Soft tissue

Skeletal muscle

Rhabdomyosarcoma

Embryonal rhabdomyosarcoma

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 1 May 2018

Minor changes: 5 January 2022

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Related topics: Rhabdomyosarcoma, NOS, spindle cell

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Table of Contents

Cite this page: Clay M. Embryonal rhabdomyosarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissueembryonalrhabdo.html. Accessed January 21st, 2022.

Definition / general

Subtype of the rhabdomyosarcoma (RMS) soft tissue cancer family whose lineage derives from the undifferentiated mesoderm
Embryonal rhabdomyosarcoma (ERMS) is the most common RMS subtype
Several distinct and prognostic patterns of growth have been noted, including the botryoid and anaplastic variants

Essential features

Most common subtype of rhabdomyosarcoma in the pediatric and adolescent setting
Anaplasia is associated with TP53 mutations, p53 protein overexpression and worse overall prognosis (Cancer 2014;120:1068)
Displays a wide spectrum of morphologic features, including cases with spindled morphology
- See Terminology section below regarding spindle cell rhabdomyosarcoma
Displays some degree of myogenic differentiation, including either MyoD1 or myogenin positivity
Not associated with recurrent gene fusions but displays some recurrent copy number changes

Terminology

Botryoid embryonal rhabdomyosarcoma ("sarcoma botryoides") only occurs in certain locations, specifically beneath a mucosal epithelial lined viscera, such as the bladder, biliary tract, vagina or upper respiratory tract, extrahepatic bile ducts or near a space; rarely in eyelid or anal region
- Often has a grape-like ("botryoid") growth pattern
- 25% of rhabdomyosarcomas, 10% of embryonal subtype
- Considered a subtype of embryonal rhabdomyosarcoma (ERMS) (Am J Surg Pathol 2001;25:856)
Anaplasia is an important prognostic feature and is defined similar to anaplastic Wilms tumor: significant nuclear variation (cells that are 3x larger than background tumor cells) and the presence of atypical multipolar mitotic figures
Spindle cell rhabdomyosarcoma:
- Over the years, tumors with spindled morphology have been regarded as a variant of ERMS
- These show a predilection for the paratesticular soft tissues and are now recognized as carriers of specific gene fusions, including NCOA2 and VGLL2 fusions or MYOD1 L122R point mutations (for an excellent recent review, see Am J Surg Pathol 2016;40:224)
- These entities will be better defined in future editions of the WHO classification and have already been distanced from ERMS with the provisional classification of spindled / sclerosing rhabdomyosarcoma

ICD coding

C49.9

Epidemiology

Most common in children 0 - 4 years old with a maximum reported incidence of 4 cases per 1 million children but can be identified at any age (Cancer 2009;115:4218)
Represent approximately 60 - 70% of childhood cases and 20% of adult cases
Rare congenital cases have also been reported (Int J Surg Case Rep 2017;31:47)

Sites

Most common in the head and neck region, including the nasal and oral cavities, as well as the orbit and middle ear (J Clin Oncol 1995;13:610)
Also common in the paratesticular soft tissues and the genitourinary tract
Extremity involvement of the somatic soft tissues is less common (< 9%)
Metastasizes to soft tissue, serosa, lung, lymph nodes and bone marrow

Pathophysiology

Derived from the undifferentiated mesoderm and shows phenotypic and biologic features of primitive skeletal muscle

Etiology

Most cases occur sporadically with no genetic predisposition
Children with predisposing familial syndromes, in which there are frequently defects in the RAS or Hedgehog pathways, are at higher risk for developing embryonal rhabdomyosarcoma (Genes Chromosomes Cancer 2009;48:975)
Seen secondarily in syndromes including Costello syndrome (HRAS), neurofibromatosis type 1 (NF1), Noonan syndrome (PTPN11 and others), Beckwith-Wiedemann syndrome (changes to 11p15), Dicer syndrome (DICER1), Li-Fraumeni syndrome (TP53) and Gorlin syndrome (PTCH1) (Cancer Med 2015;4:781, J Biomol Tech 2013;24:S47, Mod Pathol 2012;25:602)

