The Role of Ancillary Techniques in the Assessment of Soft Tissue Tumors
Moderators: Dr. John R. Goldblum and Dr. Cyril Fisher
Section 5 -
Contribution of Molecular Biology and Markers to the Prognosis and Management of Patients with Soft Tissue Sarcoma
University Institute of Pathology
In the last 10 years significant improvements have been made in the molecular approach of soft tissue
sarcomas (STS). Roughly, STS can be be separated into two two groups, those bearing specific chromosomal
abnormalities (25-30% of cases) such as gene mutations (e.g. GIST) or translocations (e.g. synovial
sarcoma, alveolar rhabdomyosarcoma, etc.. see Table 1), and those showing complex karyotypes
(leiomyosarcoma, pleomorphic liposarcoma, MPNST, unclassified spindle cell/pleomorphic STS
Because of their specificity and their increasing detectibility in paraffin-embedded tissue using FISH or
PCR-based techniques, these chromosomal abnormalities are more and more often used as diagnostic markers
of some STS. Since diagnosis, treatment, and outcome are all interdependent variables in the management
of STS, logically, improvements in sarcoma subtyping have resulted in improvements in the treatment and
prognosis of STS. In addition, with the refinements of molecular techniques, it appeared that some
genomic abnormalities correlate with patient outcome in, at least, a small subset of tumors. This
presentation will focus on the contribution of molecular biology and markers to the prognosis and
management of patients with Ewing sarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, and liposarcoma.
Gastrointestinal stromal tumors (GIST), which best illustrate the relationship between molecular biology,
response to treatment and outcome, will not be considered here.
Mostly occurring in children and adolescents, Ewing sarcoma (ES) is an aggressive neoplasm with a poor
outcome. Overall, up to 25-30% of patients have clinically apparent metastatic disease at presentation
Despite aggressive treatment regimens, one third of patients will relapse within five years of
diagnosis. It is now well established that Ewing's sarcoma (ES) and primitive peripheral neurectodermal
tumors (PNET) belong to the same spectrum of neoplasms, the ES family of tumors , characterized by
recurrent balanced reciprocal chromosomal translocations, involving the EWS gene on 22q12 and one of the
members of the ETS family of transcription factors, mainly the FLI-1 gene on 11q24 (about 85-90% of
cases), and the ERG gene on 21q22 (10-15% of cases)
In less than 1% of cases, other EWS fusion
partners are implicated such as ETV1 (on 7p22), E1AF (on 17q22), FEV (2q33) or others (see Table 1)
The presence of one of these specific translocations in a round cell tumor is diagnostic of
ES/PNET and is also a prerequisite for the inclusion of patients in ES therapeutic protocols (e.g.
EuroEwing). Secondary chromosomal aberrations (e.g. gains of chromosome arm 1q, gains of chromosomes 8
and 12, p16INK4 mutations and deletions, and p53 mutations) have also been described,
especially in patients with advanced disease
For the FLI1-EWS translocation, breakpoints tend to
cluster in given regions and some fusion gene transcripts are more frequent than others, e.g. the type I
EWS-FLI1 fusion in which the exon 7 of EWS fuses with exon 6 of FLI1 (65% of cases), and the type II
EWS-FLI1 fusion in which the exon 7 of EWS is fused with exon 5 of FLI1
Zoubeck et al  showed
in univariate analyses that for patients with localized disease, type I fusion gene was associated with
longer relapse-free survival compared with other type of fusion genes. In a series of 112 patients, De
Alava et al.  observed a positive relationship between type I EWS-Fli1 fusion and overall survival
suggesting that EWS-FLI1 transcript structure is an independent determinant of prognosis in Ewing's
sarcoma, potentially linked to a lower transactivation potential of the EWS-FLI1 type 1 fusion
oncoprotein. Similar results were more recently obtained by Avigad S et al. . De Alava et al. also
observed an asociation betwen EWS-FLI1 type 1 fusion and lower proliferative rate . By contrast,
Ginsberg et al.  failed to found any prognostic value of fusion gene in ES in univariate analyses.
It is important to note that all these results were based on retrospective studies which are a well-known
source of biases (especially regarding treatment schemes variability), a possible explanation for those
Several studies showed that circulating tumor cells could be detected by molecular techniques in
peripheral blood and/or bone marrow samples in patients with ES. The persistence of these cells after
treatment or their reappearing after a period of latency is synonymous with shortened relapse-free
intervals as compared with tumor-free samples
Secondary molecular alterations in genes regulating cellular growth and differentiation occur
frequently in ES, especially in those cases associated with EWS-FLI1 transcripts other than type 1
Among them, alterations (deletions, mutations) of the p16INK4 , p14ARF,
p27KIP1 and p53 tumor suppressors genes are of great importance, correlating frequently with
aggressive behavior and poor chemoresponse . hTERT upregulation by EWS-ETS fusion proteins also
contribute to the developement of ES  and, indeed, telomerase activity was found to be a strong
negative prognosticator in ES . Dysregulation of many other pathways including that of cyclin D1,
PDGF-C, c-Myc, TGF- b receptor II, insulin-like growth factor-1 receptors, FHIT, and VEGF have also been
associated with the development of ES
Gene expression profiling technology has provided us with
new insights into the molecular biology of ES, leading to the identification of high-risk and low-risk
patient groups , and has brought some arguments in favor of targeted therapeutic strategies such as
antiangiogenic agents or antityrosine kinase receptors (anti-IGF-1 receptor). The recent discovery that
ES could originate from bone marrow derived mesenchymal progenitor cells is another major and promising
step in the understanding of ES genesis .
