Rhabdomyosarcoma

DEFINITION AND PATHOGENESIS

Juvenile types
- Embryonal rhabdomyosarcoma (70-80%): mainly affects children < 15 years of age occurring in the head and neck, GU tract, retroperitoneum and extremities
- (Botryoid type: a variant of the embryonal type characterized by a grapelike growth pattern not occurring in the extremities, but in hollow visceral organs)
- Alveolar rhabdomyosarcoma (10-20%): usually occurs between ages 10-25, responsible for a second incidence peak
- Occurs with greater incidence in the extremities
Adult type
- Pleomorphic rhabdomyosarcoma: peak incidence >45 years of age, occurring most commonly in the thigh
- Pretreatment staging system
  - Stage Site* Invasiveness Size Nodes Metastases
  - 1 favorable T1 or T2 a or b N0, N1 M0
  - 2 unfavorable T1 or T2 a (<5cm) N0 M0
  - 3 unfavorable T1 or T2 b (>5cm) N0, N1 M0
  - 4 any site T1 or T2 a or b N0, N1 M1
    * all extremity sites unfavorable
- Intergroup Rhabdomyosarcoma Study Clinical groups
- I Localized, complete resection, no LNs
  - a) confined to nuscle/organ or origin
  - b) tumor infiltration beyond muscle/organ of origin
- II Localized/regional disease, complete macroscopic resection
  - a) resection with microscopic margin, no LNs
  - b) complete resection of tumor and LNs
  - c) tumor and LNs resected with microscopic margins
- III < wide resection with macroscopic residual
- IV Distant metastases at dx

IMPORTANCE

The most common soft tissue sarcoma of children, addolescents, and young adults, although only 14.6% occur in the extremities
Accounts for 4-8% of all pediatric malignancies
- 20% involve the extremities

CLINICAL FEATURES

Rare >45 years of age (except pleomorphic type which occurs 40-80 yrs of age)
May present at birth
M:F = 1.5:1
Discovery frequently associated with a traumatic episode (falsely diagnosed as a hematoma or benign tumor)
Most are deep-seated intramuscular masses
Often asymptomatic
Alveolar subtype reported in a neonate with Beckwith-Wiedemann Syndrome with multiple nodular and vesicular lesions on the face, limbs, and abdomen, resembling "blueberry muffin baby"
Head/neck locations
- Lower eyelid location reported in a 3-month-old
Unusual locations
- Larynx

RADIOLOGIC FEATURES

Erosion of bone in hand or foot lesions
MRI: deep-seated intramuscular mass

GROSS PATHOLOGY

Poorly defined, infiltrating into surrounding structures in extremity lesions
Firm, rubbery, and grayish-white in appearance ± necrosis or cystic degeneration

HISTOLOGIC AND MOLECULAR FEATURES

Rhabdomyoblasts have eosinophilic cytoplasm that is filamentous and granular ± transverse striations, contractile elements
Alveolar types: embryonal types = 4:3
Embryonal types (46-60%)
- Poorly-differentiated to well-differentiated looking like fetal muscle tissue with variation in cellularity denseness and alternating cellular and myxoid areas
- Scant interstitial collagen
- Elongated and rounded rhabdomyoblasts with hyperchromatic nuclei, eosinophilic cytoplasm, and fibrillary material around the nucleus ± cross striations (50-60%)
- + PAS ± diastase for intracellular glycogen in well-differentiated tumors("spider-web" cells are rhabdomyoblasts with glycogen washed out by the fixative and strands extending to the cellular periphery)
- Iron hematoxylin, PTAH, Masson trichrome shows cross striations
- "Broken-straw" sign = angulation of narrow, ribbon-shaped muscle fibers
Alveolar types (20-41%)(50% of extremity locations)
- Aggregates of tumor cells with "alveolar" spaces separated by loose fibrous septa are typical but areas may be solid cells, especially at the periphery of a tumor
- Rounded nuclei and indistinct cytoplasm
- Rhabdomyoblasts in only 30% ± cross striations (20-30%)
- Multinucleated giant cells are prominant
- Entrapment of normal muscle tissue
Pleomorphic types (~13%)(adult-type)
- Difficult to distinguish from other pleomorphic sarcomas (eg, MFH)
- Rarely with cross striations
Undifferentiated (15-20%)
Botryoid
Spindle cell
Rhabdomyosarcoma with rhabdoid features
Immunohistochemistry and special stains
- Desmin and myoglobin (beware of false + in entrapped normal muscle)
- + PAS for glycogen
- Myogenic transcriptional regulatory proteins
- + myogenin
- + MyoD1
Cytogenetics
- Li-Fraumeni syndrome associated with rhabdomyosarcoma
- Reported in Noonan syndrome due to a SOS1 mutation
- Metastatic alveolar rhabdomyosarcoma reported in Multiple Endocrine Neoplasia Type 2A
- Expression of MyoD1 geneLoss of 11p15 heterozygosity in embryonal subtype
- Translocation t(2;13) or t(1;13) with fusion gene Pax 3-FKHR or Pax 7-FKHR fusion genes respectively in alveolar subtype
EM
- Variable appearance resembling stages of embryonal muscle tissue development
- Myofilaments and polyribosomes
- Golgi apparatus is prominent

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

Poorly differentiated round or spindle cell sarcomas
Neuroblastoma
Neuroepithelioma
Ewing’s sarcoma
PNET
Poorly differentiated angiosarcoma
Synovial sarcoma
Malignant melanoma
Granulocytic sarcoma
Lymphoma
Small cell carcinoma
Benign lesions
- Granular cell tumor

DISEASE COURSE AND TREATMENT

Alveolar subtype with more aggressive clinical behavior/worse outcome than embryonal subtype
Chemotx + wide resection + chemotherapy ± XRT after careful staging
- Dictated by Intergroup Rhabdomyosarcoma Study (IRS) protocols
Aggressive regional LN sampling, if +, further proximial node evaluation
Response to chemotx overall is good; "second look" surgeries have been advocated
- Vincristine, actinomycin-D, cyclophosphamide, ± adriamycin, ifosfamide
- De novo multiple drug resistance has been reported
Metastases
- Lung (67% when metastases are present)
- LNs(depends on location and type--alveolar > embryonal)
- Bone marrow (aspirate as part of staging work-up)
- Heart
- Brain
- Abdominal organs
Prognosis depends on stage at time of diagnosis with up to 83% 5 year survival with localized disease and with histological type (alveolar type has a worse prognosis), and with ability to gain a wide margin and complete resection
Unresectable lesions will have <10% long term survivors
Embryonal histologic subtype has the most favorable prognosis
More distally located tumors generally have a better prognosis
Extemity lesions have a worse prognosis than orbital or GU lesions
12% 5-yr risk of regional failure
- Poor prognostic indicators
  - Female gender
  - LN involvement at dx

SPECIAL CONSIDERATION

A

- y
A

- A

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