1 [56, 57]. Common locations include deep soft tissue of the extremities, head and neck, and trunk. Histologically, they show a proliferation of epithelioid tumor cells having abundant amphophilic-to-eosinophilic cytoplasm, large vesicular nuclei with irregular nuclear contours, and large prominent nucleoli arranged in sheet-like patterns. A few cases focally show rhabdoid intracytoplasmic inclusions. Mitotic counts range from 4 to 85 (median count of 23) per 10 high-power fields [56]. Immunohistochemically, the tumor cells are diffusely and strongly positive for desmin and diffusely to multifocally positive for myogenin. Epithelial markers such as cytokeratin and epithelial membrane antigen are negative in most cases. None of eight cases show evidence of FOXO1 gene rearrangement by FISH or RT-PCR [56, 57]. In differential diagnosis, epithelioid rhabdomyosarcomas often morphologically resemble various carcinomas and malignant melanoma. However, skeletal muscle differentiation is not observed in these tumors.

Pleomorphic Rhabdomyosarcoma

Pleomorphic rhabdomyosarcomas often occur in adults, with a peak incidence at 60–70 years of age (mean age of about 72 years) [58]. These tumors arise most often in the lower extremity, but also head and neck. Histologically, large, atypical and frequently multinucleated polygonal eosinophilic tumor cells are arranged in sheet or haphazard patterns. Immunohistochemically, tumor cells are strongly positive for desmin, and often focally positive for MyoD1 and myogenin. Dedifferentiated liposarcoma with skeletal muscle differentiation is included in differential diagnosis, and a point of that is MDM2 gene amplification in dedifferentiated liposarcoma.

Disclosure

The authors declare that there are no conflicts of interest to disclose.

Acknowledgements

The English used in this manuscript was revised by KN International (https://www.kninter.com/).

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References

1. Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer. 2009;115:4218–4226. [Europe PMC free article] [Abstract] [Google Scholar]
2. Hosoi I. Current status of treatment for pediatric rhabdomyosarcoma in the USA and Japan. Pediatr Int. 2016;58:81–87. [Abstract] [Google Scholar]
3. Allevi F, Rabbiosi D, Colletti G, Felisati G, Rezzonico A, Ronchi P, Biglioli F. Extensive rhabdomyoma of the head and neck region: a case report and a literature review. Minerva Stomatol. 2013;62:387–395. [Abstract] [Google Scholar]
4. Kapadia SB, Meis JM, Frisman DM, Ellis GL, Heffner DK. Fetal rhabdomyoma of the head and neck: a clinicopathologic and immunophenotypic study of 24 cases. Hum Pathol. 1993;24:754–765. [Abstract] [Google Scholar]
5. Goldblum JR, Folpe AL, Weiss SW. Rhabdomyoma. In: Goldblum JR, editor. Soft tissue tumors. 6. Amsterdam: Elservier; 2014. [Google Scholar]
6. de Trey LA, Schmid S, Huber GF. Multifocal adult rhabdomyoma of the head and neck manifestation in 7 locations and review of the literature. Case Rep Otolaryngol. 2013;2013:758416. [Europe PMC free article] [Abstract] [Google Scholar]
7. Lapner PC, Chou S, Jimenez C. Perianal fetal rhabdomyoma: case report. Pediatr Surg Int. 1997;12:544–547. [Abstract] [Google Scholar]
8. Davies B, Noh P, Smaldone MC, Ranganathan S, Docimo SG. Paratesticular rhabdomyoma in a young adult: case study and review of the literature. J Pediatr Surg. 2007;42:E5–7. [Abstract] [Google Scholar]
