bone and soft tissue sarcoma

8/10/2019 Bone and Soft Tissue Sarcoma

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Bone and Soft

Tissue Sarcomas

PIEAS Lecture



Pediatric Bone “Tumors”

Benign Osteochondroma

Osteoid Osteoma Enchondroma

Chondroblastoma

Non-ossifying fibromaaka benign cortical defect

Hemangioma

Eosinophilic granuloma

Osteomyelitis

Malignant Osteosarcoma

Ewing sarcoma Malignant fibrous

histiocytoma

Non-Hodgkin Lymphoma

Eosinophilic granuloma



Malignant bone tumors

Rare

6% of all childhood malignancies

Annual US Incidence in children < 20 yrs

8.7 per million ~ 650 to 700 children/year

For perspective, Annual US Incidence Overall 4697 per million

Lung 610 per million

Breast 633 per million

Most often occur in young patients < 25 yrs

Most common bone tumors ← will focus on these

Osteosarcoma 56%

Ewing sarcoma 34%



Osteosarcoma (OS)

Primary malignant tumor of bone

Derived from primitive bone forming

mesenchyme

Malignant spindle cells produce immature

neoplastic bone matrix – osteoid

Can look heterogeneous under the microscope

Cell of origin?



Cell of origin may be mesenchymal stem cell

Osteoblastic FibroblasticChondroblastic

Telangiectatic

Small Cell



Histologic subtype (WHO) OS

Central (medullary)tumors Conventional OS

(87%) Osteoblastic – 50%

Chondroblastic – 25%

Fibroblastic – 25%

Telangiectatic (3%) Small cell

Intraosseous well-differentiated (1%)

Multifocal

Surface tumors

Parosteal (<5%)

Periosteal

High-grade surface OS

High grade vs. Low grade



Epidemiology OS

Most common during 2nd decade

75% between 10 and 20 yrs

Peak during adolescent growth spurt

Taller than average

Occurs earlier in girls

M:F 1.5:1 African-American:Caucasian 1.4:1



Associations or Risk Factors OS

Ionizing radiation

Hereditary retinoblastoma (Rb mutations)

Li-Fraumeni syndrome (p53 mutations) Rothmund-Thomson syndrome

No environmental risk factors

No consistent cytogenetic abnormality



Clinical presentation OS

Pain: dull, aching, constant, worse at

night, often attributed to trauma

Average duration of symptoms prior todiagnosis is three months

May or may not have a mass

Diagnosis of pelvic lesions often delayed

20% have detectable metastases at

diagnosis – most often (>90%) pulmonary



Diagnostic Workup OS

History and physicalexamination

Laboratory tests:

Blood tests: include LDH, Alkaline phosphatase Also CBC, liver/kidneyfunction tests

Pathology

Biopsy (open preferred)

Radiologic tests Plain films of involved bone

MRI of entire involved bone

Whole body Bone Scan

CXR and CT of Chest

PET scan (in future)

Pre-therapy evaluation alsoincludes Audiogram,echocardiogram,GFR/creatinine clearance



Radiographs OS

Usually blastic

May be lytic or mixed

bone destruction andproduction

Poorly marginated

Cortical destruction

Soft tissue

ossification



Prognostic Factors OS

Tumor Grade & Histology Parosteal favorable; telangiectatic unfavorable

Disease Extentmetastatic disease unfavorable

Tumor Size / Site axial skeletal primaries unfavorable

Age < 10 yrs unfavorable

Response of the primary tumor to pre-operativechemotherapy: very powerful predictor > 80-90% necrosis favorable



Treatment: Multimodal OS

Surgerycontrol of bulk disease

Chemotherapycontrol of micrometastases

Radiation

Tumors not very radiosensitive, so this usuallyreserved for palliation



Treatment: Surgery OS

Removal of all gross tumor with wide (>5cm)margins en bloc and biopsy site through normaltissue planes is required

