Rhabdomyosarcoma.pptx

rhabdomyosarcoma

1. Rhabdomyosarcoma

2. Introduction Rhabdomyosarcoma is the most common of the childhood soft tissue sarcomas. A highly malignant soft tissue sarcoma that arises from unsegmented , undifferentiated mesoderm or myotome -derived skeletal muscle. RMS can arise almost anywhere in the body, is locally invasive, and rapidly disseminates early in its course.

3. Epidemiology Approximately 7% of all pediatric cancers. Rhabdomyosarcoma (RMS) comprises 40% of this group and the other non- rhabdomyosarcoma soft tissue sarcomas (NR-STS) comprise the remainder. Annual incidence of 4.4 per 1 million whites and 1.3 per 1 million blacks. The male-to-female ratio is ~1.5 to 1.0, and males may have slightly better overall survival Majority of patients are <10 years of age at the time of diagnosis, and approximately 5% are <1 year of age. Two peak age frequencies, at ages 2 to 6 and in adolescence. Age has been identified as an independent predictor of prognosis, with children <1 year and >10 years having inferior survival.

4. Risk factors Cause of RMS is unknown; Environmental exposures -paternal cigarette use, prenatal x-ray exposure, and maternal recreational drug use. Disorders in development, including central nervous system, genitourinary, gastrointestinal, and cardiovascular anomalies, with congenital disorders - congenital pulmonary cysts, Gorlin basal cell nevus syndrome, neurofibromatosis, Li- Fraumeni syndrome, Beckwith- Wiedemann syndrome, and Costello syndrome. Mutations- Alveolar RMS associated two translocations,t (2;13) (p35; q14 ),present in about 60% of children with alveolar RMS. The less common translocation , t(1;13)(p36;q14). Embryonal RMS characterized by loss of heterozygosity at 11p15.5,n-myc amplification,p53 mutation also seen.

5. Site of involvement It may occur at any site in the body, most frequently involved sites are: orbit- 9% head and neck (excluding parameningeal tumors)-7% parameningeal - 25% genitourinary- 31% Extremity-13% trunk-5% retroperitoneum-7%, and other sites -3% Genitourinary sites - the bladder, prostate, vagina, uterus, urethra, and paratesticular region. Head and neck lesions are divided into parameningeal sites (nasopharynx, nasal cavity, paranasal sinuses, middle ear and mastoid region, infratemporal fossa , and pterygopalatine and parapharyngeal areas) and other head and neck sites (parotid region,cheek , masseter muscle, oral cavity, oropharynx, larynx,hypopharynx , scalp, face, and pinna )

6. NATURAL HISTORY & PATTERNS OF SPREAD RMS, a locally invasive tumor with a pseudocapsule , potential for local spread along fascial or muscle planes, lymphatic extension, and hematogenous dissemination. The overall risk of regional lymphatic spread is approximately 15%, but varies with the site of the primary lesion. Lymph node metastases are rare in orbital tumors, but they occur in approximately 15% of tumors at other head and neck sites, most commonly the nasopharynx, Regional lymph node extension occurs in approximately 25% of children with paratesticular , extremity, and truncal tumors. The risk for lymph node involvement also correlates with primary tumor invasiveness and large tumor size

7. Distant spread Hematogenous metastases at the time of presentation -approx 15% of patients, particularly those with truncal and extremity primary tumors. Common sites of hematogenous dissemination -lungs, bone marrow, and bone. Malignant pleural and peritoneal effusions may also accompany tumors primary to the chest and abdomen or pelvis.

8. Clinical presentation As it occurs in multiple primary sites, there are many site-specific clinical signs and symptoms. usually as an asymptomatic mass. When symptoms are present, d/t mass effect on associated organs and tissues. Tumors of the orbit - proptosis and ophthalmoplegia . Patients with parameningeal tumors -nasal, aural, or sinus obstruction, cranial nerve palsy, and headache. Genitourinary tumors - hematuria , urinary obstruction, or constipation.

