Rhabdomyosarcoma

surgical oncology seminar

1. Rhabdomyosarcoma

2. Most common soft tissue sarcoma in children 3% to 4% of all cases of childhood cancer More common in males and Caucasians Two-thirds of cases occur in patients under the age of 10 years Median age at diagnosis of 5 years

3. Germ-line P53 mutations Costello syndrome Beckwith- Wiedemann syndrome Neurofibromatosis type I Germ-line DICER1 mutations Parental use of cocaine and marijuana Birthing order and accelerated in utero growth

4. Site of involvement Head and neck (including the orbit and parameningeal areas [35%]) Genitourinary tract (including the bladder, prostate, vagina, vulva, uterus, and paratesticular area [26%]), and Extremities (19%) 20% of children present with disseminated disease - commonly involves the lung

5. Classification

6. Pathology and Molecular Biology International Classification of Rhabdomyosarcoma 1Superior 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

7. World Health Organization - four variants of rhabdomyosarcoma Embryonal (65%) Alveolar (25%) Pleomorphic , and Spindle cell/ sclerosing rhabdomyosarcoma

8. 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

9. EMBRYONAL • Zones of loose & dense cellularity • remarkably recapitulate normal embryonal myogenesis, in which loose primitive mesenchyme condenses to form nascent muscle • exhibit all cellular phases of myogenesis dense condensations of rhabdomyoblasts amid foci with a loose myxoid stroma. They share features with other embryonal neoplasms of childhood, such as Wilms tumors, hepatoblastomas, pancreatoblastomas, and neuroblastomas.

10. ALVEOLAR 20% of RMS < 1 Yr --- >10 Yr ( Adolescents) Extremities, trunk, perianal, perineal MORE AGGRESSIVE METASTATIC DISEASE

11. ALVEOLAR RHABDOMYOSARCOMA Fibrous septa with loose clusters of rounded cells in center - alveolar pattern Riopelle and Theriault described solid areas lacking fibrosis and resembling lymphoma, a phenomenon further noted by Enzinger and Shiraki: solid pattern in so-called alveolar tumors.

12. 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

13. BOTRYOID RHABDOMYOSARCOMA Polypoid, grape-like tumor masses Scattered malignant cells in myxoid stroma These lesions should 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. Cambium layer -subepithelial condensation of tumor cells.

14. SPINDLE CELL 1992 1992 ) ) nce akin akin to to that that of of Subtype of Embryonal MC site is Paratesticular Superior Prognosis whorled spindly appeara smooth muscle tumors relatively differentiated spindle cells having cytologic features reminiscent of smooth muscle tumors.

15. Diagnosis of exclusion Previously called Pleomorphic Rare in children More common in Adults ( 30-50 Yrs) In skeletal muscles of older people, thigh Marked pleomorphism Irregularly arranged cells Multinucliated giant cells UNDIFFERENTIATED

16. UNDIFFERENTIATED Enlarged, pleomorphic, hyperchromatic nuclei

17. Embryonal tumors High background mutation rate Single-nucleotide variants Multiple chromosomal gains and losses Most often involving chromosome 8 gains (74% of cases). Gains of chromosomes 2, 7, 11, 12, 13q21, and 20 as well as losses of 1p36, 6, 9q22,14q21, and 17 have been reported.517,518 Activating RAS pathway mutations involving KRAS, NRAS, and HRAS - 42% Mutations involving the FGFR4, ALK, BRAF, CTNNB1, PIK3CA, and PTPN11 genes MDM2 amplification, loss of PTEN, BCL2L1 amplification, homozygous deletions of CDKN2B, increased GLI expression, NF1 deletions, and ALK copy number gains

18. Alveolar tumors Worse clinical outcome Commonly arise in the trunk and extremities Characterized by a t(2;13) (q35;q14) or t(1;13) (p36;q14), in which the PAX3 gene on the long arm of chromosome 2 or the PAX7 gene in chromosome 1 is fused with the FOXO1 gene on the long arm of chromosome 13 ALK gene copy number gains are seen in the majority of cases Copy number gains and overexpression of MYCN - adverse clinical outcome Approximately 18% of alveolar rhabdomyosarcomas lack FOXO1 rearrangements – Fusion-negative alveolar rhabdomyosarcomas Behave more like patients with embryonal tumors, PAX/FOXO1 fusion is a key determinant of clinical behavior and should be incorporated into the risk stratification of the disease

19. Natural History RMS is a locally invasive Tx often with a pseudocapsule. Potential for local spread along fascia, muscle planes, Lymphatic ext n and blood dissemination. Overall risk of reg lymphatic spread=15%-20% LN mets. Rare in orbit but other H&N=15 %, MC in tumour from N asopharynx Paratesticular= 25%, Trunk & extremities= 20%

20. LN invol risk correlates with tumour invasiveness and size of tumour Hematogenous spread @ diagnosis ~ 15% Particularly truncal and extremity MC sites for spread are Lungs, BM & Bone.

21. Clinical presentation Head and neck tumors - one-third of all cases Proptosis , ophthalmoplegia , nasal drainage, and obstruction, headache, cranial nerve palsies, dysphonia , dysphagia , and palpable adenopathy.526 Patients with Genitourinary tumors -25% of cases Hematuria , dysuria , hydronephrosis palpable abdominal mass, vaginal discharge, and palpable painless masses Extremities - 20% of cases Swelling, palpable adenopathy , and pain.526 Tumors on the Trunk, pelvis, and abdomen can present with Nerve root compression, palpable mass or adenopathy , jaundice ( biliary tract tumors), and perirectal pain and swelling

22. Head & Neck (Para-meningeal) Sites: Nasopharynx, Nasal cavity, PNS, Middle ear, Pterygopalatine fossa. Have propensity for base skull invasion & intracranial extension. Common histological subtype: ERMS. Incidence of lymph node involvement (IRS III): <20%. Possibility of complete surgical excision (IRS III): <25%.