Type of surgical procedure depends on tumorlocation, size, extramedullary extent, presenceof distant metastatic disease, age, skeletaldevelopment, and life-style preference limb-sparing

amputation

Metastatic sites must also be resected

If/when relapse occurs, retrieval therapy must

include resection



Surgery alone 15-25% 5 year survival

Recurrence with local and (50%) metastatic

disease within 6 months of resection

With multiagent chemotherapy 55-68%

No difference between adjuvant orneoadjuvant chemotherapy

Those with >90% tumor necrosis and

complete resection 80-85%



Treatment: Chemotherapy OS

Bulky disease is considered somewhatchemotherapy resistant

Subclinical metastases are sensitive to

chemotherapy Most active agents include

adriamycin, cisplatinum, high-dose methotrexate,ifosfamide, etoposide

Best # and schedule of chemotherapy unclear Role of intensification after local control unclear

Immune modulators under study

Role of adjuvant chemotherapy after

thoracotomy for recurrent disease unclear



Outcomes OS

60-68% of patients with nonmetastatic

osteosarcoma of the extremity will survive

without recurrence and be cured 20% of patients with metastatic disease

will be cured

Therapy with curative intent is possiblefollowing relapse: 10-20% of these

patients may achieve long term survival



Complications / Late effects of Therapy OS

Surgical

Functional outcomes of limb salvage vs.

amputation under study

Chemotherapy

Anthracycline induced cardiomyopathy

may arise 15+ years after therapy

Cis-platinum induced ototoxicity and renaltoxicity

Ifosfamide induced renal tubular dysfunction



Ewing Sarcoma (EWS)

Represents a family of tumors including

Ewing sarcoma of bone

extraosseous Ewing sarcoma and

peripheral neuroectodermal tumor (PNET)

of bone or soft tissue

2nd most common bone tumor in children



Pathology EWS

One of many „small round

blue cell‟ tumors seen in

pediatrics

Thought to be of neural

origin, derived from

post-ganglionic

parasympathetic

primordial cells tumor cells synthesize

acetylcholine transferase



Small, Round, Blue Cell Tumor

Differential Diagnosis Lymphoma/Leukemia

Rhabdomyosarcoma Metastatic Carcinoma

Neuroblastoma

PNET/Ewing Sarcoma

Small Cell Osteosarcoma

Ewing

Tumor without

differentiation

PNET

Tumor with neural

differentiation



Incidence EWS

Occurs most commonly in 2nd decade

80% occur between ages 5 and 25

Most common bone tumor in children < 10 yrs

~110 new cases/year < 15 yrs

~200 new cases/year < 20 yrs

M:F 1.3:1 < 10 yrs1.6:1 > 10 yrs

Rare in African-Americans and Asians



Associations or Risk Factors EWS

???

Consistent cytogenetic abnormality,

t (11;22)(q24;q12) present in 90-95% resultant fusion gene is EWS/FLI-1

Also seen:

t(21;22)(q22;q12) 5-10%

EWS/ERG t(7;22) and t(17;22) the remainder

EWS/ETV1 and EWS/E1AF respectively

t(1;16)(q21;q13)

present along with t(11;22)



Location EWS

central axis (47%):

pelvis, chest wall,

spine, head & neck

extremities (53%)

#1 Femur

#2 Ilium

#3 Tibia/Fibula



Location EWS

Classical presentation is diaphyseal

Actually more common in metadiaphysis or metaphysis



Diagnostic Work-Up EWS

History and physical

examination

Laboratory tests:

CBC, liver/kidney function

tests, LDH, ESR

Urinalysis

Pathology

Bone marrow aspirate andbiopsy

Biopsy (open preferred)

Radiologic tests

Plain films of primary site

CT/MRI of primary site

CXR/CT of chest

Whole body bone scan

PET scan (in future)

Pre-therapy evaluation also

includes echocardiogram/EKG



Radiographs EWS

Destructive

Poorly Marginated

Permeative Endosteal Cortical

Erosion

Layered periostealnew bone

“Onion skinning”



Radiographs EWS



Radiology EWS

Large soft tissue

mass

MRI necessary to

determine

Soft tissue extent

Intraosseous extent



Prognostic factors EWS

Extent of diseaseMetastatic disease unfavorable

Size of disease ???

