Rhabdomyosarcoma

General

  • Arises from embryonal mesenchyme with potential to differentiate into striated muscle, although not limited to the muscle.
  • 5-year OS has improved through the studies with Intergroup Rhabdomyosarcoma Studies (IRS) I at 56%, II 63% and 71% for III.
  • STS make up 5-7% of all pediatric tumors (< 15 yrs), ½ are Rhabdomyosarcomas.
  • Peak incidence is 2-5 years.
  • 70% occur before 10 years
  • male: female is 1.4:1
  • Seen in Li Fraumeni (p53 germline mutation), neurofibromatosis type 1 and Beckwith-Wiedemann syndrome (gigantism, glossitis
  • Large percentage (actually higher than that found in Wilms) have congenital anomalies in GI, GU, CVS and CNS
  • N-myc and C-myc can be used to differentiate alveolar RMS (+ for C-myc and N-myc) from Embryonal (where – for C-myc and N-myc), if (+) for N-myc (which occurs 50% of time) will lead to fatal outcome.
  • Embryonal tumors demonstrate n-ras or k-ras mutations 35% of time.

Presentation

Incidence at Presentation (from compilation of IRS I, II and III)

Site Incidence
Head and Neck 35%
--parameningeal 16%
--other H&N 10%
--orbit 9%
trunk 10%
extremities 18%
urinary bladder and vagina 22%
retroperitonium 5%
Site Nodal incidence
H/N 5-8%
GU and extremities 10 to 40%
All sites 14%

DM to lungs, bone, BM, brain

Age Anatomic site clusters Histologic Type
Infants bladder/vagina embronal or botryoid
Younger children head and neck/GU embryonal
Older Children Trunk/ extremity alveolar or undifferentiated
  • botryoid appears grape-like and commonly found in concavity organs (bladder vagina)

Diagnosis

  • H/P
  • Radiological: CT or MRI scan of affected area, Bone scan, CT of chest
  • Biopsy of the lesion and BMA and biopsy
  • Labs: CBC and LFT and CHEM 20
  • If parameningial tumors, then CSF needs to be attained and MRI of the spine (if symptoms are present).
  • Antibody to protein Myo D is used demonstrate skeletal muscle differentiation (aka RMS)

Pathology

  • Embryonal RMS: Loss of heterozygosity at 11p15.5
  • Alveolar RMS: Cytogenetics: t (2:13)(p35: q14) or t (1:13) (p36: q14) seen in 70% of patients with alveolar RMS which results in the fusion of the transcriptional regulator (PAX 3 or 7) to a transcription factor FKHR inducing cell proliferation via transcription deregulation

Tissue obtained > look for myogenesis if (+) -> alveolar features -> if (+) then alveolar RMS otherwise Embryonal (?Botryoid)
If (-) -
> Ewings features —-> if (+) then neural features to diff PNET from EOE
If (-) then it\’s an undifferentiated sarcoma

Pathology Incidence from IRS I,II, and III
Embryonal 53%
Alveolar 21%
Undifferentiated 8%
Botryoid 6%
Pleomorphic 1%
  • All tumors are considered high grade.
  • Embryonal: intermediate prognosis and the variant botyoid has a good prognosis; racquet or tadpole shaped cells; responds well to chemotherapy; typically H/N and GU sites.
  • Alveolar: poor prognosis; round cells with trabeculae; responds poorly to chemotherapy; typically extremities and perineum
  • Undifferentiated
  • Sarcoma NOS
  • Pleomorphic: rare in children

IRS Staging

Group I complete resection
Group II microscopic residual or nodal+
Group III gross residual (> 50% of disease)
Group IV metastatic: liver, lung, bone marrow, distant muscle, CSF+, pleural of abdominal fluid+, peritoneal or pleural implants.

Post –OP Group Stage Incidence from IRS I, II, and III
I 16%
II 20%
III 48%
IV 16%

Pre-treatment staging for IRS-IV (developed by SIOP)

Stage Site T Size Node Met
I F all all N0 M0
II U all ≤5cm N0 M0
III U all >5m any M0
IV all all all all M1

F: favorable site H&N (not paramenigeal), GU (not prostate or bladder)

Prognostic Variables

  • Clinical group
Group Stage Post-op from IRS III Pre-op from IRS III
I 93% 89%
II 81% 86%
III 73% 69%
IV 30% 30%
  • Primary site relates to resectability (ie invasiveness) and incidence of LN metastases (more common in GU, Abdominal/pelvis and extremity)
  • Tumor size (5cm)
  • Lymphatic spread (uncommon in H&N)
  • Histology

