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Rhabdomyosarcoma
- 2. Introduction Most common soft tissue sarcoma of childhood . 4.4 per 1 million whites & 1.3 per 1 million black. Male : female – 1.5: 1 . Bimodal peak seen- peak at 2-6 years & in adolescence. Majority <10 year at diagnosis 5% are < 1 year RMS arises from unsegmented ,undifferentiated mesoderm or myotome derived skeletal muscle .
- 3. Younger age has embryonal histology. Age is independent prognosis factor children <1 & > 10 year has inferior survival Adults with RMS has poor prognosis RMS most seen in children with LI fraumani syndrome & neurofifromatosis
- 4. Fig. (A) (B) In hematoxylin and eosin stain, there were many high nuclear/cytoplasmic ratio small blue round cells along connective tissue strands. (C) Muscle-specific Actin stain and (D) skeletal muscle specific MyoD1 stain were positive.
- 5. PATTERN OF SPREAD Locally invasive with spread along facia ,muscle, lymphatic and hematogenous . Risk of lymphatic spread 15%, rare in orbital tumors and 25% in children with paratesticular extremities , 50% in perineal and perianal tumors . Hematogenous metastases detected 15 %of patients mainly in truncal and extremity primary tumors . Hematogenous spread mostly lungs, bone marrow and bone .
- 6. Clinical presentation Asymptomatic mass ,symptoms are usually present as mass effect on associated organs and tissues . Orbit may cause proptosis, optalmoplegia. Parameningeal present with nasal aural or sinus obstruction ,crnial nerve palsy , headache. Genitourinary – hematuria , urinary obstruction or constipation . Trunk ,pelvis & abdomen- nerve root compression, palpable mass or adenopathy ,& perirectal pain.
- 8. Staging work up & follow up evaluation for patients with Rhabdomyosarcoma
- 9. Staging systems It reflects surgical procedure for patient and not reflect biology of disease and useful in guiding decisions for radiotherapy .
- 10. Three year failure free survival was – 86% for stage 1 tumors 80% for stage 2 tumors 68% for stage 3 tumors 25% for stage 4 tumors
- 11. International Classification of Rhabdomyosarcoma 1. Superior prognosis (both are variants of embryonal rhabdomyosarcoma) a. Botryoid b. Spindle cell 2. Intermediate prognosis a. Embryonal rhabdomyosarcoma 3. Poorer prognosis a. Alveolar rhabdomyosarcoma b. Undifferentiated sarcoma
- 12. WHO - four variants of rhabdomyosarcoma – Embryonal (65%) – Alveolar (25%) – Pleomorphic, and – Spindle cell/sclerosing rhabdomyosarcoma
- 13. EMBRYONAL Favourable clinical outcome Affect younger male patients Most commonly arise in the head, neck, and genitourinary regions Loss of heterozygosity at the imprinted 11p15 locus Loss of the maternal allele and duplication of the paternal allele Encodes the IGF-2 growth factor Share features with other embryonal neoplasms of childhood, such as Wilms tumours, hepatoblastomas, pancreatoblastomas, and neuroblastomas.
- 14. Zones of loose & dense cellularity Recapitulate normal embryonal myogenesis, in which loose primitive mesenchyme condenses to form nascent muscle exhibit all cellular phases of myogenesis dense condensations of rhabdomyoblast foci with a loose myxoid stroma. variable cell population consisting of small, round tumor cells with hyperchromatic nuclei and of large, polygonal-shaped tumor cells with abundant eosinophilic cytoplasm, which contains diagnostic cross striations (arrow) A B
- 15. ALVEOLAR 20% of RMS < 1 Yr --- >10 Yr ( Adolescents) Extremities, trunk, perianal, perineal more aggressive metastatic disease
- 16. Fibrous septa with loose clusters of rounded cells in center - alveolar pattern uniform cell population consisting of cells with a high nuclear-to- cytoplasmic ratio. The cells are arranged in variably sized nests separated by fibrous tissue septa. In places, the cells appear loosely dispersed, mimicking a pulmonary alveolar pattern A B
- 17. BOTRYOID TYPE Subtype of Embryonal 10% of all Childhood RMS Mucosal Surface Vagina Billiary Bladder Nasopharynx Most common in hollow visceral organs - GU tract Superior Prognosis
- 18. Polypoid, grape-like tumor masses scattered malignant cells in myxoid Stroma abut an epithelial surface, such as that of the bladder, bile duct, vagina, or conjunctiva, and project into the lumen as multinodular excrescences of variable size. arises under the mucosal surfaces of body orifices Fig B shows Botryoid Rhabdomyosarcoma of Rhinopharynx . A B
- 19. SPINDLE CELL Subtype of Embryonal MC site is Paratesticular Superior Prognosis whorled spindly appearance smooth muscle tumours Marked collagen deposition and have a nested, storiform growth pattern. Rare in the head and neck.