23. Head & Neck ( (Non- parammeningeal ) Sites: Parotid, Oral cavity, Oropharynx and Larynx. Common histological subtype: Embryonal RMS. Buccal mucosa: Alveolar RMS Scalp Incidence of lymph node involvement (IRS III): <20%. Prophylactic / Elective nodal irradiation not recommended.

24. Pelvic RMS: Urinary Bladder Common histologic subtype: Embryonal RMS Lymph node involvement: 20% (Hypogastric & Ext. iliac) IRS III - Chemo + Radiotherapy  Surgery for residual disease IRS III - Bladder preservation: 55% with 90% survival

25. Paratesticular Along spermatic cord; from interscrotal area through the inguinal canal. Lymph node involvement: 30% (paraaortic / renal hilar) If LN +ve (radiological): Ipsilateral. Nerve sparing LN dissn ./ Regional nodal irrad n . i) dissect entire s permatic cord after orchidectomy ii) sample abdominopelvic nodes, except for Gr. I iii) scrotal violation / involvement: need scrotal RT.

26. Orbit Common histological subtype: Embryonal RMS General treatment policy: Incisional Biopsy for diagnosis  Chemo+ RT Radiotherapy volume: Entire orbit need not be included. Shield lachrymal gland & duct. Significant role of 3D CRT / IMRT. Survival: 90-95% at 5years (with CT + RT).

27. Extremity Common histological subtype: Alveolar RMS Lymph node involvement: 27-30% General treatment policy: W/E + LN sampling  Chemo + RT . Radiotherapy: No RT if R0 & N0 &  5cm tumor (primary surgery). Entire LN region irradiated if sampling +ve. Strip of tissue spared for lymph drainage.

28. Retroperitoneal: Common histological subtype: Alveolar RMS General treatment policy: W/E + Chemo + RT Poor prognosis: 5year survival - 40%.

29. Staging evaluation should include a Complete blood count Serum chemistries Bone or PET scan Bilateral bone marrow aspirates and biopsies CT of the chest CT or MRI of the primary tumor, and CT or MRI of abdomen and pelvis for abdominal, pelvic, and lower extremity tumors.

30. Malignant Round Cell Tumors ( IMMUNOCYTOCHEMISTRY) RMS NB PNET ES MCT OS NHL SCLC S-100 +/- ++ ++ +/- SYNAPTOPHYSIN + ++ ++ MIC-2 GENE + ++ ++ DESMIN ++ +/- +/- VIMENTIN ++ ++ CHROMOGRANIN + ++ +/- MUSCLE SPECIFIC ACTIN (HHF-35) +++ +/- NEUROFILAMENT ++ ++ +/- - NEUROSECRETARY GRANULES ++ + + ++ LUCOCYTE COMMON ANTIGEN - - - +++ CYTOKERATIN ++ +/- +/- ++ ++ CPK (MM & BB) ++ MYOGLOBIN ++ - -

31. Intergroup Rhabdomyosarcoma Clinical Grouping System

32. 16% of patients have group I disease (completely resected ), 20% have group II disease (microscopic residual), 48% have group III disease (incompletely resected ), and 16% present with group IV disease (metastatic)

33. RHABDOMAYOSARCO MA

34. TREATMENT SEQUENCE

35. Management Local Therapy Surgical considerations for the treatment of rhabdomyosarcoma are site specific Extensive surgeries in certain sites such as the orbit, the bladder, the vagina, and the biliary tract are unwarranted When feasible, reexcision of positive margins in patients with extremity and trunk primaries is associated with improved survival second-look procedures can help tailor the dose or eliminate the use of radiotherapy in selected cases

36. Debulking procedures has a very limited role in the management of rhabdomyosarcoma

37. Radiotherapy should be administered to all children with the exception of those with group I embryonal tumors Patients with stage 1, 2 group I alveolar tumors can be spared the use of radiotherapy

38. 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. For a gross residual tumor, the recommended dose is 45 Gy for orbital and 50.4 Gy for nonorbital primary sites

39. Selection of reduced doses of radiation for patients with orbital sites of involvement is supported by the D9602 trial Reduced doses of radiotherapy without an alkylating agent in patients with embryonal group IIA and orbital group III tumors did not compromise local control rates (~15% local failure).

40. The treatment volumes for patients requiring radiation include All areas of gross disease Areas the tumor initially infiltrated at diagnosis The timing of radiation therapy usually occurs after the initial 12 or 18 weeks of chemotherapy

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

42. FOLLOW-UP- Frequency Every 3 monthly for the 1 st yr Every 6 monthly for the 2 nd & 3 rd yr Yearly thereafter

43. FOLLOW UP- Investigations Relevant History • • Physical examination & documentation Haematological evaluation: Hb, TC, Platelet Liver Function Tests (LFT) Renal Function Tests (RFT) • Radiologica l evaluation : CXR X-ray of local part Bone scans CT chest Bone Scan/ CT scan chest is done every 6 months for the first 2 years and every year for the next 3 years. Other investigations (MRI/ CT Scan of local part) to be done as specified after discussion in the Pediatric joint clinic.