II - RHABDOMYOSARCOMA - Eurocytology

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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 14a– Alveolar rhabdomyosarcoma – Giemsa- remark the typical tigroid background

Fig 16 a- Embryonal rhabdomyosarcoma- Nuclei can have pseudo inclusions (H&E)

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