Rhabdomyosarcoma

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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
  • Unusual locations

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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