Prognostic factors

Intergroup Rhabdomyosarcoma Study Group (IRSG) has subdivided rhabdomyosarcoma into low, intermediate and high risk groups for the purpose of protocol placement in pediatric patients (Pediatr Blood Cancer 2012;59:5)
- Based on clinicopathologic variables including histologic type, extent of surgical control of local disease and primary tumor site
Botryoid variant has a particularly good prognosis, although may have late relapse (Zhonghua Bing Li Xue Za Zhi 2004;33:225, Pediatr Blood Cancer 2008;51:140)
Other favorable prognostic factors are age (between 1 and 9 years), orbital and paratesticular location and absence of metastatic disease at the time of resection
Anaplasia is a negative prognostic factor, regardless of whether it is focal or diffuse (Cancer 2008;113:3242)
Extremity involvement is associated with more relapses and lower survival

Case reports

Newborn with embryonal rhabdomyosarcoma (ERMS) presenting as a mass of the urethra at birth (Urology 2015;86:805)
Newborn girl with anaplastic rhabdomyosarcoma (Iran J Pathol 2016;11:80)
7 year old boy with primary ERMS of the anterior neck and thyroid (Laryngoscope 2013;123:2072)
11 year old boy with tonsillar mass (Case of the Week #276)
16 year old girl with ERMS of the cervix (J Med Case Rep 2014;8:241)
46 year old man with ERMS arising from a mediastinal teratoma (J Korean Med Sci 2013;28:476)
55 year old postmenopausal woman with ERMS arising from the uterine corpus (Diagn Pathol 2016;11:3)
58 year old man with cardiac ERMS (Eur J Cardiothorac Surg 2014;45:e233)

Treatment

Surgery is the preferred local therapy, with radiotherapy typically used only in the event of residual disease, nodal disease or poor response to combined chemotherapy
Intergroup Rhabdomyosarcoma Study Postsurgical Clinical Grouping System is recommended to plan treatment in pediatric cases (Pediatr Blood Cancer 2012;59:5)
American Joint Committee on Cancer (AJCC) TNM staging system remains appropriate for planning treatment in adult patients (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018)
Anaplastic tumors often require more intensive treatment (Cancer 2008;113:3242)
Botryoid variant: conservative surgery plus radiation and chemotherapy (Int J Gynecol Cancer 2008;18:190)

Gross description

Poorly circumscribed mass, white, soft or firm, infiltrative
Botryoid variant: resembles cluster of grapes or allergic nasal polyp, fleshy nodular polypoid projections of variable size into lumen

Gross images

Contributed by Mark R. Wick, M.D.

Orbital

Case #268

Parotid mass

AFIP images

Botryoid: clusters of
edematous, grape-like
masses that protrude into
lumen of hollow organs

Images hosted on other servers:

White tumor mass with focal necroses

Incision of the oral mucosa

Pitfalls and tips

Anaplasia specifically requires multipolar mitotic figures
- Make sure you are not overinterpreting degenerating or apoptotic cells
- Look for organization of the division and exclude cells that appear to be "exploding"
- Also try to avoid interpreting overlapping cells as one larger cell
Absence of a translocation does not result in the default diagnosis of embryonal rhabdomyosarcoma; tumor must adhere to the described histologic features
Some rhabdomyosarcomas defy classification (rhabdomyosarcoma, not otherwise specified); this designation is preferable to misclassification, especially in small or otherwise limited samples
Beware nonspecific staining (aberrant positivity for cytokeratin or S100 protein) vs. true staining (S100 protein as a component of malignant peripheral nerve sheath tumor)
Damaged skeletal muscle can express MyoD1 and myogenin; a different sarcoma that otherwise infiltrates skeletal muscle will very much mimic a rhabdomyosarcoma on immunohistochemistry staining
- Look for the MyoD1 / myogenin to be positive in tumor cells in a linear pattern, which suggests the staining is of background muscle and not the tumor

