Rhabdomyosarcoma

Definition

• Primitive malignant tumor of embryonal skeletal muscle progenitor cells (myoblasts)

Diagnostic Criteria

• Myogenin expression is essentially diagnostic
  • Only exception is rare expression of myogenin by melanotic neuroectodermal tumor of infancy and the composite tumors listed below
    • Malignant triton tumor (rhabdomyosarcoma plus malignant peripheral nerve sheath tumor)
    • Ectomesenchymoma (rhabdomyosarcoma plus peripheral primitive neuroectodermal tumor)
    • Malignant teratoma
    • Carcinosarcoma
• Rhabdomyosarcoma is predominantly a pediatric neoplasm
  • Most common soft tissue sarcoma of childhood
    • Up to 10% of all childhood malignancies
    • Only sclerosing and pleomorphic types show significant adult incidence
• Histologic types show markedly different clincal features (select type for criteria)
  • Embryonal (includes botryoid, spindled and NOS)
  • Alveolar
  • Mixed embryonal and alveolar
  • Sclerosing
  • Pleomorphic
• See Staging for IRSG modified TNM, do not use TNM from AJCC

Florette K. Gray Hazard MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 10/25/12

Embryonal Rhabdomyosarcoma

Definition

• Primitive myoblastic neoplasm most commonly found in hollow visceral organs, genitourinary tract and the head and neck region

Diagnostic Criteria

• Most common type of rhabdomyosarcoma, (68%)
• Considered a favorable histologic type
  • 5-year failure free survival rate: 82%
• Alternating cellular and myxoid areas
  • Foci of immature cartilage or bone are occasionally present
• Hyperchromatic histologically undifferentiated small cell population usually predominates
  • May be round or spindled
• Immature cells showing muscle differentiation frequently scattered, rarely predominate
  • Round cells with abundant, usually eccentric eosinophilic cytoplasm
    • Cross striations not typically present
    • Nuclei frequently vesicular with prominent nucleolus
  • Spindle cell myoblasts with prominent tapered fibrillar eosinophilic cytoplasm
    • May form tadpole or strap cells
    • Nuclei may be multiple
    • Cross striations may be present
• Anaplastic cellular features may be seen in approximately 13% of all subtypes of rhabdomyosarcoma.
  • Anaplasia is defined as neoplastic nuclei at least 3 times the size of their neoplastic neighbors and/or atypical mitotic figures.
  • If present, the focal or diffuse nature of the anaplasia should also be described.
    • Focal anaplasia refers to anaplastic cells loosely scattered among non-anaplastic tumor cells.
    • Diffuse anaplasia refers to anaplastic cells arranged in multiple clusters or diffuse sheets.
  • The presence of anaplasia confers a worse prognosis (see Clinical), especially when the anaplasia is diffuse
• Three histologic subtypes
  • Botryoid
    • Requires by the presence of a condensed layer of neoplastic cells beneath intact epithelium (cambium layer)
      • Typically separated from mucosa by a myxoid, hypocellular zone
    • Primarily occurs in mucosal lined sites
      • Grape like gross appearance is typical but not required
  • Spindled
    • Spindled morphology
    • Primarily found in the paratesticular and orbital regions
  • Not otherwise specified (NOS) is most common
• No PAX-FOXO1 translocations
• Common sites of involvement:
  • Genitourinary system (infants and young children)
  • Orbit
  • Head and neck
• Population: 42% children < 4 years of age
  • May be seen in adults

Alveolar Rhabdomyosarcoma

Definition

• Primitive myoblastic neoplasm found most commonly in the extremities, paranasal sinuses and parameningeal region

