II - RHABDOMYOSARCOMA

Clinical features

  • It accounts for around  50% of all childhood soft-tissue sarcomas
  • 1/3 of the cases are diagnosed in the first 3 years of life
  • Can be congenital
  • Most arise from skeletal muscle, although they may also arise in viscera
  • Those arising from skeletal muscle are particularly associated with genetic fusions
  • About 65% are diagnosed in children (50% occur in the first decade)
  • Slight male predominance
  • Rare familial forms are reported in association with Li-Fraumeni, basal cell nevus syndrome, pleuropulmonary blastoma, Beckwith-Wiedemann syndrome and neurofibromatosis
  • Association with congenital anomalies of the central nervous system, genitourinary tract, gastrointestinal tract and cardiovascular system
  • Association with low economic background
  • Bimodal age distribution: peak at 3 - 5 years; and at 16 -17 years
  • 95% of the cases in children belong to the alveolar or embryonal subtype
  • Clustering of the primary tumour site, age and morphology (embryonal/alveolar) is a distinctive feature:
    • Embryonal
      • In infants (may be congenital)
      • Mainly located in the orbit or perineum
      • Head and neck, nasopharynx and genitourinary  tract
      • Rarely spreads to regional lymph nodes
    • Alveolar
      • In adolescence
      • The most aggressive subtype
      • Extremities, perineal and periorbital regions
      •  Uncommon presentation: leukaemia-like
      • Metastasis to regional lymph nodes and along fascial planes
  • Symptoms depend on the localization

 

Fig 13a – Alveolar rhabdomyosarcoma - Cellular smears with a  background with apoptotic bodies and loosely cohesive aggregates of uniform, small round blue cells (H&E). 
Fig 13b- In some cells nuclei are eccentric giving a rhabdoid appearance. (H&E)
Fig 13c-Alveolar rhabdomyosarcoma-Neoplastic cells have nuclei with fine chromatin and inconspicuous nucleoli (H&E); in Giemsa stains 
Fig 13d- cytoplasm has small glycogen blebs and cells lie in a tigroid background.

 

Fig 14a– Alveolar rhabdomyosarcoma – Giemsa- remark the typical tigroid background
Fig 14 b; c– Rhabdomyosarcoma, NOS– A “tadpole” shaped cells can be seen in both images (H&E)
Fig 14 b; c– Rhabdomyosarcoma, NOS– A “tadpole” shaped cells can be seen in both images (H&E)
Fig 15 – Embryonal rhabdomyosarcoma – Strands of primitive rhabdomyoblasts with little or no differentiation. Cells with ovoid to spindle nuclei and scant cytoplasm (Giemsa)

 

Fig 16 a- Embryonal rhabdomyosarcoma- Nuclei can have pseudo inclusions (H&E)
Fig 16 b, occasional multinucleated (Strap cells) can be seen (H&E) and are very helpful in differentiating from other small round cell tumors.
Fig 17 - embryonal rhabdomyosarcoma –Myxoid matrix (more frequent in embryonal rhabdomyosarcoma)

 

 

  • Embryonal (ERMS)
    • Clusters or isolated cells
    • Myxoid stroma and “tigroid” background in 20% of the cases (Giemsa staining)
    • Lymphoglandular-like bodies present in 20%
    • More cellular variation: whole range from primitive mesenchymal cells (fusiform or stellate cells) to highly differentiated rhabdomyoblasts
    • Binucleated or multinucleated tumour cells (strap cells) provide an important clue for differential diagnosis with other entities
    • Presence of “tadpole” or “racket cells” and ribbon-like cells
    • Nuclei with finely granular chromatin
    • Cytoplasmic glycogen vacuoles
  • Alveolar  (ARMS)
    • Cellular smears
    • Background with apoptotic bodies can simulate a Burkitt cell lymphoma
    • Tigroid background
    • Loosely cohesive aggregates of uniform, small round blue cells
    • Fine chromatin
    • Multinucleated neoplastic giant cells with eosinophilic cytoplasm
    • Inconspicuous nucleoli (occasionally can be prominent)
    • Vacuoles of glycogen in the cytoplasm
    • In some cells, a rhabdoid phenotype can be seen

