Rhabdomyosarcoma

 

Epidemiology:

    • Largest category of soft tissue sarcomas in children and adolescents
    • Embryonal rhabdomyosarcomas are the most common subtype
      • Children < 10y mostly
        • majority < 5y
        • may occur in adults
      • whites highest incidence
    • alveolar rhabdomyosarcomas:
      • adolescents and young adults; all ages may be affected
      • 21% of rhabdomyosarcomas
    • pleomorphic rhabdomyosarcoma:
      • adults (almost exclusively)
      • M > F

 

Common sites:

    • embryonal:
      • head and neck (47%)
        1. soft tissues of orbit and eyelid
        2. oropharynx
        3. parotid
        4. audiotory canal
        5. middle ear
        6. pterygoid fossa
        7. nasopharynx
        8. nasal passages
        9. paranasal sinuses
        10. tongue
        11. cheek
      • GU system (28%)
        1. bladder
        2. prostate
        3. paratesticular soft tissues
      • Skeletal musculature of the extremities (<9%)
      • Other locations include biliary tract, retroperitoneum, pelvis, perineum, abdomen, visceral organs (liver, kidney, heart, lungs), skin
      • spindle cell:
        1. scrotal soft tissues
        2. head and neck
      • botryoid:
        1. by definition must arise beneath a mucosal epithelial surface
        2. urinary bladder
        3. biliary tract
        4. pharynx
        5. conjunctiva
        6. auditory canal
    • alveolar:
      • extremities
      • paraspinal
      • perineal
      • paranasal sinuses
    • pleomorphic:
      • deep soft tissues o flower extremities usually

 

Gross features:

    • embryonal:
      • poorly circumsbribed mass
      • fleshy
      • pale tan
    • spindle cell:
      • firm, fibrous
      • tan-yellow
      • whorled cut surface
    • botryoid lesions:
      • cluster of variably sized polyploid sessile or pedunculated tumour nodules within hollow viscera
    • alveolar:
      • infiltrative
      • fleshy
      • grey tan
      • variable amounts of fibrous tissue
      • high stage at presentation
      • disseminated (rare)
    • pleomorphic:
      • large (5-15cm)
      • well circumscribed
        1. surrounded by a pseudocapsule often
      • whitish firm cut surface
      • necrotic and hemorrhagic foci often

 

Histologic features:

    • embryonal rhabdomyosarcoma:
      • cells histologically identical to developing striated muscle in various stages of myogenesis (rhabdomyoblasts)
        • most primitive:
          1. stellate cells
          2. lightly amphophilic cytoplasm
          3. central, oval nuclei
        • differentiating:
          1. eosinophilic cytoplasm
          2. elongated shapes
            1. “tadpole”, “strap”, “spider” cells
        • terminally differentiated:
          1. brightly eosinophilic cytoplasm
          2. cytoplasmic cross-striations
          3. multinucleation
          4. myotube forms
          5. these cells predominate following chemotherapy
      • architecture similar to embryonic muscle:
        • alternating areas of dense cellularity and loose myxoid tissues
        • proportions of each varies
      • spindle cell variant:
        • densely arrayed whorls or fascicles of spindle cells
          1. may have storiform or wavy architecture
        • often resemble smooth muscle cells
          1. blunted central nuclei
          2. tapered ended cytoplasm
        • cross striations may be present and/or bright eosinophilia
      • botryoid variant:
        • linear aggregates of tumour cellstightly abutting the epithelial surface (cambium layer)
        • polypoid nodules often with an abundant loose myxoid stroma
      • anaplastic variant:
        • enlarged, atypical cells
        • hyperchromatic nuclei
        • may be focal (single, dispersed cells) or diffuse (clone-like clusters of anaplastic cells present)
        • may be seen as part of embryonal (more commonly) or alveolar rhabdomyosarcoma
    • alveolar:
      • round cell cytological features reminiscent of lymphoma
      • primitive myoblastic differentiation
      • 3 major histological subtypes:
        • typical:
          1. discrete nests separated by fibrovascular septa
          2. nests show central clusters of cells with loss of cohesion at the periphery
          3. picket fence alignment of cells along the septa
          4. mixture of undifferentiated cells and rhabdomyoblasts
          5. giant cells with rhabdomyoblastic differentiation are common
          6. may see:
            1. clear cell morphology
        • solid:
          1. lacking fibrovascular stroma
          2. sheets of round cells
          3. variable rhabdomyoblastic differentiation (often little)
          4. cytologic features same as in typical subtype
        • mixed embryonal and alveolar:
          1. foci with embryonal histology
            1. myxoid stroma
            2. spindle cell myoblasts
          2. areas with alveolar histology (usually typical histology)
    • pleomrophic:
      • pleomorphic cytologically
      • undifferentiated round to spindle cells
      • admixture of polygonal, spindle/tadpole/racquet-like contoured cells
        • densely eosinophilic cytoplasm
        • cross-striations are rare
      • at least one skeletal muscle-specific immuno marker required for diagnosis

