12 bone and soft tissue sarcomas 200609 v2

8/2/2019 12 Bone and Soft Tissue Sarcomas 200609 v2

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Bone and Soft

Tissue Sarcomas

Resident EducationLecture Series


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Pediatric Bone Tumors

Benign Osteochondroma

Osteoid Osteoma Enchondroma

Chondroblastoma

Non-ossifying fibromaakabenign cortical defect

Hemangioma

Eosinophilic granuloma

Osteomyelitis

Malignant Osteosarcoma

Ewing sarcoma Malignant fibrous

histiocytoma

Non-Hodgkin Lymphoma

Eosinophilic granuloma


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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%


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Osteosarcoma (OS)

Primary malignant tumor of bone

Derived from primitive bone forming

mesenchyme

Malignant spindle cells produce immatureneoplastic bone matrix osteoid

Can look heterogeneous under the microscope

Cell of origin?


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Cell of origin may be mesenchymal stem cell

Osteoblastic FibroblasticChondroblastic

Telangiectatic

Small Cell


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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 (


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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


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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


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Clinical presentation OS

Pain: dull, aching, constant, worse atnight, 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 atdiagnosis most often (>90%) pulmonary


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Location OS

Most common in longbonesMay have altered gait

or function

90% are metaphysealMay cross growth

plate

Location: #1 distal femur

#2 proximal tibia

#3 proximal humerus


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Diagnostic Workup OS

History and physicalexamination

Laboratory tests: Blood tests: include LDH,

Alkaline phosphataseAlso CBC, liver/kidneyfunction tests

Pathology

Biopsy (open preferred)

Radiologic tests Plain films of involved bone

MRI of entireinvolved bone

Whole body Bone Scan

CXR and CT of Chest

PET scan (in future)

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


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Radiographs OS

Usually blastic

May be lytic or mixed

bone destruction andproduction

Poorly marginated

Cortical destruction Soft tissue

ossification


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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


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Treatment: Multimodal OS

Surgerycontrol of bulk disease

Chemotherapycontrol of micrometastases

RadiationTumors not very radiosensitive, so this usually

reserved for palliation


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Treatment: Surgery OS

Removal of all gross tumor with wide (>5cm)margins en blocand 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 mustalso be resected

If/when relapse occurs, retrieval therapy must

include resection


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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 andcomplete resection 80-85%


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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


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Outcomes OS

60-68% of patients with nonmetastaticosteosarcoma 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 thesepatients may achieve long term survival


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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


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Pathology EWS

One of many small round

blue cell tumors seen in

pediatrics

Thought to be of neuralorigin, derived frompost-ganglionicparasympathetic

primordial cells tumor cells synthesize

acetylcholine transferase


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Small, Round, Blue Cell Tumor

Differential Diagnosis Lymphoma/Leukemia

Rhabdomyosarcoma Metastatic Carcinoma

Neuroblastoma

PNET/Ewing Sarcoma

Small Cell Osteosarcoma

Ewing

Tumor withoutdifferentiation

PNET

Tumor withneuraldifferentiation


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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


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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)


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Clinical Presentation EWS

Pain & swelling of affected area

May also have systemic symptoms:

Fever Anemia

Weight loss

Elevated WBC & ESR

Mean duration of symptoms 9 months 20-25% present with metastatic disease

Lungs (38%)

Bone (31%)

Bone Marrow (11%)


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Location EWS

central axis (47%):

pelvis, chest wall,

spine, head & neck extremities (53%)

#1 Femur

#2 Ilium

#3 Tibia/Fibula


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Location EWS

Classical presentation is diaphyseal

Actually more common in metadiaphysis or metaphysis


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Diagnostic Work-Up EWS

History and physicalexamination

Laboratory tests:

CBC, liver/kidney functiontests, 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 alsoincludes echocardiogram/EKG


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Radiographs EWS

Destructive

Poorly Marginated

Permeative Endosteal Cortical

Erosion

Layered periostealnew bone

Onion skinning


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Radiographs EWS


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Radiology EWS

Large soft tissuemass

MRI necessary todetermine

Soft tissue extent

Intraosseous extent


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Prognostic factors EWS

Extent of diseaseMetastatic disease unfavorable

Size of disease ???

Primary site Pelvis least favorable

Distal bones and ribs most favorable

Age Younger (


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Treatment EWS

Multidisciplinary approach must provideboth 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


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Treatment: Multimodal EWS

Surgery local control where possible

Radiation local control where surgery not possible or

incomplete

Chemotherapycontrol of micrometastases


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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


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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


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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


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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


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Outcomes EWS

Local Rx only >80% distant failure

Combination chemotherapy + local control 55-75% EFSlocalized tumors

20-30% EFSmetastases present at diagnosis

Patients with spine or paravertebral disease have aslightly worse prognosis overall, as well as a higherrate of local failure and tumor recurrence


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Bone tumors:

Compare & Contrast


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Soft Tissue

Sarcomas

Rhabdomyosarcoma

MOST COMMON


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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 tumoractivity and response totherapy

Bone Marrow Evaluation Look for metastatic disease


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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


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Incidence and Etiology 250 US cases/yr;

most


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Clinical PresentationDetected by mass appearance or

functional disturbance

systemic symptoms are Rare


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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


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Prognostic IndicatorsHistologic subtype

Stage & Group

Site often related to size, potential formetastases

In general- Better outcome with earlyresponse to treatment

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


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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


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Treatment and Prognosis, contd

Radiation therapy (RT): rhabdo initiallythought to be radio-insensitive, but with

increased doses RT shown to be helpful RT to all except completely resected Stage I

patients; hyperfractionated vs conventionaltreatment; dose reduction for selected

patients under study Emergency RT for SC compression, IC

meningeal extension


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Treatment and Prognosis, contd

Chemotherapy for all

Prognosis:


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From ABP

Certifying Exam Content Outline Know that the presenting symptom of

osteosarcoma is usually bone pain or swelling


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Credits

Anne Warwick MD MPH

12 bone and soft tissue sarcomas 200609 v2

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