Recent prognostic classifications of rhabdomyosarcoma (RMS) of infancy and childhood showed that
spindle cell and botryoid RMS subtypes have the best prognosis, alveolar RMS (20-25% of RMS cases),
undifferentiated RMS and RMS with extensive/diffuse anaplasia the worst, and that the prognosis of
conventional embryonal RMS is intermediate between the two former categories . Because of the
propensity of alveolar RMS for local recurrence, early metastatic dissemination and resistance to
treatment, patient with this neoplasm are usually enrolled in intensive (chemo)therapeutic protocols.
Thus, identifying an alveolar RMS component is of paramount importance as it directly influences
treatment and outcome. As opposed to embryonal RMS which is characterized by a loss of heterozygosity on
the short arm of chromosome 11 (11p15.5), most alveolar rhabdomyosarcomas bear either the t(2;13)
(q35;q14) (70-80% of cases) or the t(1;13) (p36;q14) (10%) translocation (see table1). From a diagnostic
point of view, detection of PAX3-FKHR and PAX7-FKHR fusion transcripts (resulting from the t(2;13) and
t(1;13) translocations, respectively), in a small round cell tumor displaying adequate histopathologic
and immunohistochemical features, is synonymous with alveolar RMS. Molecular testing is particulartly
important either for the recognition of the solid variant of alveolar RMS or for reliably identifying an
alveolar component in an otherwise embryonal-looking tumor. RT-PCR-based techniques are highly sensitive
for the detection of tumor-specific fusion transcripts allowing for the detection of a few tumor cells
admixed with many nontumor cells. This method is, thus, particularly suitable for assessing the presence
of few residual tumor cells in bone marrow or peripheral blood samples before and after chemotherapeutic
The PAX3-FKHR fusion is often associated with the classical alveolar growth pattern
and the presence of multinucleate giant cells, whereas tumors with PAX7-FKHR fusion tend to show lower
apoptotic/mitotic activity . From a prognostic point of view, tumors with PAX7-FKHR fusion tend to
behave less aggressively than PAX3-FKHR. In a series of 34 cases, Kelly et al.  first noticed
better outcomes among the PAX7-FKHR group by univariate analysis. A subsequent retrospective anaylsis
 confirmed these results, showing that, in the context of metastatic disease, patients with
t(1;13)-positive alveolar RMS do significantly better in terms of survival than those with the t(2;13)
translocation (4-year survival: 75% versus 8%). Bone marrow involvement was also significantly more
frequent in PAX3-FKHR-positive patients . Since the number of cases (n=19) examined was very small,
these results need to be confirmed in well-controlled prospective studies incorporating a larger number
Early detection of RMS cells in bone marrow or peripheral blood samples has been shown to be
prognostically relevant. In 1997, Kelly et al.  showed that, using RT-PCR, tumor cells from
alveolar rhabdomyosarcoma were detectable in bone marrow (but not in peripheral blood samples) from
patients for whom there was no histologic evidence of disease by conventional light microscopic
examination. This capacity of RT-PCR to detect ocult metastatic disease was subsequently confirmed by
others , which supports a positive role for RT-PCR in staging and follow-up procedures. As for Ewing
sarcoma, the presence of alveolar rhabdomyosarcoma tumor cells in bone marrow, as detected by RT-PCR
alone, seems to be predictive of shortened disease-free survival and/or overall survival
suggesting that these patients should be treated with more intensive therapy. RT-PCR can also be used as
a method to assess the efficacy (chemosensitivity) of chemotherapeutic protocols, based on the monitoring
of tumor cell clearance in bone marrow and/or peripheral blood samples after drug administration .