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Vimentin

High

 

MyoD1 (nuclear staining)

High

High

Myogenin (nuclear?)

High

High

 MYF-4

(nuclear)

 

High

“only rhabdo”

Desmin

 

Poor

MSA

 

Not specific

Myoglobin (differentiated cells)

 

 

Myosin (differentiated cells)

 

 

Creatine kinase M (differentiated cells)

 

 

NSE

30%

 

CK

Occasional

 

S100

Occasional

 

Neurofilaments

Occasional

 

CD20

Occasional

 

Immunoglobulins

Occasional

 

 

Molecular features:

    • embryonal:
      • loss of 11p15 (most)
      • complex structural and numerical chromosomal changes
      • extra copies of chromosomes 2, 8, 13
      • rearrangements of 1p11-q11 and 12q13 regions in a fraction of cases
    • alveolar:
      • t(2;13)(q35;q14) (majority)
        1. t(1;13)(p36;q14) (smaller subset)
        2. cause juxtaposition of the PAX3 (chr2) / PAX7 (chr1) genes with the FKHR gene (chr13)
          1. PAX3/FKHR or PAX7/FKHR fusion proteins
            1. potent transcriptional activators
            2. high levels of these chimeric proteins in the nucleus
      • amplifications:
        1. PAX7/FKHR fusion gene (majority of cases with the 1;13 translocation
        2. 12q13-15 (30%)
          1. candidate oncogenes – GLI, CDK4, MDM2
        3. 2p24 (30%)
          1. candidate oncogene – MYCN – also amplified in several other tumours (neuroblastoma)
        4. others less frequent:
          1. 13q31
          2. 2q34-qter
          3. 15q24-26
          4. qp36
    • pleomorphic:
      • highly complex karyotypes
      • no characteristic translocations

 

Other features:

    • EM:
      • Characteristics of developing striated muscle:
        1. bundles of 5 and 15nm thick and thin filaments punctuated by abortive Z-bands
        2. myosin-ribosome complexes – parallel arrays of 15nm filaments and ribosomes (earliest diagnostic stage)
      • pleomorphic:
        1. rudimentary sarcomere formation is key criterion
    • embyronal rhabdomyosarcoma encompasses spindle cell, botryoid, and anaplastic variants
    • prognostic features:
      • younger – better
      • embryonal – better
      • alveolar – worse, more aggressive
      • mixed – same as alveolar
      • spindle cell – better
      • botryoid – better
      • pleomorphic - poor
      • histologic subtype in adults not prognostic
    • Beckwith-Wiedemann syndrome
      • Inherited alterations of 11p15 region
      • Increased risk of several cancers including embryonal rhabdomyosarcoma

 

References:

    • WHO Tumours of Soft Tissue and Bone (2002)