- 20. UNDIFFERENTIATED Diagnosis of exclusion aka Pleomorphic Rare in children More common in Adults ( 30-50 Yrs) In skeletal muscles of older people, - Marked pleomorphism - Irregularly arranged cells - Multinucleated giant cells - Hyperchromatic
- 22. HEAD AND NECK : PARAMENINGEAL SITES Parameningeal sites are nasopharynx , nasal cavity, paranasal sinuses, middle ear, pterygopalatine fossa & infratemporal fossa They spread by invading the base of skull & direct extension to CNS a pattern of spread seen in 41% patients. Patients with known meningeal dissemination should receive CSI , dose of 50.4Gy in 28# . Surgery is rarely indicated because complete resection not possible ,does not obviate need of high dose radiation therapy 5year survival 75% with adequate radiotherapy .
- 23. Coronal T1 contrast enhanced MRI obtained at presentation in a child with Intracranial extension from a pterygoplatine fossa RMS. A
- 24. Fig. 1. (A) Brain computed tomography demonstrated a large soft tissue mass lesion involving the left paranasal sinus, nasal cavity, and orbital cavity with crossing of the midline to the right paranasal sinus and nasal cavity. (B) Brain magnetic resonance imaging axial view, coronal view, and sagittal view revealed obvious intracranial extension with cribriform plate destruction to bilateral frontal base regions. B
- 25. C MRI of right masticator space rhabdomyosarcoma
- 26. HEAD & NECK:NON PARAMENINGEAL SITE Children with these tumors have better outcome & 5 year survival is 80 % in IRS4. Site are scalp, parotid, oral cavity ,larynx, oropharynx , cheek and amenable for complete gross resection . 15% patients have lymph node metastasis . Radiotherapy depend on amount of residual tumor. Draining lymph node are not routinely irradiated unless involved clinically or pathologically.
- 27. BLADDER AND PROSTATE : 75% Patients are of <5 years at presentation & more than 95% are of embryonal histologic subtype botryoid . Patients with tumors arising from prostrate has inferior outcome as compared to those arising from bladder. IRS 2 study treated these patients chemotherapy then by delayed surgery or by RT.3yearsurvival s inferior that is 52% compared to 80% those treated with primary radical surgery & only 22% survived with intact bladder .
- 28. IRS3 study intensify therapy by use of planned irradiation 6weeks after the start of treatment & added cisplatin & doxorubicin 5 year survival was 82% with locoregional disease & 64% have retaining functional bladder. Demonstrating need of routine radiotherapy early in treatment. CWS-96 protocol treated these patients with multiagent chemotherapy follow by response adapted RT & surgery. Children with complete resection did not receive RT ,whereas others receive 32-44.8 Gy using 1.6 Gy twice daily . 5 year EFS was 70%.
- 29. The MRI below shows an embryonal RMS which has arisen from the dome of the bladder
- 30. Alveolar Rhabdomyosarcoma of Prostate
- 31. PARATESTICULAR TUMORS: At presentation usually painless inguinal or scrotal mass that does not transilluminate . Mostly they present with early stage that is amenable for complete resection & cure rate is 90%. IRS 3 study retroperitoneal lymph node sampling showing a 14% incidence of node involvement for <10 years age & 47% in >10 year . IRS 4 a thin cut CT without surgical sampling was used for staging and incidence of detected nodes dropped to 4% & 13% fot the two age groups .
- 32. A) Macroscopic images of a paratesticular rhabdomyosarcoma from an 8-month-old infant. The tumor appears as a pale pink and slightly myxoid lesion adjacent to the comparatively smaller testis, showing a smooth and glistening tunica albuginea. (B) Low-power view of a paratesticular rhabdomyosarcoma, spindle cell variant, arising adjacent to the epididymis in an 8-year-old boy. (C) Histological features the spindle cell appearance with multiple enlarged cells with abundant, pink cytoplasm (H&E, 100). (D) High magnification from C, showing a “strap” cell with abundant, “myogenic” cytoplasm featuring the classic striations of skeletal muscle (arrow)
- 33. Surgical procedure is inguinal orchidectomy . In IRS study the high risk of nodal involvement led to recommend for ipsilateral retroperitoneal nerve sparing node dissection for staging of all >10 years . Patients with nodal disease 5 year survival is 69% & 96 % for those without nodal involvement. Regional lymph node irradation is recommend in nodal involvement . If scrotal irradiation is done then orchidopexy is considered prior to treatment to protect remaining structures .