Diagnostic Criteria

• Second most common type of rhabdomyosarcoma, comprises 31% of RMS
• Considered an unfavorable histologic type
  • 5-year failure free survival rate: 65%
• Sheets of uniform cells, frequently discohesive, broken up by fibrous septae
  • Generally round to oval nuclei
    • Hyperchromatic with small nucleoli
  • Occasional rhabdomyoblasts seen in 30% of cases
    • Fibrillar cytoplasm but only rare cross striations
    • Usually round
  • Sheets broken up by fibrous septae
    • Vessels contained in septae
• Two histologic subtypes
  • Classical
    • Nests of neoplastic cells arranged in alveolar spaces
    • Cells adhere to the periphery of the alveoli
      • Hobnail or tombstone appearance
      • May look like a non-cohesive papillary pattern
    • Non-cohesive cells appear to float in the center
    • Multinucleated giant cell forms may be seen
      • Nuclei usually peripheral, wreath-like
    • Normal muscle fibers may be entrapped
  • Solid
    • Sheets of neoplastic cells
    • Nests separated by thin fibrovascular septae but alveoli are not seen
  • PAX-FOXO1 translocations aid in diagnosis and determination of prognosis
    • Considered diagnostic if present (see Supplemental Studies)
      • PAX3-FOXO1 t(2;13)(q35;q14) – 60%
      • PAX7-FOXO1 t(1;13)(p36;q14) – 20% (better prognosis)
      • Fusion negative ~ 15%
• Anaplastic cellular features may be seen in approximately 13% of all subtypes of rhabdomyosarcoma.
  • Anaplasia is defined as neoplastic nuclei at least 3 times the size of their neoplastic neighbors and/or atypical mitotic figures.
  • If present, the focal or diffuse nature of the anaplasia should also be described.
    • Focal anaplasia refers to anaplastic cells loosely scattered among non-anaplastic tumor cells.
    • Diffuse anaplasia refers to anaplastic cells arranged in multiple clusters or diffuse sheets.
  • The presence of anaplasia confers a worse prognosis (see Clinical), especially when the anaplasia is diffuse
• Common sites of involvement:
  • Extremities
  • Trunk
• Population: most >10 years of age
  • May be seen in adults

Mixed Alveolar/Embryonal Rhabdomyosarcoma

Definition

• Rhabdomyosarcoma exhibitiig a mixture of alveolar and embryonal patterns

Diagnostic Criteria

• Tumors showing mixed histologic features of embryonal and alveolar subtypes
  • These histologically distinct morphologies may be intermixed or distinct from each other
  • There is no percentage cutoff that facilitates classification of one tumor subtype over another
  • The presence of both alveolar and embryonal morphologic features is all that is required for the designation of mixed alveolar/embryonal rhabdomyosarcoma.
  • Anaplasia should be evaluated and reported as described for embryonal and alveolar subtyes
• Expression of myogenin and PAX-FOXO1 fusion transcripts is variable
  • They may be concordant or discordant with histologic pattern, diffuse, focal or negative
• Behavior and incidence unknown
• Common sites of involvement
  • Extremities
  • Trunk
• Population: most <10 years of age, however all ages have been reported
  • Rare case reports in adults (i.e. prostate gland)

Sclerosing Rhabdomyosarcoma

Definition

• Rhabdomyosarcoma with a densely sclerotic background stroma.

Diagnostic Criteria

• Neoplastic cells set in a densely hyalinized eosinophilic background stroma
  • Arranged in nests, microalveoli or cords
  • May produce a pseudovascular pattern
• Composed of small undifferentiated cells
  • Giant cells or myoblasts are rare
• Anaplastic cellular features may be seen in approximately 13% of all subtypes of rhabdomyosarcoma.
  • Anaplasia is defined as neoplastic nuclei at least 3 times the size of their neoplastic neighbors and/or atypical mitotic figures.
  • If present, the focal or diffuse nature of the anaplasia should also be described.
    • Focal anaplasia refers to anaplastic cells loosely scattered among non-anaplastic tumor cells.
    • Diffuse anaplasia refers to anaplastic cells arranged in multiple clusters or diffuse sheets.
  • The presence of anaplasia confers a worse prognosis (see Clinical), especially when the anaplasia is diffuse
• No distinct translocation
• Common sites of involvement:
  • Extremities
  • Trunk
  • Retroperitoneum
• Rare, <1% of rhabdomyosarcoma
  • Reported in children and adults of all ages
• Unknown behavior

Pleomorphic Rhabdomyosarcoma

Definition

• Malignant neoplasm with large pleomorphic cells exhibiting skeletal muscle differentiation

Diagnostic Criteria

• Unfavorable histologic type
  • 5-year failure free survival rate: ~ 40%
• Markedly enlarged pleomorphic cells
  • Abundant deeply eosinophilic cytoplasm
    • Cross striations rare
  • Multinucleated forms may be seen
  • Spindled to epithelioid neoplastic cells admixed
  • Lacks background of uniform immature cells
    • Presence of immature cells suggests instead anaplasia in embryonal or alveolar subtypes
• Requires demonstration of skeletal muscle differentiation
  • MyoD1 or myogenin
• Anaplastic cellular features may be seen in approximately 13% of all subtypes of rhabdomyosarcoma.
  • Anaplasia is defined as neoplastic nuclei at least 3 times the size of their neoplastic neighbors and/or atypical mitotic figures.
  • If present, the focal or diffuse nature of the anaplasia should also be described.
    • Focal anaplasia refers to anaplastic cells loosely scattered among non-anaplastic tumor cells.
    • Diffuse anaplasia refers to anaplastic cells arranged in multiple clusters or diffuse sheets.
  • The presence of anaplasia confers a worse prognosis (see Clinical), especially when the anaplasia is diffuse
  • Anaplasia can be very difficult to assess in pleomorphic subtype
• No distinct translocation
• Common sites of involvement:
  • Deep extremities
  • Retroperitoneum
• Most often seen in adults
  • Rare cases reported in children

