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Solid Tumour Section
Mini Review
Bone: Osteosarcoma
Anne-Marie Capodano
Laboratoire de Cytogénétique Oncologique, Hôpital de la Timone, 264 rue Saint Pierre, 13005 Marseille,
France (AMC)
Published in Atlas Database: September 2002
Online updated version : http://AtlasGeneticsOncology.org/Tumors/OsteosarcID5043.html
DOI: 10.4267/2042/37938
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2003 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Patients with hereditary diseases such as RothmundThomson syndrome, Bloom syndrome, and LiFraumeni syndrome were found to have increased risk
of having osteosarcoma develop.
Identity
Note
Osteosarcoma is a malignant neoplasm of bone. It is
among the most common non hematologic primary
malignant tumors of bone in both children and adults.
The conventional type arises in the intramedullary
cavity of the bone and represents 75% of all
osteosarcomas.These tumors penetrate and destroy the
cortex of the bone and extend into surrounding soft
tissues. In conventional intramedullary osteosarcoma,
the predominant histologic pattern may be osteoblastic,
fibroblastic, chondroblastic, giant cell rich, malignant
fibrous histiocytoma like or partially telangiectatic.
Clinics
Approximately 85% of patients with de novo
osteosarcoma present before 20 years of age. More than
60% are in their second decade of life. Males are
affected more often than females. Conventional
osteosarcoma shows a marked predilection for the
metaphyseal regions of the long bones. The distal
femur accounts for one third of all cases, followed by
proximal tibia, and the proximal humerus.
The most common presenting complaint is pain,
usually from 1 to 8 months duration. Pathologic
fractures are uncommon occuring in less than 5% of
patients.
The classic radiographic finding is a large infiltrating
metaphyseal lesion that arises in medullar bone and
erodes through the cortex to from a large soft tissue
mass. Osteosarcomas appear most often with a mixed
lytic and sclerotic appearance.
Clinics and pathology
Epidemiology
The age of presentation of osteosarcoma occurs chiefly
in two groups: 10 - 25 years of age, and more than 60
years of age. Osteosarcoma may arise as a de novo
lesion or develop secondarily to a known premalignant
lesion such as Paget disease, osteogenesis imperfecta,
bone lesion, chronic osteomyelitis, fibrous dysplasia,
giant cell tumor, osteoblastoma, or to a process such as
radiation therapy. Several chemical agents such as
beryllium oxyde were shown to be inducers of
osteosarcoma.
Some cases of osteosarcoma appear to be familial: in
particular
children
with
familial
bilateral
retinoblastoma have a incidence of osteosarcoma
several hundred times that of an age-matched general
population. This appears to represent both a genetic
predisposition to de novo neoplasia and an increased
susceptibility to radiation-induced sarcoma.
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
Pathology
Osteosarcoma is composed of proliferating spindleshaped cells that directly produce osteoid or immature
bone (fig 1).
Approximately 75 % of osteosarcomas arise in the
intramedullary cavity and are referred to as “classical”
or
“conventional”
osteosarcoma
(fig
2).
“³Conventional” osteosarcomas can be divided into
histological subtypes according to their predominant
stromal differentiation: fibroblastic, telangiectatic and
giant-cell rich.
45
Bone: Osteosarcoma
Capodano AM
Microscopic features : osteoblastic osteosarcoma with atypical cells elaborating immature osteoid.
Others types of osteosarcomas are:
- cortex-associated osteosarcomas,
- low grade (central) osteosarcomas,
- osteoblastoma-like osteosarcomas,
- disease-associated osteosarcomas,
- multicentric osteosarcomas,
- post-irradiation osteosarcomas.
- Osteosarcoma of the gnathic bones.
Most osteosarcomas are easily recognized based on
their hight-grade obviously anaplastic cells and
uniquivocal osteoid production. The neoplastic cells in
high grade conventional osteosarcomas have marked
nuclear pleiomorphism, conspicious chromatin
abnormalities, prominent nucleoli and many mitotic
figures some of which are atypical. In the
fibrosarcomatous pattern of osteosarcoma, the stroma is
composed of spindle cells. Osteosarcomas may contain
large areas that resemble malignant fibrous
histiocytoma.
absence of metastases. The most reliable prognostic
factor is the histological response to pre-operative
chemotherapy. Elevated expression of P-glycoprotein
in immunochemistry was associated with a decreased
probability of event-free survival. The expression of
HER2/neu may be a predictor of chemotherapy
response and prognosis in osteosarcoma. For some
authors, it is correlated with a poor survival rate.
At present, RB gene LOH (loss of heterozygosity)
appears as an early predictive feature for primary
osteosarcomas, indicating a possible unfavourable
outcome whereas its absence is correlated with a
favourable prognostic.
Cytogenetics
Cytogenetics Morphological
The majority of osteosarcomas are characterized by
complex chromosomal abnormalities with pronounced
cell-to-cell variation or heterogeneity. A high
frequency of aneuploidy and numerous structural
abnormalities has been described.
High-grade tumors were seen to be hyperdiploïd
whereas low-grade tumors were seen to be diploïd.