- 34. Gynecologic tumors Accounts for 4% of all RMS tumors & vagina is the most common site . Mostly diagnosed at 3 years of age & present as vaginal mass . Botryoid is most common morphology . IRS4 & IRS 5 reveals high rate of local filure for vaginal tumors when local control with surgery is omitted. COG STS committee call for radiotherapy in all patients with post surgical micro or macro scopic tumor. Children 1 to 9 years has 95% 5 year survival .
- 35. Botryoid embryonal RMS of the female urogenital tract in an infant
- 36. EXTREMITY Alveolar or undifferentiated subtype usually. Large ,deeply invasive , & associated with high probability of lymphatic and hematogenous spread . Complete surgical resection is difficult to achieve, so chemotherapy and radiotherapy is recommended . Regional lymph node involvement is 24% & dissection is performed for staging purpose not for treatment.
- 37. Sentinel lymph node mapping & biopsy is being investigated for their diagnosis & prognostic value. radiotherapy to involved regional lymphatics is mandatory , improve local control OS at 3 years is 70% & failure free survival is 55%. .
- 38. (A) Coronal T2-weighted , (B) sagittal T2-weighted, (C) axial T1-weighted and (D) T2-weighted TSE images with Dixon fat suppression
- 39. For metastasis Patients < 10 years of age & have 1 Or 2 metastatic site , long term survival is 55%. Intensive multiagent chemotherapy plays a major role in these patients . Metastatic site should be treated with radiotherapy wherever is possible
- 40. Treatment
- 42. SURGERY Only 20% patients have long term survival , except in orbit where 50 % those with localized disease. 0nly 20 % tumors are located in sites where excision is possible. 60% tumor is amenable for biopsy & complete resection is better than subtotal resection or biopsy alone . TNM staging indicated prognosis is dictated by tumor size & invasiveness not by initial surgical approach. .
- 43. Initially biopsy then surgical excision is indicated without any compromise of function IRS 5 study evaluated whether delayed primary excision (DPE) able to reduce dose of RT for local control but the results similar after high dose RT for bladder RMS.
- 44. CHEMOTHERAPY Single agent activity is measured as age response rate Vincritine 59%, dactinomycin 24%, cyclophosphamide 54%, cisplatin 15 to 21 %, dacarbazine11%, mitomycin C 23%, ifosfamide 86%. Embryonal histology with no gross residual disease or lymph node involve may treated with VA for 1 year with RT.
- 45. IRS 5 study suggest omitting alkylating agents : local control is compromised . Patients with unresectable pelvic tumors benefit with addition of doxorubicin & cisplatin to VAC . Patients with metastatic RMS benefit with addition of ifosfamide & etoposide to standard VAC regimen.
- 46. RADIOTHERAPY Treatment encompass the involved region before chemotherapy with margins that encompass surgical sites & biopsy tracts Prophylactic lymph node irradiation not done with clinically node negative . Local control of gross tumor require dose of 50 to 55Gy. 90% of patients with microscopic residual tumor achieve local control with 41.4 Gy.
- 47. Dose response with age suggests that lower doses given to infants & children have high relapse rates . Local control is more for tumor <5cm in diameter than for larger lesion . Radiotherapy avoided with dactinomycin & doxorubicin as they causes radiation recall injury . In contrast cyclophosphamide & vincristine can be given with radiotherapy.
- 53. Standard regimen ( 0f equivqlent efficacy) IVA REGIMEN : 9 CYCLES Ifosfamide 3g/m2for two days Vincristine 1.5mg/m2 (max2mg) for one day Actinomycin D 1.5mg/m2(max2mg) for one day VAC REGIMEN 9-15 CYCLES Cyclofosfamide 1200 mg/m2 for one day Vincristine 1.5mg/m2(max2mg ) one day Actinomycin D 1.5mg/m2 (max2mg) for one day
- 54. IRS Study
- 57. IRS III 5- year survival was 71% for IRSIII group which 8% improvement over IRS II . 5 year progression free survival was 65% a 10% improvement from IRS II. Group I patient – 5year PFS – VA- 83%. 5year PFS-VAC- 76%. Group II patient excluding orbit ,head & paratesticular were not improved with addition of doxorubicin over VA chemotherapy * 1 year & radiation therapy.
- 58. Patients with group III tumors ,excluding those in special pelvic, orbit , far better for intensive regimen used in IRSIII than pulsed therapy used in IRS II that is VAC or VAC vincristine & doxorubicin VADR. 5 year PFS were 62% & 52% Patients with tumors of bladder ,vagina & central pelvis in clinical group III improved more than IRS II Patients with unfavorable histology group I & II receive VADR- VAC +cisplatin & radiation improved over IRS II receive VA or VAC . Whole brain RT is omitted for patients with parameningeal primary tumors.