9. Walterhouse DO, Pappo AS, Meza JL, Breneman JC, Hayes-Jordan AA, Parham DM, Cripe TP, Anderson JR, Meyer WH, Hawkins DS. Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol. 2014;32:3547–3552. [Europe PMC free article] [Abstract] [Google Scholar]
10. Hawkins DS, Chi YY, Anderson JR, Tian J, Arndt CAS, Bomgaars L, Donaldson SS, Hayes-Jordan A, Mascarenhas L, McCarville MB, McCune JS, McCowage G, Million L, Morris CD, Parham DM, Rodeberg DA, Rudzinski ER, Shnorhavorian M, Spunt SL, Skapek SX, Teot LA, Wolden S, Yock TI, Meyer WH. Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2018;36:2770–2777. [Europe PMC free article] [Abstract] [Google Scholar]
11. Hostein I, Andraud-Fregeville M, Guillou L, Terrier-Lacombe MJ, Deminière C, Ranchère D, Lussan C, Longavenne E, Bui NB, Delattre O, Coindre JM. Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded specimens. Cancer. 2004;101:2817–2824. [Abstract] [Google Scholar]
12. Nishimura R, Takita J, Sato-Otsubo A, Kato M, Koh K, Hanada R, Tanaka Y, Kato K, Maeda D, Fukayama M, Sanada M, Hayashi Y, Ogawa S. Characterization of genetic lesions in rhabdomyosarcoma using a high-density single nucleotide polymorphism array. Cancer Sci. 2013;104:856–864. [Europe PMC free article] [Abstract] [Google Scholar]
13. Liu C, Li D, Jiang J, Hu J, Zhang W, Chen Y, Cui X, Qi Y, Zou H, Zhang W, Li F. Analysis of molecular cytogenetic alteration in rhabdomyosarcoma by array comparative genomic hybridization. PLoS ONE. 2014;9:e94924. [Europe PMC free article] [Abstract] [Google Scholar]
14. Kohashi K, Oda Y, Yamamoto H, Tamiya S, Takahira T, Takahashi Y, Tajiri T, Taguchi T, Suita S, Tsuneyoshi M. Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype. J Cancer Res Clin Oncol. 2008;134:1097–1103. [Abstract] [Google Scholar]
15. Seki M, Nishimura R, Yoshida K, Shimamura T, Shiraishi Y, Sato Y, Kato M, Chiba K, Tanaka H, Hoshino N, Nagae G, Shiozawa Y, Okuno Y, Hosoi H, Tanaka Y, Okita H, Miyachi M, Souzaki R, Taguchi T, Koh K, Hanada R, Kato K, Nomura Y, Akiyama M, Oka A, Igarashi T, Miyano S, Aburatani H, Hayashi Y, Ogawa S, Takita J. Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma. Nat Commun. 2015;3(6):7557. [Europe PMC free article] [Abstract] [Google Scholar]
16. Hung YP, Lee JP, Bellizzi AM, Hornick JL. PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours. Histopathology. 2017;71:786–794. [Abstract] [Google Scholar]
17. Takemoto J, Kuda M, Kohashi K, Yamada Y, Koga Y, Kinoshita I, Souzaki R, Taguchi T, Oda Y. HuC/D expression in small round cell tumors and neuroendocrine tumors: a useful tool for distinguishing neuroblastoma from childhood small round cell tumors. Hum Pathol. 2019;85:162–167. [Abstract] [Google Scholar]
18. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study. Cancer. 1978;41:1937–1948. [Abstract] [Google Scholar]
19. Kohashi K, Oda Y, Yamamoto H, Tamiya S, Izumi T, Ohta S, Taguchi T, Suita S, Tsuneyoshi M. Highly aggressive behavior of malignant rhabdoid tumor: a special reference to SMARCB1/INI1 gene alterations using molecular genetic analysis including quantitative real-time PCR. J Cancer Res Clin Oncol. 2007;133:817–824. [Abstract] [Google Scholar]
20. Kohashi K, Izumi T, Oda Y, Yamamoto H, Tamiya S, Taguchi T, Iwamoto Y, Hasegawa T, Tsuneyoshi M. Infrequent SMARCB1/INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Hum Pathol. 2009;40:349–355. [Abstract] [Google Scholar]