Supplemental studies

Immunohistology

• Desmin is an effective screening stain as nearly all cases of all types are positive
  • Smooth muscle neoplasms are also desmin positive
• More specific and virtually diagnostic are myogenin and MyoD1
  • The only sensitivity exception is the sclerosing type, which may show only dot like desmin and may be only variably positive for myogenin
  • The only specificity exception is rare expression by melanotic neuroectodermal tumor of infancy
    • Composite tumors must be ruled out
  • MyoD1 reagents may produce nonspecific cytoplasmic staining
    • Myogenin is preferred by many for this reason

Genetic Study

• PAX-FOXO1 fusion transcripts are specific for alveolar rhabdomyosarcoma.
  • PAX3-FOXO1 t(2;13)(q35;q14) – 60%
  • PAX7-FOXO1 t(1;13)(p36;q14) – 20% (better prognosis)
  • Nonspecific minor translocations and fusion negative cases may occur
    • Fusion negative ~ 15%
    • Amplifications of genes: MYCN, MDM2, CDK4, IGF-R1
    • FGFR1-FOXO1 t(8;13;9)(p11.2;q14;9q32)
    • PAX3-NCOA1 t(2;2)(p23;q53)
    • PAX3-NCOA2 t(2;8)(q35;q13)
• There is no specific genetic abnormality specific for embryonal or other subtypes of rhabdomyosarcoma.
  • A number of nonspecific genetic abnormalities have been described
    • LOH at 11p15.5
    • Gains of chromosomes 2,7,8,11,12,13,17,19 and 20
    • Amplifications of genes: MYCN, MDM2, CDK4, IGF-R1
• We test all cases of pediatric rhabdomyosarcoma for FOXO1 abnormalities with FISH on paraffin sections
  • Classical cytogenetic study is then necessary in positive cases to determine the specific fusion partner
  • All pediatric specimens considered suspicious for soft tissue sarcomas should have a portion of unfixed tissue set aside for cytogenetic study
• No specific genetic abnormalities associated with anaplasia

Differential Diagnosis

Embryonal rhabdomyosarcoma

• DDx is generally that of small round blue cell tumors
  • Usually resolved by immunohistochemistry

	Nblast	ALL	Ewing Sarc (PNET)	Rhabdo	MNTI	DSCT	Wilms Tumor
Synapto	pos	neg	neg	neg	pos	neg	neg
NB84	pos	neg	neg	neg	neg	neg	neg
CD45RB (LCA)	neg	pos	neg	neg	neg	neg	neg
CD99	neg	pos	pos	neg	rare	neg	neg
Myogenin	neg	neg	neg	pos	rare	neg	neg
MyoD1	neg	neg	neg	pos	neg	neg	neg
Keratin	neg	neg	rare	rare	pos	pos	neg
Desmin	neg	neg	neg	pos	rare	pos	neg
WT1(C)	neg	neg	neg	neg	neg	pos	pos
S100	neg	neg	rare	neg	rare	neg	neg
HMB45	neg	neg	neg	neg	pos	neg	neg

Nblast = Neuroblastoma; ALL = Precursor T Lymphoblastic Leukemia; Rhabdo = Rhabdomyosarcoma; MNTI = Melanotic Neuroectodermal Tumor of Infancy; DSCT = Desmoplastic Small (Round) Cell Tumor; Synapto = Synaptophysin

The small cell pattern of DSCT may be confused with rhabdomyosarcoma. Both are desmin positive.

Embryonal Rhabdomyosarcoma	Desmoplastic Small Cell Tumor
No desmoplastic stroma	Prominent desmoplastic stroma
Keratin variable, faint and focal	Keratin 90% positive, prominent
EMA negative	EMA 90% positive
WT1 rare, focal	WT1 positive
Muscle actin positive 95%	Muscle actin rare
Median age 7 years	Mean age 25 years
No consistent genetic abnormality	t(11;22)(p13;q12)

