The Understanding and

Treatment of
Musculoskeletal Tumors
diagnosis: conventional, molecular, and new technologies.

DARMADJI ISMONO
Department of Orthopaedic Surgery and Traumatology
dr. Hasan Sadikin General Hospital
Medical School of Padjadjaran University
Iyan n.34 th Mrs. 18-02-2007
Ridwan 12 th
Tn. Sarka, 22th MRS 27-02-07
Mrs. Yuyun, 45 y.o
MRS 13-03-07
 The Understanding and
Treatment of
Musculoskeletal Tumors
diagnosis: conventional, molecular, and new technologies.

Problem dan Penatalaksanaan MST

DARMADJI ISMONO
Department of Orthopaedic Surgery and Traumatology
dr. Hasan Sadikin General Hospital
Medical School of Padjadjaran University
Pioneers in musculoskeletal oncology: Musculoskeletal Tumor Society Founders
Lecture.
Information from Industry
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Medscape Newsletters

Diagnosis Based On Molecular Changes

Regis J. O'Keefe, MD, PhD, from the University of Rochester Medial Center in
Rochester, New York, presented data on the molecular diagnosis of musculoskeletal
tumors.

A comparison study of staging systems for bone sarcomas

Clin Orthop Relat Res. 2003; (415):64-71 (ISSN: 0009-921X)
Heck RK; Stacy GS; Flaherty MJ; Montag AG; Peabody TD; Simon MA
Campbell Clinic/University of Tennessee, Department of Orthopaedics, Memphis, TN
38104, USA. rheck@campbellclinic.com

Validation of a functional evaluation system in patients with musculoskeletal tumors.

Clin Orthop Relat Res. 2003; (411):217-26 (ISSN: 0009-921X)
Lee SH; Kim DJ; Oh JH; Han HS; Yoo KH; Kim HS
Department of Orthopaedic Surgery, Seoul National University College of Medicine,
Seoul, Korea.
 Diagnosis Based On Molecular
Changes
Gene abnormalities

genetic
P53 is a tumor suppressor and mutations in p53 are present in about 50% to 55% of all cancers. It has
effects on the cell cycle, DNA repair, and apoptosis, and typically has a short half-life

Fusion proteins
aberrations
The SYT-SSX fusion protein is found nearly always in sarcoma , and TLS/FUS-CHOP

Gene amplification
"genetic fingerprinting" of
Gene amplifications may be present in some tumors. Liposarcomas are often associated with a 12q13-15
amplicon

tumors
P-glycoprotein expression
The role of P-glycoprotein expression in soft-tissue tumors remains a controversial area
 General Considerations
incidence, pathogenesis, clinical features, diagnosis,
treatment

Clinical history
Physical signs
the heterogeneity,
Biochemical findings (lab)

unpredictable behavior, and

Radiographic features
Scintigraphy (bone scan)

Computed tomograpphy
difficulty in classification is
Arteriography (angiography)

MRI evident
Biopsy
Microscopic appearance
Types of Specialists:
Orthopaedic surgeon plastics surgeons, vascular surgeons,
Radiologist rehabilitation specialists and a diverse
Patologist group of allied health professionals.
Medical oncologist

The evolution of diagnosis in

sarcomas has progressed
from
histologic,
to histochemical,
to immunohistochemical,
to chromosomal abnormalities, and,
now, to molecular diagnosis.
PERIOSTEAL REACTIONS
 RATE OF GROWTH
(Lodwick)

Grade 1
1a. Sclerotic margin
without complete cortical
penetration
1b. Sharp margin, non-sclerotic
margin without total
cortical penetration
1c. Poorly defined margin,
totally penetrated the
cortex
Grade 2
geographic lesion + moth-eaten
and/or permeative destruction

Grade 3
motheaten and/or permeative
destruction only
MRI
Imaging

 Bone Scan : Positive if bone damaged or

highly vascular

 PET : (positron emission tomography)

 active for STS
 seeking metastases, additional lesions
 lymph node extensions
Biopsy

 Essential part of work up

 Most case : identify , key info
determining treatment protocol
 Open biopsies : complication risk, more
accurate
Small incision, avoid transverse incision
Obtain sufficient tissue :
Frozen section Grading
Tissue identification Immunological studies
Electron microscopy Flow cytometry
Biopsy