21. Kohashi K, Oda Y, Yamamoto H, Tamiya S, Matono H, Iwamoto Y, Taguchi T, Tsuneyoshi M. Reduced expression of SMARCB1/INI1 protein in synovial sarcoma. Mod Pathol. 2010;23:981–990. [Abstract] [Google Scholar]
22. Kohashi K, Nakatsura T, Kinoshita Y, Yamamoto H, Yamada Y, Tajiri T, Taguchi T, Iwamoto Y, Oda Y. Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression. Hum Pathol. 2013;44:526–533. [Abstract] [Google Scholar]
23. Kohashi K, Yamamoto H, Kumagai R, Yamada Y, Hotokebuchi Y, Taguchi T, Iwamoto Y, Oda Y. Differential microRNA expression profiles between malignant rhabdoid tumor and epithelioid sarcoma: miR193a-5p is suggested to downregulate SMARCB1 mRNA expression. Mod Pathol. 2014;27:832–839. [Abstract] [Google Scholar]
24. Kohashi K, Yamada Y, Hotokebuchi Y, Yamamoto H, Taguchi T, Iwamoto Y, Oda Y. ERG and SALL4 expressions in SMARCB1/INI1-deficient tumors: a useful tool for distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Hum Pathol. 2015;46:225–230. [Abstract] [Google Scholar]
25. Kohashi K, Tanaka Y, Kishimoto H, Yamamoto H, Yamada Y, Taguchi T, Iwamoto Y, Oda Y. Reclassification of rhabdoid tumor and pediatric undifferentiated/unclassified sarcoma with complete loss of SMARCB1/INI1 protein expression: three subtypes of rhabdoid tumor according to their histological features. Mod Pathol. 2016;29:1232–1242. [Abstract] [Google Scholar]
26. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017;108:547–552. [Europe PMC free article] [Abstract] [Google Scholar]
27. Hays DM, Newton W, Jr, Soule EH, Foulkes MA, Raney RB, Tefft M, Ragab A, Maurer HM. Mortality among children with rhabdomyosarcomas of the alveolar histologic subtype. J Pediatr Surg. 1983;18:412–417. [Abstract] [Google Scholar]
28. Arnold MA, Anderson JR, Gastier-Foster JM, Barr FG, Skapek SX, Hawkins DS, Raney RB, Jr, Parham DM, Teot LA, Rudzinski ER, Walterhouse DO. Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma with Low-Risk Clinical Features: A Report from the Children's Oncology Group. Pediatr Blood Cancer. 2016;63:634–639. [Europe PMC free article] [Abstract] [Google Scholar]
29. Thompson LDR, Jo VY, Agaimy A, Llombart-Bosch A, Morales GN, Machado I, Flucke U, Wakely PE, Jr, Miettinen M, Bishop JA. Sinonasal tract alveolar rhabdomyosarcoma in adults: a clinicopathologic and immunophenotypic study of fifty-two cases with emphasis on epithelial immunoreactivity. Head Neck Pathol. 2018;12:181–192. [Europe PMC free article] [Abstract] [Google Scholar]
30. Rooper LM, Bishop JA, Westra WH. INSM1 is a sensitive and specific marker of neuroendocrine differentiation in head and neck tumors. Am J Surg Pathol. 2018;42:665–671. [Abstract] [Google Scholar]
31. Stegmaier S, Poremba C, Schaefer KL, Leuschner I, Kazanowska B, Békássy AN, Bielack SS, Klingebiel T, Koscielniak E. Prognostic value of PAX-FKHR fusion status in alveolar rhabdomyosarcoma: a report from the cooperative soft tissue sarcoma study group (CWS) Pediatr Blood Cancer. 2011;57:406–414. [Abstract] [Google Scholar]
32. Skapek SX, Anderson J, Barr FG, Bridge JA, Gastier-Foster JM, Parham DM, Rudzinski ER, Triche T, Hawkins DS. PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer. 2013;60:1411–1417. [Europe PMC free article] [Abstract] [Google Scholar]