 

  • Although these two main subtypes of rhabdomyosarcoma show some differences in cytomorphology, most authors do not rely on cytology alone, to make the differential diagnosis
  • Cytogenetic and molecular techniques together may be of great help; confirmation by means of histology is sometimes required

 

Immunocytochemistry

  • Alpha-actin: positive
  • Desmin: positive
  • Myosin: positive
  • Myoglobin: positive
  • Myogenin: positive (more sensitive than Myo-D1 on formalin-fixed material); strong and diffuse  nuclear expression mainly in alveolar type and correlated with poor prognosis
  • MyoD1: positive - (more sensitive than myogenin in frozen material). Together with myogenin these are the more sensitive and specific markers of skeletal muscle
  • HHF35: positive
  • CD56 (N-CAM): positive , sometimes strongly positive (11,12)
  • “Aberrant” staining: NSE, synaptophysin, Leu7, cytokeratin, neurofilaments, S-100 protein and CD99
  • WT1: Positive (only cytoplasm)

 

Genetic studies

  • Alveolar subtype has two main characteristic translocations:
    • t (2; 13) (q35; q14) in 70% of the cases
    •  t(1;13)(p36;q14) in 10-20% of the cases
      • Associated with:
        •  younger patients
        • better prognosis
        • involvement of extremities
    • In 30% of the cases no translocation is found by RT_PCR
    • Solid variants are more likely to be PAX/FKHR negative
    • Fusion negative RMS behave similarly to ERMS
  • Embryonal subtype :
    •  Loss of heterozygosity (LOH) at the 11p15 locus of the IGF II gene
    • 1p deletion
  • Both subtypes of rhabdomyosarcoma have over expression of the IGF II gene

 

Differential diagnosis

  • Peripheral neuroectodermal tumours (PNET)
    • Tigroid background
    • Synaptophysin: positive
    • Chromogranin: positive
    • NSE: positive
    • Desmin: positive (occasional)
    • Myogenin or actin: negative
    • t(11;22)(q24;q12)
  • Desmoplastic small cell tumour
    • Usually intra-abdominal
    • Nuclei with granular chromatin
    • Higher C/N ratio
    • Prominent desmoplastic stroma
    • Divergent differentiation
    • Myo-D1-negative
    • Myogenin: negative
    • WT1- nuclear positivity
  • Neuroblastoma
    • Usually secrete catecholamine’s
    • Neuroblasts generally at different stages of differentiation
    • Typical neuroendocrine chromatin (“salt-and-pepper”)
    • Neuropil frequently present
    • Rosettes frequently present
    • CD56 N-CAM: positive
    • Vimentin: negative
    • Synaptophysin: positive
    • Muscle markers: negative
  • Lymphoma
    • Lymphoglandular bodies (Giemsa stain)
    • Single cells
    • CD45: positive
    • Muscle markers: negative
  • Rhabdoid tumour
    • Lack of strap-shaped and ribbon-like cells
    • More monotonous population with rhabdoid features
    • Pale nuclei with vesicular chromatin
    • INI1 : negative

 

Main points

  • Overall five-year survival: 50%-75%
  • Prognosis depends on:
    • Age at diagnosis; best survival is found when diagnosed between one and eight years of age
    • Tumour site: two-year disease-free survival in orbital region is 77%, versus 24% for intrathoracic tumours
    • Stage
    • International prognostic classification of paediatric rhabdomyosarcoma
      • Superior prognosis
        • Botryoid
        • Spindle
      • Intermediate prognosis
        • Embryonal
      • Poor prognosis
        • Alveolar
        • RMS with diffuse anaplasia
        • Undifferentiated sarcoma
      • Uncertain prognosis
        • Rhabdoid features
  • t (1; 13) (q36; q14)
    •  associated with younger patients
    • and tumours in the extremities
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