9. Diagnostic Workup

10. Staging Systems INTERGROUP RHABDOMYOSARCOMA STUDY CLINICAL GROUPING CLASSIFICATION

11. INTERGROUP RHABDOMYOSARCOMA STUDY PRETREATMENT STAGING SYSTEM

12. Pathological classification

13. EMBRYONAL Favorable 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 Zones of loose & dense cellularity remarkably recapitulate normal embryonal myogenesis They share features with other embryonal neoplasm of childhood- Wilms tumors, hepatoblastomas, pancreatoblastomas,neuroblastomas.

14. 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 Polypoid , grape-like tumor masses Scattered malignant cells in myxoid stroma

15. SPINDLE CELL Subtype of Embryonal MC site is Paratesticular Superior Prognosis whorled spindly appear smooth muscle tumors relatively differentiated spindle cells having cytologic features reminiscent of smooth muscle tumors.

16. ALVEOLAR 20 % of RMS < 1 yr - >10 yr ( Adolescents) More aggressive,metastatic disease Extremities , trunk, perianal, perineal Fibrous septa with loose clusters of rounded cells in center - alveolar pattern

17. Prognostic factors Histology Stage Primary site (most important prognostic factor) Tumor size Lymph Node involvement (especially in extremities) Metastatic disease Group Extent of resection

18. Event-free survival of patients treated on Intergroup Rhabdomyosarcoma Study IV by stage and site A: For patients with nonmetastatic “favorable” site tumors (stage 1), the best outcome was seen for orbital primary tumors

19. For patients with nonmetastatic unfavorable site tumors (stage 2 or 3), the best outcome was for those with genitourinary (bladder–prostate) tumors, whereas those with extremity tumors had an inferior outcome.

20. Risk stratification Low-risk patients: with localized embryonal RMS occurring at favorable sites (stage 1) and patients with embryonal RMS occurring at unfavorable sites with either completely resected disease (group I) or microscopic residual disease(group II) The FFS for this group is approximately 90%. Intermediate-risk patients : with embryonal RMS occurring at unfavorable sites with gross residual disease (group III) and patients with nonmetastatic alveolar RMS at any site and have variable outcomes, ranging from 30% to 85% FFS. High-risk patients are those with metastatic disease and have FFS rates of 26% to 40%.

21. Treatment modalities Surgery Radiotherapy Chemotherapy

22. Surgery Before the advent of radiation and chemotherapy, complete resection of RMS was the clear goal of surgical treatment. Radical surgeries such as pelvic exenteration , radical prostatectomy, cystectomy , amputations, and orbital exenteration . Most of these children had severely compromised quality of life functionally, cosmetically, and psychologically. With the introduction of effective adjunctive treatment, preservation of function and appearance became major goals. The concept of reasonable surgery has evolved. It involves removal of the bulk of tumor with maximal conservation of anatomic structures, including preservation of bladder, bowel, and sexual function in patients with tumors of genitourinary origin; limb function in patients with extremity tumors; and vision, voice, deglutition, and appearance in patients with head and neck tumors.

23. In suspected RMS, the initial surgical procedure should be an incisional biopsy. Surgical excision is indicated if it can be done without compromise of function or cosmesis . Normal tissue margins of at least 5 mm around the tumor -complete resection (IRS group I), If microscopic disease remains after initial resection, a primary re-excision can be considered prior to beginning chemotherapy. Second-look operations (also termed delayed primary excisions) may be useful for converting partial responses after chemotherapy into complete responses, and there is evidence that these procedures may improve survival.However further studies are going on.

24. Chemotherapy Chemotherapy is necessary in all cases. Several drugs have demonstrated single-agent activity vincristine (59%), dactinomycin (24%), cyclophosphamide (54%), cisplatin (15% to 21%), dacarbazine (11%), mitomycin -C (36%), etoposide (15% to 21%), ifosfamide (86%), irinotecan (23%), and topotecan (46%)

25. Most common regimen used in North America consists of vincristine , actinomycin D, and cyclophosphamide (VAC) Ifosfamide is preferentially used in the European trials

26. Radiation therapy Goal of RT today is to provide local and regional control, with or without surgery, in conjunction with chemotherapy. Radiotherapy should be administered to all children with the exception of those with group I embryonal tumors. Treatment portals are designed to encompass the involved region at the time of presentation (before chemotherapy) with margins that encompass surgical sites and biopsy tracts. A biopsy should be performed of clinically suspicious lymph nodes, or they should be included in the radiation therapy portal. Prophylactic lymph node irradiation is not necessary in children with clinically negative findings who will be receiving combination chemotherapy.