International Classification of Rhabdomyosarcoma

Prognosis Frequency 5 year actuarial survival
Superior
Botryoid
Spindle Cell
6%
3%
95%
88%
Intermediate
Embryonal
79% 66%
Poor
Alveolar
Undifferentiated
32%
1%
54%
40%

Paratesticular is usually spindle cell
GU is usually botryoid or embryonal

  • Age: younger do better except < 1 with alveolar(almost all adults DOD).
  • Lymphocyte count
  • Sex

Risk Grouping (% for OS-5)
Clinical Group
("post-op") I II III IV
Embryonal (F) Low Risk (88%)
Embryonal (U) High Risk (<30%)
Alveolar Intermediate Risk (55-76%)
F: favorable site H&N (not paramenigeal), GU (not prostate or bladder)
U: unfavorable sites includes all others

Treatment

Historically aggressive surgery and radiation without chemo are curative in 25% of patients
Higher for orbital and GU (bladder) primaries
Chemotherapy alone leads to high local failure rates

  • According to IRS Post-op Groups:
  • Group I: radical or wide excision followed by

chemotherapy – intensive VA
Add RT for alveolar histology (41.4 Gy in 23 fx at 180 cGy/fx.)

  • Group II: marginal resections done and then

Chemotherapy – intensive VA
All get RT (41.4 Gy in 23 fx at 180 cGy/fraction.

  • MSK, St. Jude\’s say its okay less than 40Gy.
  • IRS V try to go to 36Gy for favorable histology (embryonal) and sites (orbit, GU, testicular)
  • Group III: Gross residual/unresectable

Chemotherapy up front – VCR, AMD, CYT (no benefit to ADR)
All get RT, start in week 9 (50.4 Gy in 28 fx at 180 cGy/fraction, 3-5 cm on tumor)
Resect if expendable bone?
If signs of intracranial extension (+CSF, + CN, BOS erosion) then start with CSI RT (30 Gy/20 fx at 150 cGy/d CSI) then take tumor to 50.4 Gy. Use chemo concurrently.

  • St. Jude\’s data gave chemotherapy for III and IV and based on response stratified patients. Those with a CR for 39-42Gy at 1.8Gy/day and 1.1 BID to 49.4-63.8Gy for GR. If have CR then LC was 100% and if GR then 75%.
  • ** IV** compared standard 5040 versus BID to 5960 and found no difference between 2 groups.

Timing of Radiation

  • RT should be started early for (+) CSF, spinal cord compression, intracranial metastases, enlarged cranial foramina, CN palsies or base of skull invasion; otherwise RT should start at 9 weeks (after 2nd cycle of chemotherapy).
  • Actinomycin should not be delivered concurrently with RT.

Treatment of Specific Sites

Bladder

  • >90 % are embryonal (1/3 are botryoid)
  • 20% with (+) regional LN most commonly (hypogastric and external iliacs)
  • tumorectomy/conservative surgery followed by CMT/RT with excellent cure rates although 1/3 require salvage exenteration (approximately 22-23% retain bladder from IRS I and II)
  • delay of RT > 4 months was a poor prognostic factor for local control
  • IRS-III had 60% rate of retaining bladder with 90% survival using neoadjuvant chemo with RT started at 6 weeks.
  • Site of disease important (ie dome usually resected at diagnosis compared to bladder neck or trigone).
  • Treated 4 fields versus 2 fields (if high energy photons are available).

Prostate

  • More locally invasive, larger and tend to disseminate early than bladder primaries
  • Usually non-boytroid histology

Orbital

  • Local control 94% with RT
  • Survival depends on histology 94% for embryonal versus 74% for alveolar (5 year survival)
  • Usually eyelid and can involve the CNS
  • Treat with chemotherapy + RT to dose of 5040cGy

Paratesticular

  • Usually embryonal
  • 20-40% with ipsilateral nodal disease (follows spermatic cord to renal hilum to para-aortic LN) so recommend nodal dissection
  • 26% of patients from IRS I and II had (+) retroperitoneal LN and 16% had (+) ipsi inguinal LN
  • if transcrotal biopsy is perform rather than inguinal approach the pt is automatically put into group II and the hemiscrotum must be irradiated
  • OS is good approaching 90%

Vagina

  • 90% less than 5 yrs old & almost exclusively embryonal (usually botryoid)
  • 20% survive treated with exenteration alone; 25% survive treated with chemo alone.
  • Treat with neoadjuvant chemotherapy + surgery (avoid exenteration) +/- RT based on completeness of surgery (18/21 – 86% 3 yr survival with this technique)
  • Consider brachytherapy

Vulvar

  • Usually older (8 years old) & alveolar histology
  • Surgery: wide excision, usually hemivulvectomy, followed by chemotherapy +/- RT
  • External Beam Radiation Therapy
  • IRS IV standard
  • Group II 41.4 Gy and Group III 50.4 Gy
  • IRS V investigation
  • Subdivide Group II N0 to receive 36 Gy
  • Brachytherapy may be considered
  • Flamant ect. Report disease control and functional preservation in 15/17 patients with vaginal RMS using brachytherapy.