Primary site Pelvis least favorable

Distal bones and ribs most favorable

Age Younger (<10) more favorable

Histologic ??? Response to chemotherapy

Neural differentiation



Treatment EWS

Multidisciplinary approach must provide

both local control and systemic therapy

Local control measures should notcompromise systemic therapy

When treatment fails, it is usually due to the

development of distant metastatic disease



Treatment: Multimodal EWS

Surgery local control where possible

Radiation local control where surgery not possible or

incomplete

Chemotherapycontrol of micrometastases



Treatment: Local Control EWS

Surgery and/or Radiation therapy

No randomized studies comparing surgery to

radiation therapy slightly more local recurrence when radiation used for

local control

current suggestion for surgery where possible without

loss of function and without mutilation Combination therapy if incomplete resection

Radiation doses usually 4500 – 5500 cGy



Surgical Indications EWS

Expendable bone (fibula, rib, clavicle)

Bone defect able to be reconstructed with

modest loss of function

May consider amputation if considerable

growth remaining

Trend toward improved outcomes withchemo + surgery vs. XRT



Radiation therapy Indications EWS

Unresectable without significant morbidity

Pelvic lesions

Spine lesions

Lung metastases

May consider chemo + XRT to allow for surgicalresection or add XRT if surgical margins positive



Treatment: Chemotherapy EWS

All patients require chemotherapy

Active agents include

Vincristine, cyclophosphamide, adriamycin,dactinomycin,

ifosfamide, etoposide, topotecan, melphalan

Effective chemotherapy has improved local

control rates achieved with radiation to 85-90% Role of SCT for high risk Ewing sarcoma still

under investigation



Outcomes EWS

Local Rx only >80% distant failure

Combination chemotherapy + local control 55-75% EFS – localized tumors

20-30% EFS – metastases present at diagnosis

Patients with spine or paravertebral disease have a

slightly worse prognosis overall, as well as a higher

rate of local failure and tumor recurrence



Complications / Late effects EWS

Radiation

Second malignant neoplasms

Relatively high rate, especially bone tumors

Bone growth arrest

Chemotherapy

Anthracycline-induced cardiomyopathy Veno-occlusive disease of the liver

Infertility

Second malignant neoplasms



Bone tumors:

“Compare & Contrast”



Epidemiology

Osteosarcoma

#1 bone tumor

2nd decade of life Rare under 10 yr

M:F 1.5:1

15% more common in African-Americans

than in Caucasians

Ewing Sarcoma

#2 bone tumor

2nd decade of life Not rare under 10 yr

M:F ~1.4:1

Rare in African- Americans, other

ethnic groups



Presentation

Osteosarcoma

Pain

Often mass Duration of symptoms

3 months

Ewing Sarcoma

Pain

Often mass/swelling Duration of symptoms

9 months

Systemic symptoms Fever, weight loss



Associations / Risk Factors

Osteosarcoma

Lots

Radiation Hereditary

retinoblastoma

Li-Fraumeni

Rothmund-Thomson

Cytogenetics None characteristic

Ewing Sarcoma

None established

Cytogenetics t(11;22)



Location of diseaseOsteosarcoma Majority occur in the

distal femur, proximaltibia and proximal

humerus

Mostly metaphyseal

Most mets to lungs

Ewing Sarcoma Fairly even split between

the extremities and theaxial skeleton

Axial occur in pelvis,chest wall, spine, headand neck

Classically diaphyseal

Mets to lungs, bone, bonemarrow



Radiology

Osteosarcoma

“starburst”