27. Target volumes: Gross tumor volume tumor as seen at the time of initial diagnosis. Clinical target volume of 1 cm is added, can be modified to account for anatomic barriers to tumor spread (such as the bony orbit in primary orbital tumors) or to account for regression of “pushing” the tumor border after chemotherapy, such as may occur in large pelvic tumors that initially displace contents of the peritoneal cavity. Planning target volume adds about 5 mm. Many current treatment protocols use a cone-down boost or simultaneous integrated boost to any gross post-treatment tumor volume after a microscopic tumor dose has been delivered.

28. Three-dimensional conformal and intensity-modulated radiotherapy treatment planning techniques are valuable for ensuring adequate treatment of the tumor volume and minimizing acute and chronic toxicity from the irradiation of uninvolved, adjacent structures. Proton-beam radiotherapy is being increasingly utilized as it decreases integral dose to normal structures compared to photon-based techniques. Isodose distribution in the axial and coronal planes for treatment of a middle ear RMS using protons. The physical properties of protons permit complete sparing of the contralateral structures and ipsilateral eye.

29. Local control of gross disease in most anatomic sites requires doses of 50 to 55 Gy. IRS-V D9602 study support lesser dose of 45 Gy for gross tumor at orbital sites, especially if cyclophosphamide is included in the systemic therapy regimen. Doses for node-negative microscopic residual disease are 36 Gy 41.4 Gy for those with microscopic disease and pathologically proven but grossly negative nodal disease. There was no difference in locoregional disease control, failure-free survival, or overall survival between conventional and Hyperfractionated regime. Therefore, the standard of care for group III RMS continues to be conventionally fractionated radiation with chemotherapy. Raney R, Walterhouse DO, Meza JL, et al. Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol 2011;29:1312–1318. Breneman J, Meza J, Donaldson S, et al. Local control with reduced dose radiotherapy for low-risk rhabdomyosarcoma : a report from the Children’s Oncology Group D9602 study. Int J Radiat Oncol Biol Phys 2012;83(2):720–726. Donaldson SS, Meza J, Breneman JC, et al. Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma —a report from the IRSG. Int J Radiat Oncol Biol Phys 2001;51:718–728.

30. Interstitial radiation therapy may play a role as primary treatment or as a boost after external-beam therapy for selected sites. The advantages of precise shaping of the dose distribution, sharp falloff of radiation dose, and shortening of overall treatment time are especially attractive in dealing with infants and young children

31. Treatment algorithm

32. Orbit Most favorable prognostic site. Paucity of lymphatics in this area means that lymphatic extension is rare. Most tumors in this site have embryonal histology, hematogenous metastasis at the time of diagnosis is uncommon. Biopsy only should be performed to provide the diagnosis. Primary treatment typically consists of vincristine , actinomycin -D, and cyclophosphamide (VAC) or vincristine and actinomycin -D (VA) chemotherapy with local radiotherapy beginning between the 3rd and 12th week of treatment. Radiation doses of approximately 50 Gy are often used, although results from the IRS-V study suggest that 45 Gy may be sufficient when given with a cyclophosphamide -containing chemotherapy combination. Using this approach, cure rates of >90% can be achieved.

33. Radiotherapy can be directed to the tumor plus a margin without necessarily irradiating the entire orbit. Technique is very important for minimizing corneal and lacrimal gland dose and for preserving useful vision and appearance. Photon irradiation with the eyelid open can minimize the corneal dose when an anterior field is used and may be associated with improved long-term functional outcome. Three-dimensional conformal or intensity-modulated radiotherapy technique is optimal for treating the target volume and sparing normal structures, and proton radiation has also been used successfully.