 Needle biopsy :
- FNAB
- Core ( under CT , USG )
 Classification (Aegerter,1975)
I.Reactive Bone Lesion II.Hamartomas III.True Neoplasms of
Affecting Bone Bone
A. Osteogenic
A.Osteogenic A. Oteogenic 1. Osteosarcoma
1. Osteoid osteoma 1. Osteoma 2. Parosteal sarc
2. Osteoblastoma 2. Osteochondroma B. Chondrgenic
1. Benignchondroblasto
B. Chondrgenic ma
B.Collagenic 1. Enchondroma 2. Chondromyxoid
fobroma
1. Subperiosteal cortical
defect C. Collagenic 3. Chondrosarcoma
2. Non-osteogenic fibroma 1. Angioma C. Collagenic
2. Aneurysmal bone 1. Fibrosarcoma
cyst 2. Angiosarcoma
D. Myelogenic
1. Ewing’s tumor
2. Reticulum cell sarc
3. Hodgkin’s disease
E. Osteoclastoma (GCT)
SurgicalStaging System (SSS)
William F. Enneking
 Stage I: (G1,T1,Mo)
 Low-grade, intracompartmental,
metastase (-)
 Stage IB:(G1,T2,Mo)
 low-grade, extracompartmental,
metastase (-)
 Stage IIA:(G2,T1,Mo)
 High-grade,intracompartement.
Metastase (-)
 Stage IIB:(G2,T2,Mo)
 High-grade,extracompartment.
Metastase (-)
 Stage IIIA: (G1 or G2,T1,M1)
 Intracompartment, metastase
(+)
 Stage IIIB:(G1 or G2,T2,M2)
 Extracompartment, metastase(+)
Gene expression profiling
(molecular pattern or signature)

The EXT1,2 genes in

chondrosarcoma. Using genomic
techniques, new tumor suppressor
genes have been identified in
addition to p53, and Rb

serum lactate dehydrogenase

(prognostic indicator)
Chondrosarcoma:

-aberrations on chromosomes 2, 11. 14, 15, and 21

-expression of telomerase reverse transcriptase----

immunohistochemical staining of this enzymes was
corralated with the clinical outcome.

-identify molecular targets in treatment discovered

indian hedgehog gene (Ihh) always turned “on” ,
-when inhibitory Ihh drug (triparanol), blockade was
effective for decreasing the level of expression.
Kristy L. Weber JBJS; jun 2005;87,6
NEW Treatment

Radiation
 Decrease local recurrence & possibly metastasis
 Pre-op, Intra-op, Post-op
limb-sparing
 Brachytherapy
 Dosage : 40 – 60 Gy ( or more )
surgery to replace
Extend of surgery
Anatomic site
amputation
Micro and Macros retention of diseased tissue
Principles of Treatment
Accurate diagnosis
Benign neoplasms and non-malignant
lesion: surgically (excision,
curettement, bone grafting)

Malignant primary neoplasms:

surgical ablation, eradication, with
or without radiotherapy and
adjuvant chemotherapy

Enneking’s staging system

Limb-sparing, extremity saving,

Limb-salvaging
Soft Tissue Sarcoma
Synovial Sarcoma

 Translocation : 11, 12, 18 chromosome

 distinguish from other STS
 Dormant long period  clinical
aggressive
Fibrosarcoma
 Identified by specific t ( 12 ; 15 ) translocation
 M : F = 60 : 40 ,
 Age : 2 – 87 ( m : 48 + 20 yrs )
 Rhabdomyosarcoma

 Chromosome : 11p 15,5  diagnostic

 Children w/ Rhab until 1970s Fatal
 With chemo survival mostly
GTNM ( AJCC 5th ed)
STAGE Description Prognostic Factors
Low grade, small, superficial or
IA deep G1-2, T1a-1b, N0,M0 G1 well diff
IB low grade, large, superficial G1-2, T2a, N0,M0 G2 moderately diff
IIA Low grade, large, deep G1-2, T2b, N0,M0 G3 Poorly diff
High grade, small, superficial or
IIB deep G3-4, T1a-1b, N0,M0 G4 Undiff
IIC High grade, large, superficial G3-4, T2a, N0,M0 T1 Small size (< 5 cm)
T1a superficial to fascia
T1b deep to fascia
III High grade, large, deep G3-4, T2b, N0,M0 T2 Large size ( > 5 cm )
T2a superficial to fascia
T2b deep to fascia
Any G, any T, N1 or N1 Regional lymph node
IV Any metastasis M1 metastasis
M1 Systemic metastasis
TREATMENT of STS
Chemotherapy
 Pre-op & Post-op
 Principal agents : ifosfamide & doxorubicin
 Reduce extend of resection
 Connective tissue oncology service at Massachusetts GH
: MAID
Mesna 2500 mg/msq : 4 days
Doxorubicin 20 mg/msq : 3 days
Ifosfamide 2000 mg/msq : 3 days
Dacarbazine 250 mg/msq : 4 days

