Rhabdomyosarcomas are embryonal (most common in young children), alveolar (most common in adolescents), or pleomorphic (most common in adults), which are associated with a worse prognosis in that order also.
The most common group, representing about 70% of rhabdomyosarcomas. About 50% of these tumours arise in children under the age of 5 and only 15% in those over 12. The incidence is 4.6 per million children per year. Botryoid, anaplastic and spindle cell rhabdomyosarcomas are included in this grouping. They are overall more common in males.
The second most common group, representing about 15-20% of rhabdomyosarcomas. Sex ratio is equal. Alveolar rhabdomyosarcomas are more common in older children; the median age of diagnosis is 9.
Pleomorphic rhabdomyosarcoma almost always occurs in adults and represents the smallest group of rhabdomyosarcomas. Age is usually over 60.
Aetiology and Pathogenesis
Most cases are sporadic. A small number may be related to a familial or germline mutations:
- Li Fraumeni syndrome, due to germline mutation of TP53, is associated with rhabdomyosarcoma in very young children under 3 years of age in a minority of cases and very rarely in older children.
- Neurofibromatosis is associated with a 20-fold increase in rates of rhabdomyosarcoma.
- Beckwith-Weidermann syndrome is an overgrowth syndrome due to mutation in the 11p15 chromosome. This region is associated with embryonal rhabdomyosarcoma.
- Costello syndrome which is a post-natal undergrowth syndrome and macrocephaly. It arises from germline mutation of KRAS or HRAS.
The less aggressive variants of embryonal rhabdomyosarcoma - namely botryoid and spindle cell - follow a more benign course. Botryoid only occurs in hollow viscera (bladder, pharynx, vagina). Spindle cell usually arises in the testis or head and neck.
The typical form of embryonal rhabdomyosarcoma usually arises in the head and neck (50%; about 1/4 orbital, 3/8 parameningeal, 3/8 elsewhere) and genitourinary system (30%); other sites are less common and the limbs account for < 10%. It follows an intermediate course (66% 5 year survival). Lymph node metastases are common in genitourinary sites.
Alveolar rhabdomyosarcoma more commonly arises in the limbs and follows an aggressive course. They also commonly arise in the paranasal sinuses and perineum, but other sites are uncommon.
Pleomorphic rhabdomyosarcoma is uncommon and usually follows a similar course to other pleomorphic sarcomas. The usually arise in the lower limbs.
Presentation is dependent on the site of disesase:
- Orbital rhabdomyosarcoma presents with exophthalmos and loss of vision
- Parameningeal rhabdomyosarcomas can present with CNS symptoms due to invasion of the cranium
- Upper aerodigestive tract tumours present with swallowing or breathing difficulties
- Genitourinary and gastrointestinal tumours present with a mass or with bleeding/obstructive symptoms
- Extremity tumours present with an enlarging mass that may be painful
The differential diagnosis for rhabdomyosarcoma of the orbit includes haemangioma (proliferation of endothelial cells), lymphovascular malformations and infantile fibromatosis.
Tumours have poorly defined borders, are tan in colour and have a fleshy appearance.
Spindle cell rhabdomyosarcoma forms a tan, whorled well defined mass.
Botryoid rhbadomyosarcoma is a mucosal lesion that forms small sessile nodules that protrude from the surface.
Embryonal rhabdomyosarcoma resembles developing skeletal muscle in the embryo. This ranges from rhabdomyoblasts (small cells with an oval eccentric nucleus and eosinophilic cytoplasm) to more differentiated 'tadpole' cells which are elongated and may become multinucleated. Treatment with chemotherapy may induce terminal differentiation.
The spindle cell variant consists of spindle cells arranged in fascicles. It may resemble other spindle cell tumours but cross striations may be present in the cytoplasm, which also tends to stain more intensely.
Botryoid rhabdomyosarcoma has the same appearance as typical embryonal rhabdomyosarcoma but the cells closely approximate the overlying epithelium. This appearance is called the cambium layer.
Immunohistochemistry is variable depending on the differentiation of cells. Rhabdomyoblasts may only stain positively for vimentin; more differentiated cells begin staining for desmin and muscle specific actin. MyoD1 and myogenin are highly specific markers and usually are taken up by most cells.
As mentioned above, abnormalities in the region of chromosome 11p15 are common, often involving IGF2 and CDKN1C. There are other complex rearrangements. Specific translocations are not seen as in alveolar rhabdomyosarcoma.
Tumours are large, fleshy and tan to grey in colour.
Alveolar rhabdomyosarcoma is a small round blue cell tumour. It arises in three common forms:
- Typical, with nests of small round blue cells separated by a fibrovascular stroma
- Solid, with sheets of small round blue cells with some differentiated cells present
- Mixed, which contains areas of spindle cell myoblasts that resemble embryonal rhabdomyosarcoma
Staining is similar to embryonal rhabdomyosarcoma (vimentin, MyoD1 and myogenin)
Alveolar rhabdomyosarcomas usually carry one of two common translocations involving the FKHR gene on chromosome 13. These translocations (of PAX3 or PAX7 on chromosomes 2 and 1) lead to a chimeric transcription factor.
These tumours more closely resemble other pleomorphic sarcomas. They often have a pseudocapsule and a haemorrhagic, necrotic and white cut surface. Microscopically they contain anaplastic spindle cells together with polygonal rhabdomyoblast-like cells. Cross striations are rare. Immunohistochemistry stains positively for rhabdomyosarcoma markers to some degree. Complex genetic changes are usually present.