34. Proton treatment for an orbital rhabdomyosarcoma . A: A multiplanar view of a large orbital rhabdomyosarcoma involving the superior orbit and invading lacrimal gland. B: Axial view of proton plan. C: Dose–volume histogram

35. Head and Neck: Parameningeal Sites Nonorbital RMS of the head and neck is grouped parameningeal sites (nasopharynx, nasal cavity, paranasal sinuses, middle ear, pterygopalatine fossa , and infratemporal fossa ) nonparameningeal sites Have propensity for invading the base of the skull, creating a potential for cranial nerve palsy & direct extension into the central nervous system(41%) Many (35%) of children with tumor arising in a parameningeal site would later have meningeal extension, Prognosis of these patients is improved with appropriate imaging, multiagent chemotherapy, and adequate irradiation of the primary tumor and adjacent meninges ,

36. Patients with known meningeal dissemination should receive craniospinal irradiation. A radiation dose of 50.4 Gy in 28 fractions to the primary site is commonly used.

37. 12-year-old girl was treated at age 3 years for an embryonal rhabdomyosarcoma of the nasal cavity. Her treatment consisted of excisional biopsy, followed by VAC ( vincristine , actinomycin -D, and cyclophosphamide) chemotherapy and 41.4 Gy radiotherapy. Slight hypoplasia of the midface is evident, but overall cosmesis is excellent.

38. Head and Neck: Nonparameningeal Sites Better outcome than their parameningeal counterparts (80% 5-year failure-free survival in IRS-IV) and require less-intensive chemotherapy. Sites -the scalp, parotid, oral cavity, larynx, oropharynx, and cheek. These tumors may be more amenable to complete gross surgical excision Approximately 15% of these patients present with regional lymph node metastases. Radiotherapeutic management is based on the amount of residual tumor after surgery. Draining regional lymph nodes are not routinely irradiated unless they are considered to be involved with tumor by clinical or pathologic assessment.

39. Pelvis: Bladder and Prostate Rhabdomyosarcoma Bladder and prostate RMS combined represent approximately one half of genitourinary RMS RMS of this location tends to occur in very young children; Most are under the age of 5 at the time of diagnosis. Urinary abnormalities, including dysuria , polyuria , incontinence, and in particular urinary retention, are early signs 80% of tumors in modern series have favorable histology, embryonal or botryoid type. Regional lymph node involvement for this site is not uncommon, particularly when tumors arise from the prostate, and documented in the range of 20–30%. External iliac nodes are most commonly involved. Only 15% have demonstrable systemic metastases at diagnosis

40. First radiographic evaluation is typically ultrasound. CT scan and/or MRI of the abdomen and pelvis provide greater detail allowing for evaluation of the primary mass and retroperitoneal lymphatics/

41. Evolved from pelvic exenteration to less-aggressive organ preserving therapy while maintaining high survival rates. The goal of multimodality therapy is to cure with preservation of bladder function. If the tumor cannot be removed completely with preservation of bladder and urethral function, definitive surgery is delayed in attempt to achieve a response with chemotherapy +RT that will allow for an organ-preserving surgical procedure. Alkylating based chemotherapy followed by RT is recommended. Second look surgery if any residual after RT. Three-dimensional treatment planning is preferred for better visualization and delineation of target volumes and normal structures. Four-field techniques may be used, AP/PA or slightly oblique anterior or posterior fields provide the benefit of shielding femoral head growth plates. IMRT may be of benefit for some cases but concern is for growth plates and risk of second malignancy. Protons therapy may be of benefit.

42. Axial (A), sagittal (B), and coronal (C) images of a proton radiation plan for a young child receiving radiation for microscopic disease following chemotherapy and surgical resection. D: Bladder–prostate dose–volume histogram displaying growth plates and clinical tumor volume. Prescription dose 36 Gy(RBE) to CTV. Femoral head growth plates receive a maximum dose of 3 Gy(RBE); pelvic growth plates receive a range 6–20 Gy(RBE).

43. Paratesticular tumors Represent 7% of all RMS and may arise anywhere along the spermatic cord, from the intrascrotal area through the inguinal canal. At presentation, the tumor usually is a painless scrotal or inguinal mass that does not transilluminate . Surgical procedure for the primary tumor is inguinal orchiectomy . If there is no evidence of invasion into the scrotum & proximal spermatic cord is free of tumor no further local therapy is necessary. Lymph node involvement: 30% ( paraaortic / renal hilar ) If LN + ve (radiological): Ipsilateral . Nerve sparing LN dissn ./ Regional nodal irradiation. The most common use of RT for paratesticular RMS is for nodal disease.