33. Barr FG, Qualman SJ, Macris MH, Melnyk N, Lawlor ER, Strzelecki DM, Triche TJ, Bridge JA, Sorensen PH. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res. 2002;62:4704–4710. [Abstract] [Google Scholar]
34. Sumegi J, Streblow R, Frayer RW, Dal Cin P, Rosenberg A, Meloni-Ehrig A, Bridge JA. 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. Genes Chromosomes Cancer. 2010;49:224–236. [Europe PMC free article] [Abstract] [Google Scholar]
35. Liu J, Guzman MA, Pezanowski D, Patel D, Hauptman J, Keisling M, Hou SJ, Papenhausen PR, Pascasio JM, Punnett HH, Halligan GE, de Chadarévian JP. FOXO1-FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma. Mod Pathol. 2011;24:1327–1335. [Abstract] [Google Scholar]
36. Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, Ambrogio L, Auclair D, Wang J, Song YK, Tolman C, Hurd L, Liao H, Zhang S, Bogen D, Brohl AS, Sindiri S, Catchpoole D, Badgett T, Getz G, Mora J, Anderson JR, Skapek SX, Barr FG, Meyerson M, Hawkins DS, Khan J. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014;4:216–231. [Europe PMC free article] [Abstract] [Google Scholar]
37. Davicioni E, Anderson MJ, Finckenstein FG, Lynch JC, Qualman SJ, Shimada H, Schofield DE, Buckley JD, Meyer WH, Sorensen PH, Triche TJ. Molecular classification of rhabdomyosarcoma–genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol. 2009;174:550–564. [Europe PMC free article] [Abstract] [Google Scholar]
38. Wang NP, Marx J, McNutt MA, Rutledge JC, Gown AM. Expression of myogenic regulatory proteins (myogenin and MyoD1) in small blue round cell tumors of childhood. Am J Pathol. 1995;147:1799–1810. [Europe PMC free article] [Abstract] [Google Scholar]
39. Cessna MH, Zhou H, Perkins SL, Tripp SR, Layfield L, Daines C, Coffin CM. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol. 2001;25:1150–1157. [Abstract] [Google Scholar]
40. Choi EY, Thomas DG, McHugh JB, Patel RM, Roulston D, Schuetze SM, Chugh R, Biermann JS, Lucas DR. Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology. Am J Surg Pathol. 2013;37:1379–86. [Abstract] [Google Scholar]
41. Yamada Y, Kuda M, Kohashi K, Yamamoto H, Takemoto J, Ishii T, Iura K, Maekawa A, Bekki H, Ito T, Otsuka H, Kuroda M, Honda Y, Sumiyoshi S, Inoue T, Kinoshita N, Nishida A, Yamashita K, Ito I, Komune S, Taguchi T, Iwamoto Y, Oda Y. Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Virchows Arch. 2017;470:373–380. [Abstract] [Google Scholar]
42. Chiles MC, Parham DM, Qualman SJ, Teot LA, Bridge JA, Ullrich F, Barr FG, Meyer WH. Soft Tissue Sarcoma Committee of the Children's Oncology Group. Sclerosing rhabdomyosarcomas in children and adolescents: a clinicopathologic review of 13 cases from the Intergroup Rhabdomyosarcoma Study Group and Children's Oncology Group. Pediatr Dev Pathol. 2004;7:583–94. [Abstract] [Google Scholar]
43. Nascimento AF, Fletcher CD. Spindle cell rhabdomyosarcoma in adults. Am J Surg Pathol. 2005;29:1106–1113. [Abstract] [Google Scholar]
44. Nascimento AF, Barr FG. Spindle cell/Sclerosing rhabdomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. pp. 134–5. [Google Scholar]
45. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, Zin A, Agaram NP, LaQuaglia MP, Wexler LH, Antonescu CR. A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases. Am J Surg Pathol. 2016;40(2):224–235. [Europe PMC free article] [Abstract] [Google Scholar]