Nevertheless some authors studied the association
between the degree of aneuploidy and prognosis and
response to chemotherapy. They reported that patients
whose tumors showed a non diploid DNA content had
a longer event-free survival after surgical resection and
chemotherapy than did those with diploid tumors. The
most commonly identified numeric chromosomal
abnormalities were gain of chromosome 1 and loss of
chromosomes 9, 10, 13 and 17. The chromosomal
breakpoints most commonly involved in structural
rearrangements include 1p11-13, 1q11-12, 1q21-22,
11p14-15, 14p11-13, 15p11-13, 17 p and 19q13.
Treatment
Osteosarcoma is a chemosensitive tumor especially to
high-dose methotrexate. The usual therapy is 8 to 12
weeks pre-operative chemotherapy, followed by
conservative surgery or amputation, then by postoperative chemotherapy adapted to the histological
response to pre-operative chemotherapy. But, 30 to
40% of patients have a bad histological response to preoperative treatment and a worse long term prognosis.
Prognosis
Molecular
events
associated
with
disease
aggressiveness and chemotherapy response may serve
as prognostic factors.
Age, localisation, tumoral mass, initial metastatic
disease are prognostic factors. The most important
predictor of outcome at diagnosis is the presence or
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
46
Bone: Osteosarcoma
Capodano AM
Macroscopy aspect of an osteosarcoma : hemorragic and destructive tumor of the metaphysis of the right tibia. Bilateral rupture of
cortical and invasion of epiphyseal plate.
Many studies were reported in osteosarcomas with
comparative genomic hybridization (CGH). DNA
sequence copy number increases have been identified
on the regions 1q21, 3q26, 6p, 8q, 12q12-13, 14q24qter, 17p11-12, Xp11.2-21 and Xq12.
The most interesting of these abnormalities are copy
number increase at 8q, 1q and 17p. Patients with copy
number increases at 8q have a shorter survival, whereas
patients with a copy number increase at 1q21 showed a
shorter survival. Amplicon, 17p was identified as in
conventional cytogenetic and in CGH.
Ring
chromosomes,
double
minutes
and
homogeneously staining region are seen in some
osteosarcomas. They signify the presence of gene
amplification. Ring chromosomes frequently observed
in paraosteal osteosarcomas, low-grade tumor, are
associated with amplification of DNA at chromosome
12q13-15 in CGH technique. This region contains
MDM2 and CDK4 genes.
osteosarcomas show alteration of the RB gene in 70%
of cases.
- Loss of heterozygosity (LOH) at 13q, the site of gene
RB is present in approximately 60% to 70% of
osteosarcomas. And recently LOH at the RB locus has
been proposed as a poor prognostic factor in
osteosarcoma.
- Gross structural rearrangement of the RB gene is
present in 30% of these tumors and point mutations in
only 10%.
- Abnormalities of the RB gene are commonly seen in
osteosarcoma but other components of the RB-pathway
gene can be subject to genetics alterations: INK4, p16,
CDK4 and cyclin D1. The INK4A gene located on
chromosome 9p21 is inactivated in about 10% of
osteosarcomas. Loss of p16 expression is also found in
10 % to 15 % of tumors and is correlated with
decreased survival in pediatric osteosarcomas.
- Amplification of the 12q13-15 chromosomal region
which contains both CDK4 and MDM2 is seen in about
10% of osteosarcomas.
Genes involved and proteins
P53
Cytogenetics Molecular
Note
Alterations in the P53 pathway:
Inactivation of the p53 pathway is central event in
many tumors including osteosarcoma. The p53 gene is
located on chromosome 17p13, chromosomal region
frequently
altered
in
cytogenetic
analysis.
Abnormalities of p53 were identified in 50 % of cases.
p53 mutations are more often missense type.
Alterations of p53 observed in osteosarcoma can be
allelic loss (75-80%) or gene rearrangements (10-20%)
or point mutations (20-30%). In patients with the LiFraumeni syndrome who have a germline mutation of
Note
A number of important genes have been identified,
including various tumor suppressor genes, oncogenes
and genes coding for growth factors. Inactivation of
both P53 and RB pathways appears to be a central
event in the genesis of osteosarcoma.
RB
Alterations in the RB gene pathway:
- It is known that patients affected by hereditary RB
have 1000 times the incidence of osteosarcoma
compared with the general population. Sporadic
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
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Bone: Osteosarcoma
Capodano AM
Mentigny M, Patricot LM, Oberling F. Loss of heterozygosity of
the RB gene is a poor prognostic factor in patients with
osteosarcoma. J Clin Oncol. 1996 Feb;14(2):467-72
p53 they are a high risk of osteosarcoma. And in 3% of
patients with sporadic osteosarcoma, germline
mutations in p53 are identified.
Some genes are involved in the regulation of p53 and
abnormalities of these are detected in cases of
osteosarcoma.
- The MDM2 gene located on chromosome 12q13
encodes a protein that negatively modulates p53
function by binding the p53 protein. MDM2 is
amplified in 5-10% of osteosarcomas.