Microscopic (histologic) description

Composed of primitive mesenchymal cells that show variable degrees of skeletal muscle differentiation
They are moderately cellular but in the typical pattern often contain both hypo- and hypercellular areas with a loose, myxoid stroma
Perivascular condensations of tumor cells in the less cellular regions are common
Sheets of small, stellate, spindled or round cells with scant or deeply eosinophilic cytoplasm and eccentric, small oval nuclei with a light chromatin pattern and inconspicuous nucleoli
Can occasionally identify tumor cells that contain generous amounts of eosinophilic cytoplasm, a feature of rhabdomyoblastic differentiation (so called "strap" cells)
- These may become more prominent with chemotherapy (chemotherapeutic induced cytodifferentiation)
May have cells with elongated tails of cytoplasm (tadpole cells)
If densely cellular, may resemble solid alveolar rhabdomyosarcoma (Am J Clin Pathol 2013;140:82)
Botryoid variant frequently shows a "cambium layer," a hypercellular zone immediately beneath the epithelial surface
- Cells are undifferentiated, round or spindled with minimal cytoplasm, frequent mitotic figures
- Deeper layers of the tumor are typically less cellular but overall conform to the histology of embryonal rhabdomyosarcoma (ERMS) with variation by region
Rare morphological patterns:
- Rhabdomyosarcoma with rhabdoid features (epithelioid or rhabdoid-like RMS, Am J Surg Pathol 2011;35:1523)
- Clear cell change (Pediatr Pathol Lab Med 1996;16:951)
- Cartilaginous metaplasia (Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:e288)
- Do not confuse with these different entities:
  - Ectomesenchymoma: melanocytic, neuroblastic / ganglionic or Schwannian differentiation in the setting of background ERMS
  - Malignant triton tumor: rhabdomyosarcomatous differentiation in a malignant peripheral nerve sheath tumor; very bad prognosis

Microscopic (histologic) images

Contributed by Erdener Özer, M.D., Ph.D.

Small spindled and round cells with variable eosinophilic cytoplasm; H&E and stains

Contributed by Mark R. Wick, M.D.

Orbital

Myogenin

Case #276 - tonsillar mass

Various images

Actin

Desmin

Myogenin

MyoD1

AFIP images - Anaplastic rhabdomyosarcoma:

Extremely hyperchromatic nuclei are 3x larger than nuclei of adjacent tumor cells, mixed with smaller, undifferentiated, round and spindle cells

Bizarre mitotic figure (left side)

Rare cells suggest skeletal muscle differentiation

AFIP images - botryoid variant:

Polypoid or lobulated masses of
cells covered by mucosa, with underlying
hypercellular zone of poorly differentiated
cells (cambium layer)

Tumor with sheets of
round or spindle cells
resembling benign polyp
or fibroinflammatory lesion

Deep foci of hypercellularity is common with round or spindled undifferentiated cells mixed with differentiating rhabdomyoblasts

Tumor may have only focal cambium layer
and consist primarily of paucicellular
edematous tissue with scattered
undifferentiated or atypical large cells

Images hosted on other servers:

Anaplastic
rhabdomyosarcoma

Botryoid variant: vaginal tumor

Cytology description

Cellular with features of a small round cell tumor
Rarely intranuclear cytoplasmic inclusions (Diagn Cytopathol 2009;37:740)

Cytology images

Contributed by Erdener Özer, M.D., Ph.D.

Small round cell tumor

Positive stains

Desmin, MyoD1 or myogenin are critical to document (Pathol Oncol Res 2008;14:233)
- Without myogenic differentiation (MyoD1 or myogenin), it is very difficult to diagnose embryonal rhabdomyosarcoma
- These stains will be less diffuse than in alveolar rhabdomyosarcoma and can be extremely focal
Vimentin in all cells (even most primitive)
Actin, myoglobin, myosin and creatine kinase M staining in more differentiated cells
There may be aberrant staining for several antigens: occasional immunoreactivity to cytokeratin, S100 protein, neurofilaments and B cell markers such as CD20
PAS highlights glycogen in most tumors
Botryoid variant: Desmin, MyoD1, smooth muscle actin, muscle specific actin (Pediatr Dev Pathol 2005;8:427)

Electron microscopy description

Developing striated muscle, thick and thin filaments

Molecular / cytogenetics description

11p15.5 loss of heterozygosity or loss of imprinting is a frequent finding
Chromosomal aneuploidies are very common, especially with gains of chromosome 8 (seen in 90% of patients)
- Additional gains frequently seen include chromosomes 2, 11, 12, 13 and 20
No diagnostic translocation found to date (see Terminology regarding spindled rhabdomyosarcoma)
Inactivating mutations of TP53 and CDKN2A and activating mutations of RAS family genes (Genes Chromosomes Cancer 2011;50:397)
Frequency of ALK dysregulation is debatable, as are any significant associated clinical features (Mod Pathol 2013;26:772)