46. Agaram NP, LaQuaglia MP, Alaggio R, Zhang L, Fujisawa Y, Ladanyi M, Wexler LH, Antonescu CR. MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification. Mod Pathol. 2019;32:27–36. [Europe PMC free article] [Abstract] [Google Scholar]
47. Rekhi B, Upadhyay P, Ramteke MP, Dutt A. MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod Pathol. 2016;29(12):1532–1540. [Europe PMC free article] [Abstract] [Google Scholar]
48. Tsai JW, ChangChien YC, Lee JC, Kao YC, Li WS, Liang CW, Liao IC, Chang YM, Wang JC, Tsao CF, Yu SC, Huang HY. The expanding morphological and genetic spectrum of MYOD1-mutant spindle cell/sclerosing rhabdomyosarcomas: a clinicopathological and molecular comparison of mutated and non-mutated cases. Histopathology. 2019;74:933–943. [Abstract] [Google Scholar]
49. Argani P, Reuter VE, Kapur P, Brown JE, Sung YS, Zhang L, Williamson R, Francis G, Sommerville S, Swanson D, Dickson BC, Antonescu CR. Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney. Am J Surg Pathol. 2018;42:1562–1570. [Europe PMC free article] [Abstract] [Google Scholar]
50. Agaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, Wexler L, Francis G, Sommerville S, Swanson D, Dickson BC, Suurmeijer AJH, Williamson R, Antonescu CR. Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype. Am J Surg Pathol. 2019;43:695–702. [Europe PMC free article] [Abstract] [Google Scholar]
51. Prieto-Granada CN, Wiesner T, Messina JL, Jungbluth AA, Chi P, Antonescu CR. Loss of H3K27me3 Expression Is a Highly Sensitive Marker for Sporadic and Radiation-induced MPNST. Am J Surg Pathol. 2016;40:479–489. [Europe PMC free article] [Abstract] [Google Scholar]
52. Cleven AH, Sannaa GA, Briaire-de Bruijn I, Ingram DR, van de Rijn M, Rubin BP, de Vries MW, Watson KL, Torres KE, Wang WL, van Duinen SG, Hogendoorn PC, Lazar AJ, Bovée JV. Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol. 2016;29:582–590. [Europe PMC free article] [Abstract] [Google Scholar]
53. Asano N, Yoshida A, Ichikawa H, Mori T, Nakamura M, Kawai A, Hiraoka N. Immunohistochemistry for trimethylated H3K27 in the diagnosis of malignant peripheral nerve sheath tumours. Histopathology. 2017;70:385–393. [Abstract] [Google Scholar]
54. Otsuka H, Kohashi K, Yoshimoto M, Ishihara S, Toda Y, Yamada Y, Yamamoto H, Nakashima Y, Oda Y. Immunohistochemical evaluation of H3K27 trimethylation in malignant peripheral nerve sheath tumors. Pathol Res Pract. 2018;214:417–425. [Abstract] [Google Scholar]
55. Hornick JL, Nielsen GP. Beyond "Triton": malignant peripheral nerve sheath tumors with complete heterologous rhabdomyoblastic differentiation mimicking spindle cell rhabdomyosarcoma. Am J Surg Pathol. 2019;43:1323–1330. [Abstract] [Google Scholar]
56. Jo VY, Mariño-Enríquez A, Fletcher CD. Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16 cases of a morphologically distinct variant of rhabdomyosarcoma. Am J Surg Pathol. 2011;35:1523–1530. [Abstract] [Google Scholar]
57. Zin A, Bertorelle R, Dall'Igna P, Manzitti C, Gambini C, Bisogno G, Rosolen A, Alaggio R. Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular study. Am J Surg Pathol. 2014;38:273–278. [Abstract] [Google Scholar]
58. Noujaim J, Thway K, Jones RL, Miah A, Khabra K, Langer R, Kasper B, Judson I, Benson C, Kollàr A. Adult pleomorphic rhabdomyosarcoma: a multicentre retrospective study. Anticancer Res. 2015;35:6213–6217. [Abstract] [Google Scholar]
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