- Another important protein is the p14 product of the
INK4 gene. The p14 protein exerts a protective effect
on p53. For some authors either or two singular events:
INK4A deletion or 12q13 amplification can inactivate
two separate pathways of cell cycle control. But direct
genetic alteration of both p53 and RB do not co-exist
with either INK4A deletion or 12q13 amplification. So,
three pathways of cell are possible to induction of an
osteosarcoma.
Bridge JA, Nelson M, McComb E, McGuire MH, Rosenthal H,
Vergara G, Maale GE, Spanier S, Neff JR. Cytogenetic
findings in 73 osteosarcoma specimens and a review of the
literature. Cancer Genet Cytogenet. 1997 May;95(1):74-87
Sztán M, Pápai Z, Szendrôi M, Looij M, Oláh E. Allelic Losses
from Chromosome 17 in Human Osteosarcomas. Pathol Oncol
Res. 1997;3(2):115-120
Goto A, Kanda H, Ishikawa Y, Matsumoto S, Kawaguchi N,
Machinami R, Kato Y, Kitagawa T. Association of loss of
heterozygosity at the p53 locus with chemoresistance in
osteosarcomas. Jpn J Cancer Res. 1998 May;89(5):539-47
Benassi MS, Molendini L, Gamberi G, Ragazzini P, Sollazzo
MR, Merli M, Asp J, Magagnoli G, Balladelli A, Bertoni F, Picci
P. Alteration of pRb/p16/cdk4 regulation in human
osteosarcoma. Int J Cancer. 1999 Oct 22;84(5):489-93
Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey
JH, Meyers PA. Expression of HER2/erbB-2 correlates with
survival in osteosarcoma. J Clin Oncol. 1999 Sep;17(9):2781-8
DCC
Wei G, Lonardo F, Ueda T, Kim T, Huvos AG, Healey JH,
Ladanyi M. CDK4 gene amplification in osteosarcoma:
reciprocal relationship with INK4A gene alterations and
mapping of 12q13 amplicons. Int J Cancer. 1999 Jan
18;80(2):199-204
Note
Others suppressor genes than RB and p53 can exist in
osteosarcomas LOH have been describe on
chromosomal region 3q26 and 18q22. On 18q22, is
located DCC gene (deleted in colon cancer).
Abnormalities of these regions are seen in Paget’s
disease where osteosarcoma risk is increased.
Note
Some other oncogenes are known to be associated with
osteosarcomas.
- C-fos is expressed in 61% of tumors. It was more
frequently expressed in higt-grade lesions and more
often (42%) in patients who developed metastases.
- Likewise, c-myc is overexpressed in patients with
metastatic oseosarcomas.
Her 2/neu is associated with 40% of tumors and
decreased survival.
- SAS gene located on 12q13 is amplified in 36% of
osteosarcomas and 100% of parosteal osteosarcomas.
A possible mechanism linked to specific genetic
alterations was incriminated in acquired methotrexate
resistance of osteosarcomas. In particular increased
expression
of
dihydrofolate
reductase
was
demonstrated in 62% of cases after surgery.
Wolf M, Tarkkanen M, Hulsebos T, Larramendy ML, Forus A,
Myklebost O, Aaltonen LA, Elomaa I, Knuutila S.
Characterization of the 17p amplicon in human sarcomas:
microsatellite marker analysis. Int J Cancer. 1999 Jul
30;82(3):329-33
Belchis DA, Gocke CD, Geradts J. Alterations in the Rb, p16,
and cyclin D1 cell cycle control pathway in osteosarcoma Ped
Pathol Mol Med. 2000;9:377-89.
Boehm AK, Neff JR, Squire JA, Bayani J, Nelson M, Bridge JA.
Cytogenetic finding in 36 osteosarcoma specimens and a
review of the literature. Ped Pathol Mol Med 2000;19:359-76.
Ladanyi M, Gorlick R. Molecular pathology and molecular
pharmacology of osteosarcoma. Ped Pathol Mol Med
2000;19:391-413.
Maitra A, Roberts H, Weinberg AG, Geradts J. Loss of
p16(INK4a) expression correlates with decreased survival in
pediatric osteosarcomas. Int J Cancer. 2001 Jan 20;95(1):34-8
Nevins JR. The Rb/E2F pathway and cancer. Hum Mol Genet.
2001 Apr;10(7):699-703
Bell W, Siegal GP. Osteosarcoma. In: Molecular biology and
pathology of paediatric cancer. Cullinane C, Burchill S, Squire
J, Lewis I, and O'Leary J Eds. Oxford University Press, London
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This article should be referenced as such:
Capodano AM. Bone: Osteosarcoma. Atlas Genet Cytogenet
Oncol Haematol. 2003; 7(1):45-48.
Feugeas O, Guriec N, Babin-Boilletot A, Marcellin L, Simon P,
Babin S, Thyss A, Hofman P, Terrier P, Kalifa C, Brunat-
Atlas Genet Cytogenet Oncol Haematol. 2003; 7(1)
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