Alveolar rhabdomyosarcoma	Alveolar Soft Part Sarcoma
Variably shaped alveolar spaces	Regular alveolar spaces
Fibrous septa around nests	Thin walled vascular septa
Cells generally 10-30 microns diameter	Cells larger
Pleomorphic nuclei	Only mild pleomorphism
Dense nuclei	Vesicular nuclei
Small nucleoli	Prominent nucleoli
No crystals	Crystals in up to 80% of cases
Uniformly desmin, actin positive	Occasionally desmin, actin positive
Frequently MyoD1 positive	MyoD1 rare or negative
Translocations t(2;13) or t(1;13)	der(17)t(X;17)(p11.2;q25)

Sclerosing Rhabdomyosarcoma	Desmoplastic Small Cell Tumor
Keratin 5-50% positive, focal, weak	Keratin 90% positive, prominent
EMA negative	EMA 90% positive
WT1(C) negative	WT1(C) positive
Any age group	Mean age 25 years
No consistent genetic abnormality	t(11;22)(p13;q12)

Both are desmin positive with a prominent sclerotic/desmoplastic stroma

• Other sarcomas with a prominent sclerotic/desmoplastic background may also mimic sclerosing rhabdomyosarcoma
  • These include, but are not limited to, osteosarcoma, extraskeletal myxoid chondrosarcoma, epithelioid fibrosarcoma and angiosarcoma
  • These sarcomas can be readily differentiated from sclerosing rhabdomyosarcoma by the characteristic histologic features (i.e. malignant osteoid formation, etc…) and the immunohistochemical profile (i.e. myogenin/myoD1 expression in rhabdomyosarcoma)

Pleomorphic Rhabdomyosarcoma	High Grade Pleomorphic Sarcoma (MFH)
Myogenin and/or MyoD1 positive	Myogenin and MyoD1 negative
Desmin positive	Desmin reactivity infrequent

Both may have pleomorphic cells with abundant eosinophilic cytoplasm and cross striations are not typically seen in either

Pleomorphic Rhabdomyosarcoma	Embryonal Rhabdomyosarcoma with Numerous Round Differentiated Myoblasts
Rare in children, peak incidence in 5th decade	Most occur in children, typically children < 10 years of age
Lacks uniform background of immature cells	Has uniform background of immature cells
Nuclei of large cells are very pleomorphic	Nuclei of large cells typically uniform

Staging and Clinical Risk Groups

Clinical Risk Groups classify patients into low, intermediate and high risk groups based on:

• Histologic type
• Site
• Size
• Pathologic TNM (see below)

Pathologic Staging is performed using the Pretreatment TNM Staging System established by the Intergroup Rhabdomyosarcoma Study Group (Note: this is not the TNM system described in the AJCC Cancer Staging Manual).

Clinical Staging is performed using the Intergroup Rhabdomyosarcoma Pretreatment Clinical Staging System based on Pathologic TNM (above), Site and Size:

Clinical Group is determined using the Intergroup Rhabdomyosarcoma Clinical Grouping System based on extent of disease:

Clinical Risk Group is determined using the Children's Oncology Group Stratification for Rhabdomyosarcoma based on the above determined group and stage:

:

Pathology Report

Pathology Report should include:
Histologic subtype
Presence or absence of anaplasia (focal or diffuse)
Size of tumor
Location of tumor
Margin status
Translocation status, if known
Modified pathologic TNM, see Staging for the Intergroup Rhabdomyosarcoma Study Group scheme (Note: this is not the TNM system described in the AJCC Cancer Staging Manual)

Clinical

• See Grading for determination of prognostic groups
• Incidence:  The most common soft tissue sarcoma of childhood; up to 10% of all childhood malignancies
  • Distribution by subtypes in children
    • Embryonal 68%, alveolar 31%, others rare
  • Different distribution in adults
    • Pleomorphic 43%, embryonal 34%, alveolar 23%
• Usually presents as a painless mass
  • May be symptomatic depending on organ of involvement (i.e. bladder - urinary dysfunction, orbit - diplopia, etc.)
• 34% present with localized disease (5-year survival rate >80%)
• 30% present with distant metastases (5-year survival rate 33%)
• Effect of anaplasia on 5-year overall survival:
  • No anaplasia – 68%
  • Focal anaplasia – 60%
  • Diffuse anaplasia – 45%

Classification / Lists

Small round blue cell tumors

• Cellular myxoid liposarcoma
• Desmoplastic small cell tumor
• Melanotic neuroectodermal tumor of infancy
• Mesenchymal chondrosarcoma
• Nephroblastoma
• Neuroblastoma
• Peripheral primitive neuroectodermal tumor
• Poorly differentiated synovial sarcoma
• Precursor B lymphoblastic leukemia / lymphoma
• Precursor T lymphoblastic leukemia / lymphoma
• Rhabdomyosarcoma
• Small cell osteosarcoma

Bibliography

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