44. Gross nodal disease present after surgery receives a dose of 50.4 Gy. This may be reduced to 41.4 Gy for microscopic disease if there is pathologic confirmation of tumor response. Lymph nodes are generally present within 2 cm of the vessels. Vessels and any involved lymph nodes should be contoured. Anterior and posterior opposed fields are generally used. Structures that are at risk in close proximity include bowel, kidneys, bladder, and bony structures.

45. Gynecologic Tumors Tumors arising in the vulva, vagina, cervix, and uterus are about one-third as common as bladder and prostate primary tumors and account for 4% of all RMS. Vagina is the most common site of origin. Patients with vaginal tumors are often much younger than those with other pelvic RMS, with most girls diagnosed before the age of 3 years. Most present with a vaginal mass or discharge;

46. Botryoid morphology is common. Receive chemotherapy and radiotherapy based on the amount of tumor present after initial surgery. Intracavitary and interstitial brachytherapy are useful irradiation techniques in some of these patients. Survival after treatment is excellent. Children ages 1 to 9 years have a 98% 5-year survival

47. 3D-CRT vs IMRT vs Proton

48. Brachytherapy plan for a vaginal rhabdomyosarcoma . This 3-year-old girl relapsed after chemotherapy alone. Prescription dose delivered was 60 Gy. A: Axial CT treatment planning image showing percent isodose prescription lines. This plan demonstrates rapid fall off allowing for sparing of the pelvic growth and femoral growth plates as well.

49. Other Pelvic Sites include perianal , perirectal , and perineal primary sites. Regional lymph node involvement is relatively common. The location of these primary tumors creates surgical and irradiation challenges. Combined chemotherapy and radiation therapy programs are favored over primary surgical procedures

50. Extremity Tumors arising in the extremity are often of the alveolar or undifferentiated subtypes, Large, deeply invasive, and associated with a high probability of lymphatic and hematogenous metastasis. Complete surgical resection is difficult to achieve, associated with a high risk of residual disease. Because radiation therapy and multiagent chemotherapy have been shown to provide excellent local control, it is advisable to avoid disfiguring and mutilating surgical procedures, Regional lymph node involvement is present in approximately 24% of patients and confers a more guarded prognosis

51. Radiotherapy of involved regional lymphatics is mandatory, aggressive treatment of in-transit nodal sites may improve overall local control. Radiation therapy for extremity primary tumors requires careful immobilization techniques, sparing of nonirradiated skin for lymphatic drainage, and use of shrinking fields. Overall survival at 3 years is about 70%,failure-free survival is only 55%.

52. Retroperitoneal Retroperitoneal tumors comprise 11% of RMS. Children usually present with abdominal pain, back or lower extremity pain, and/or an abdominal mass . Median age at diagnosis is approximately 6 years Common histological subtype: embroyonal type but Alveolar is also seen General treatment policy : Chemo + RT Poor prognosis: 5year survival - 40%.

53. Metastatic Disease Hematogenous or distant lymph node metastasis at the time of diagnosis is an ominous finding. The subset of patients who are <10 years of age and have only one or two sites of metastatic disease may have long-term survival chances of >50%. Intensive multiagent chemotherapy plays a major role in the treatment of these patients.

54. Follow up

55. Take home message Rhabdomyosarcoma (RMS): 350 cases annually in the United States Embryonal rhabdomyosarcoma : 75% , botryoid subtype Alveolar rhabdomyosarcoma : 25% Nonmorbid “up-front” surgery Radiation therapy (RT) for primary and metastatic sites of disease: Microscopic disease: 36 Gy Microscopic nodal disease: 41.4 Gy Gross disease: 50.4 Gy Local failure: Group I/II: 10% Group III: 13%

56. Vincristine , dactinomycin ( Actinomycin D), cyclophosphamide(VAC)–based chemotherapy Experimental chemotherapy and biologic agents for patients with metastatic disease Five-year event-free survival: Low risk (group I/II embryonal RMS): 90% Intermediate risk (alveolar RMS or group III): 75% High risk (metastatic): 25% to 35%

57. Commonest site of Rhabdomyosarcoma ???

58. Common histology ??? Embroyonal

59. Prognostic factors??? Site of tumor ,Stage ,Histology ,Age

60. Thank you