Extremity

  • Poor prognosis
  • Alveolar histology in ½ of cases, (+) LN in 10 to 15 % of patients, 27% incidence of DM at diagnosis

Retroperitoneal

  • have poor prognosis due to inability to deliver high enough dose of RT and 23% incidence of (+) LN

Trunk

  • poor prognosis with unfavorable histology and large tumors

Perineal

  • have poor prognosis with 56% incidence of alveolar histology.

Parameningeal

Sites

  • nasopharynx
  • nasal cavity
  • paranasal sinus
  • middle ear
  • mastoid
  • infratemporal fossa
  • pterygopalatine
  • and parapharyngeal areas.

Pathology

  • Embryonal to Alveolar 4:1 ratio

LN Risk

  • 41% of H&N sites, (+) LN at most 20%

Parameningeal RMS can extend intracranially

  • Tefft from IRS-1 showed 20 out of 57 patients with parameningeal tumors had meningeal dissemination.
  • produce neoplastic meninigitis (35%).
  • Meningeal extension is associated with high risk of CNS relapse and a 90% chance of death.
  • Risk factors for tumor access to subarachnoid area (1 RF led to 51% PFS vs. 0 RF with 81% PFS at 3 years)
    • Skull base erosion
    • CN palsy
    • Intracranial extension

RT Field and Dose and Timing

Local Field Only Most Cases

  • Treat tumor with 2 cm margin

Day 0 Treatment

  • CN palsy
  • Brain base bone erosion +/- intracranial extensino

CSI – 30 Gy/20 fx

  • CSF(+)
  • intracranial mets
  • spinal mets

WBRT

  • No need (IRS-V)

Chemotherapy: Treat all patients with chemotherapy.

  • IRS-I tested VAC versus VA in group II and "pulse" VAC plus Adria versus "pulse" VAC in groups III and IV
  • No benefit to addition of Cytoxan (II) or Adria (III or IV)
  • IRS-II demonstrated no benefit to pulse VAC versus cyclic VA in group II and no benefit to addition of Adria to pulse VAC for groups III and IV.
  • IRS-III demonstrated Cytoxan did not add any benefit to VA in favorable histology group I patients, group II paratesticular and group II and III orbit and head patients.

- Adria and Cis-platin improved survival in addition to VAC in unfavorable histology group I and II patients and group III special pelvic, orbit and head sites; No benefit to group IV.

  • For the favorable groups use intensive VA and for unfavorable use pulse VAC (VCR, AMD, and CYT).
  • No benefit of adding ADR.
  • If patient has CN palsies, +CSP, enlarged foramen, BOS erosion, spinal cord compression and intracranial extension then start chemotherapy with radiotherapy.
  • Without these factors then start the chemotherapy and at week 9 then give RT.

Radiation

  • Without chemo doses of 50 to 65 Gy achieve 90% local control in patients with microscopic residual
  • IRS-I randomized group I patients to receive post op RT vs. observation with no difference in survival (91% vs 83%)

** 40 to 60 Gy @ 1.5to 2 Gy/fx immediately post-op
** Local control was related to size (6 cm) and Age
** Local failure rate 32% with <40 Gy and 12% >40 Gy (for Age >6), although not seen when stratified by treatment group.
** Entire muscle bundle did not have to be treated and LN were only covered if involved.

  • IRS-II

** Local Failure increased with increasing group stage (10% for II, 20% for III and 41% for IV)
** Local failure worse with unfavorable histology (41% versus 13%)
** Local failure worse with larger tumors (>5 cm – 34% versus <5 cm – 23%)
** Fields used had 5 cm margin with doses based on Age and size of tumor

  • IRS-III randomized not only by group, but by histology

** Dose 41.4 Gy for group I and II, otherwise was dependant on size and age
** 41.4 Gy for age < 6 and size < 5 cm, 50.4 Gy if age > 6 and size >5 cm, otherwise use 45 Gy
** Group I unfavorable tumors received post-op RT

  • IRS-IV

** Evaluating hyperfractionation to limit normal tissue morbidity (59.4Gy @ 1.1 Gy BID vs 50.4 @ 1.8 qD)
** No difference found between the two regimens, although the hyperfractionated schedule was designed to show improved local control and not a difference in late tissue effects.

Long Term Toxicity

== Male and Female Fertility ==

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