Differential diagnosis

Alveolar rhabdomyosarcoma (ARMS):
- Diffuse and strong nuclear staining for myogenin and MyoD1; molecular studies (including FISH) show PAX-FOXO1 fusion gene product in approximately 85% of cases (Am J Clin Pathol 2013;140:82)
- Histologically, ARMS are more uniform and show more predictable patterns of growth (a finding which correlates with their consistent driver fusion event - they look like a "translocation" sarcoma)
Desmoplastic small round cell tumor:
- Tumor nodules on serosal surfaces, strongly keratin+ and EMA+, may be desmin+ but muscle specific actin-
- Associated with desmoplasia and histologically more closely mimic alveolar rather than embryonal rhabdomyosarcoma (ERMS)
- Will not display myogenin or MyoD1 positivity; beware false positivity if they infiltrate background skeletal muscle
- See Pitfalls and tips above
Ewing / PNET:
- Another round cell tumor, often displays Homer Wright rosettes
- Nuclei are far more uniform and pale, not dense and hyperchromatic; CD99+, desmin-, MyoD1-, myogenin-
- Look for characteristic rearrangements including t(11;22) or t(12;22)
- In general, although there can be histologic overlap, if you sample the tumor enough you will find more atypia and cell to cell variability in rhabdomyosarcoma
Large cell lymphoma:
- CD45+, B / T cell markers present, desmin-, myogenin-, MyoD1-, muscle specific actin-
- Histologically, can be very difficult to distinguish but lack of myogenic antibodies can be very helpful
Monophasic synovial sarcoma:
- Negative for muscle markers, usually far more spindled and organized (long fascicles) when compared to ERMS
- Cytokeratin and EMA expression will show scattered and focal positivity in the spindled cells, the characteristic pattern seen in nearly all of these lesions
- Molecular or FISH testing for the t(X;18) fusion, if needed
Myxoid liposarcoma (MLS):
- Although MLS typically is very easy to distinguish from ERMS, it can have a very similar background matrix that is loose and lightly basophilic
- Cells can focally resemble one another as well
- Look for signet ring lipoblasts in MLS, more bland histology and more uniformity when compared to ERMS
- Immunostaining and molecular features are also easily utilized to differentiate the two entities
Neuroblastoma:
- Undifferentiated neuroblastoma can be very difficult to distinguish histologically; you may need to rely on the clinical presentation and the immunoprofile
- Elevated urinary catecholamines, rosettes, granular chromatin, neuropil
- S100+ (often), chromogranin+, synaptophysin+, GFAP+
- Absence of myogenic markers
Pleomorphic rhabdomyosarcoma:
- Exclusively adults, usually in their 60s - 70s
- Usually deep soft tissue of the extremity and remarkable for its universal diffuse cytologic atypia
- Uniformly pleomorphic and does not contain elements of embryonal rhabdomyosarcoma
- Anaplastic, as opposed to ERMS which occasionally displays anaplasia in a background of classic EMRS
Wilms tumor:
- Can have rhabdomyoblastic differentiation, especially in the setting of chemotherapy
- Beware any tumor in the kidney or any metastatic site in a patient with a previous Wilms tumor
- Epithelial and blastemal components can be very focal following chemotherapy
- If a Wilms tumor displays this pattern, it usually shows abundant cytodifferentiation, as opposed to classic rhabdomyosarcoma, which is usually focal

Additional references

Arch Pathol Lab Med 2015;139:1281, CAP: Protocol for the Examination of Specimens From Patients With Rhabdomyosarcoma [Accessed 21 November 2017]

Board review style question #1

Which FISH testing may assist in making distinction between the dense pattern of embryonal rhabdomyosarcoma and the alveolar subtype of rhabdomyosarcoma?

ETV6-NTRK3
EWS-FLI1
PAX3-FOXO1
SYT-SSX1
TPM3-ALK

Board review style answer #1

C. PAX3-FOXO1. This fusion gene product occurs in approximately 80% of alveolar rhabdomyosarcoma cases. Additionally, PAX7-FOXO1 rearrangements are present in a minority of cases.

Board review style question #2

Which histologic features in embryonal rhabdomyosarcoma are needed to diagnose anaplasia?

3x nuclear size variability and tripolar mitotic figures
Alternating hypercellular and hypocellular areas
Coagulative necrosis
More than 20 mitoses per 10 high power fields
Solid growth pattern

Board review style answer #2

A. Multipolar mitotic figures (including tripolar mitoses) and nuclear anaplasia (3x variation in nuclear size) are required to diagnosis anaplasia in embryonal rhabdomyosarcoma (ERMS). Solid growth pattern is irrelevant and necrosis can be seen in any subtype of rhabdomyosarcoma. ERMS typically displays the alternating pattern of hypo and hypercellularity (also a buzzword for high grade malignant peripheral nerve sheath tumors). There is no requirement for a specific mitotic rate.