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
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nce akinakintotothatthat
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• 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
FOXO1rearrangements –
• 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 extn 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 Nasopharynx
• 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

23. 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%.

24. 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.

25. 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

26. 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 irradn.
• i) dissect entire spermatic cord after orchidectomy
• ii) sample abdominopelvic nodes, except for Gr. I
• iii) scrotal violation / involvement: need scrotal RT.

27. 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).

28. 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.

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

30. • 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.

31. 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 ++ - -

32. Intergroup Rhabdomyosarcoma Clinical Grouping System

36. • 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)

38. RHABDOMAYOSARCO
MA

39. TREATMENT SEQUENCE

40. 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

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

42. • 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

43. • 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

44. • 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).

45. • 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

46. 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

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

50. FOLLOW UP- Investigations
• Relevant History
•
•
Physical examination & documentation
Haematological evaluation:
• Hb, TC, Platelet
• Liver Function Tests (LFT)
• Renal Function Tests (RFT)
• Radiological 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.