 Substantially decrease local recurrence

 Complications : skin & GIT, 1 death of neutropenia
Treatment of STS
RADIATION I
2 days
MAID I Radiation 2 Gy/day
Rest Period
11 days ( 22 Gy)

RADIATION II
2 days MAID II
Radiation 2 Gy/day
Rest Period
11 days ( 22 Gy)

MAID III

SURGERY
( 3 weeks after MAID III)
Results of STS Treatment
Massachusetts GH Orthopaedic Oncology Group

 1220 ps, 1972 – June 2001

 Survival rate overall : 72 % ( similar other
institutions )
 Poorest survival :
leiomyosarcoma ( 51%), clear cell sarcoma ( 59 %),
alveolar soft part sarcoma ( 62 % ), MFH ( 64 % ).
 Best survival :
epithelioid sarcoma ( 89 %), fibrosarcoma ( 85 % )
 Recurrent rate : low ( < 4 % ) generally
Management of Bone
Metastases
Focused on methods to decrease pain and
skeletal events while maintaining function
Lung Cancer,
cyberknife radiosurgery
Management
 The orthopedist must be sure of the
diagnosis and not embark on treatment for
the wrong diagnosis.
 Solitary lesions in patients with a remote
history of malignancy require complete
investigation and biopsy.
 Pathologic fractures do not require
immediate fixation. They require careful
surgical planning and a team approach to
the underlying malignancy.
Management
 Femoral neck fractures should be treated by
endoprosthetic replacement, and
consideration should be given to long-
stemmed femoral components.

 The orthopaedist should assume that the

fracture will never heal.

 Immediate full and unrestricted weight

bearing should be planned.
osseointergration
 A New Paradigm

 Stem cells are primal, undifferantial

optimal treatment of
cells which have the unique potential
to produce any kind of cell in the body.
patients
Medical researches believe stem cells
have the potential to change the face of
human disease by being used to repair
specific tissues or to grow organs.
Prevention
 avoidinga carcinogen or altering its
metabolism; pursuing lifestyle or
dietary practices that modify cancer-
causing factors or genetic
predispositions; and/or medical
intervention (chemoprevention) to
successfully treat preneoplastic
lesions.
 Future Directions
How can this knowledge lead to
the development of more effective
therapies ?
Genomic context: chromosome: 6;
 Recent studies indicate
Maps:that cancer cells
6p21
might influence osteoblast proliferation by
inducing common osteoblast signalling
pathways, many of which lead to the
activation of RUNX2 (runt-related transcription factor
2), also Rb and p27
 Future Directions


Proteomics
Evolution of Diagnosis: Future Perspective on
Molecular Changes, in the
Two-dimensional gel future outcome should
electrophoresis
be improve
 Competentthe identification of new targets
 imaging : PET (positron emission tomography) scanning
and mechanisms,
 predictive immunological
 selective chemo & grouping
functional rad therapy:
of adjunctive
genes and& neoadjuctive
 Gene identification & repair
signaling : assist development
pathways,
 Improved surgery
and pharmacologic reagent analysis
 Modular Endoprostheses for Children With
Malignant Bone Tumors
Michael D. Neel, MD, and G. Douglas Letson, MD
Results: Thirty-seven children with malignant bone tumors underwent primary tumor
resection and reconstruction with a modular prosthetic device. Fourteen had subsequent
successful expansions with modular prostheses. A new prosthesis, in which lengthening is
achieved by an external electromagnetic field rather than an open surgical procedure, is
discussed.

•Cadaveric allografts
•Autologous
vascularized epiphyseal
 Limb Salvage Management of Pathologic
Fractures of Primary Malignant Bone Tumors
Walid Ebeid, MD, Sherif Amin, MD, and Amr Abdelmegid, MD

Pathologic fractures of primary

bone sarcoma should not
be considered an absolute
indication for amputation.

Patients should be treated by

neoadjuvant chemotherapy,
and their tumors should then be resected
with adequate
margins that might entail performing an
extended wide
 The human genome
CONCLUSIONS has just been
described
•EARLY DETECTION
(VERY EXPENSIVE)
•LATE must be AMPUTATION
(paliative treatmant)
•SO
•PREVENTION
•HEREDITARY
•SOSIAL PROBLEM