Usually blastic,

often lytic with

cortical destruction

Soft tissue

calicification

Ewing Sarcoma

“onion skin”

Permeative,

destructive,

cortical erosion

Soft tissue mass may

be difficult to see

without MRI



Treatment

Osteosarcoma

Local control

Surgery NO radiation

Systemic control

Chemotherapy

Ewing Sarcoma

Local control

Surgeryand/or radiation

Systemic control

Chemotherapy



Outcomes

Osteosarcoma

Local disease only

55-65% overall 80-85% if > 90%

necrosis

Metastatic disease 20% if to lungs

<10% if to bones

Ewing Sarcoma

Local disease only

60-75% overall

Metastatic disease

40% if only to lungs

<20% if elsewhere



Late effects

Osteosarcoma

Chemotherapy

related

Surgery related

Ewing Sarcoma

Chemotherapy

related

Surgery related

Radiation related



Soft Tissue

Sarcomas

Rhabdomyosarcoma

MOST COMMON



Staging Work-Up –

What are we looking for? CT/MRI (primary)

Helpful to delineate softtissue planes; pre-surgicalevaluation

CT (chest) Look for metastatic disease

in the lungs (common siteof metastases)

CT (body) Look for lymph nodeinvolvement

Bone Scan Look for metastases to

bone

CT/PET May give helpful

information about tumor„activity‟ and response totherapy

Bone Marrow Evaluation Look for metastatic disease



RhabdomyosarcomaMalignant tumor of mesenchymal origin,

generally in cells of skeletal muscle

lineageSmall, round, blue cell tumorTwo main histological types:

embryonal and alveolarAbout 20% are undifferentiated or have

other histological subtypes



Incidence and Etiology 250 US cases/yr;

most <9

M:F ratio of 1.3:1.0higher in industrialized “West”

Histology varies according to age at dx

Associated with familial syndromes such as

Li-Fraumeni and neurofibromatosis Genetic factors may be involved



Clinical PresentationDetected by mass appearance or

functional disturbance

‘systemic’ symptoms are Rare



Clinical Presentation – Detected by mass appearance orfunctional disturbance

35% Head/neck (orbit & parameninges)with proptosis, opthalmoplegia (orbital)and nasal/sinus S/S, ICP (parameningeal)

22% GU (bladder or prostate)with S/S of hematuria, obstruction,pelvic or testicular mass, constipation



Diagnostic Workup/StagingH & P

Imaging studies of affected area and to

determine mets; used as baseline data Tumor biopsy is necessary for diagnosis

Formal „staging‟ to determine „risk group‟ acombination ofTNM system, classified per tumor histology

IRS Clinical Group Stage System



Prognostic IndicatorsHistologic subtype

Stage & Group

Site – often related to size, potential formetastases

In general - Better outcome with earlyresponse to treatment

For Localized tumors: older age, regionallymph node involvement, and bony erosionare associated with worse prognosis



Treatment and PrognosisTreatment multimodal - per protocol

Surgery: resection where feasible;

second surgery if residual disease afterfirst surgery

Shift from more radical procedures to

function-sparing procedures, withsupport of Chemotherapy and Radiation



Treatment and Prognosis, cont‟d

Radiation therapy (RT): rhabdo initiallythought to be radio-insensitive, but withincreased doses RT shown to be helpful

RT to all except completely resected Stage Ipatients; hyperfractionated vs conventionaltreatment; dose reduction for selected

patients under study Emergency RT for SC compression, IC

meningeal extension



Treatment and Prognosis, cont‟d

Chemotherapy for all

Prognosis: <20% to 95%

site, stage & histology dependent--Better: orbital, non-bladder/prostate GU

--Worse: pelvic, truncal, retroperitoneal, cranial,parameningeal, paravertebral, extremity; mets atdx; alveolar histology

Recurrence rare after 3-4 years;



THANK YOU

bone and soft tissue sarcoma

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