Beside the potential prognostic value of fusion transcripts in terms of survival, molecular studies
also confirmed that myogenin is a reliable immunohistochemical marker of alveolar RMS and that this
marker could be used in routine practice in making the distinction between alveolar and embryonal RMS
In the series of Hostein et al. , 72% of those neoplasms containing >50% myogenin-positive
cells were PAX fusion positive, including 89% of alveolar rhabdomyosarcomas. Interestingly, 11% of these
tumors had been classified as embryonal rhabdomyosarcomas prior to molecular examination, underlining the
fact that any tumor displaying >50% myogenin-positive cells should be tested for PAX fusion
transcripts before being (mis)diagnosed as an embryonal RMS. By contrast, all tumors containing less
than 50% myogenin-positive cells were PAX fusion negative. Recently, gene expression profiling analyses
identified a list of genes that might be of value in discriminating between RMS of favorable and
unfavorable outcome (e.g. essentially between ARMS and non ARMS), including AP2 b , P-cadherin, EGFR, and
fibrillin-2 . AP2 b and P-cadherin were expressed essentially in alveolar RMS (specificity: 98%;
sensitivity: 64%) whereas EGFR and fibrillin-2 were detected in embryonal rhabdomyosarcoma with a
specidicity of 90% and a sensitivity of 60% .
Amplification and/or overexpression of N-MYC was associated with adverse outcome in alveolar
rhabdomyosarcoma . The development of molecular-based targeted therapies (e.g. epidermal growth
factor tyrosine kinase inhibitors, rapamycin analogues, a vaccine directed against small peptide
fragments spanning the PAX3-FKHR fusion, etc..) in the treatment of rhabdomyosarcoma is just at the
beginning [reviewed in ref. 37].
Synovial sarcoma (SS) accounts for 10 to 15% of STS and can be confused with numerous other STS types
including MPNST, Ewing sarcoma, and fibrosarcoma. As opposed to many other sarcoma subtypes, SS is
(relatively) chemosensitive and, thus, accurate identification is of relevance for patients. SS bears
the t(X;18) translocation which involves the SYT gene on chromosome 18 (18q11) and either the SSX1
or the SSX2 genes on chromosome X (p11.23), only rarely SSX4 . SSX1 and SSX2 are involved in 95% of
SS, regardless of morphology. The t(X;18) translocation is specific for SS and is not observed outside
this tumor type. Besides the diagnostic usefulness of the detection of the t(X;18) translocation, it has
been suggested that fusion type could be an important prognostic factor in SS patients
a preliminary study  suggested that tumors harboring the SYT-SSX1 fusion were more aggressive and had
a higher propensity for metastatic dissemination than SYT-SSX2 neoplasms. These results were confirmed
by subsequent studies  ,
including a large multi-institutional study of 243 patients . In the
latter study, fusion type emerged as the most important prognostic factor for overall survival, by
multivariate analysis, in patients with localized disease at diagnosis. A similar work performed by the
French Sarcoma Group failed to confirm these results , showing that histologic grade, not fusion
type, was the best predictor of outcome. Even worse, In the study of the French sarcoma Group, SSX2
tumors had a worse outcome compared to SSX1 tumors, a finding also observed by Nakagawa et al.  in a
smaller series. In both the Ladanyi et al., and the FNCLCC studies, biphasic SS were rarely associated
with SYT-SSX2 transcripts, suggesting a close relationship between morphology and genetics. The
prognostic value of chromosomal instabilities in SS has also been examined. A recent study showed that
tumors harbouring an increased number of genetic aberrations (≥3) had a worse clinical course, and
that gains of SAS and loss of CCND1 genes were negative prognostic indicators . Studies of gene
expression in SS showed that many SS overexpress EGFR, C-Erb2 (especially in the epithelial component of
biphasic SS), IGF2, insulin-like growth factor receptor-1 and insulin-like growth factor binding proteins
As these proteins seem to play a significant role in SS growth and maintenance, inhibition of
these signalling pathways may represent a promising therapeutic approach. High Ki-67 proliferative index
and p53 overexpression also correlated with an increased risk of tumor recurrence
Most myxoid liposarcomas bear the translocation t(12;16) (>95% of cases), involving the FUS/TLS
gene on 16p11 and the CHOP gene on 12q13, or the t(12;22) translocation (see Table 1) . As in many
translocation-positive sarcomas, the genomic breakpoints of the t(12;16) are widely dispersed in specific
introns of the TLS and CHOP genes and vary from one tumor to another. In a recent study, Antonescu et
al.  showed that the molecular variability of chimeric fusion transcripts in myxoid LPS had no
significant impact on disease-free survival and histologic grade. Overexpression of P53 and reduced
expression of p14ARF and p16INK4, as assessed by immunohistochemistry are observed more frequently in the
round cell component and correlate with poor prognosis
Myxoid liposarcoma can easily be
confused with a well-differentiated LPS showing extensive myxoid changes, especially in the
retroperitoneum. In this situation, the detection of fusion transcripts characteristic of the t(12;16)
or t(12;22) translocations is of paramount importance. Along the same lines, it has been shown that
multifocal myxoid liposarcomas do not exist but, rather, represent metastatic deposits from a single,
monoclonal lesion .
Well-Differentiated and Dedifferentiated Liposarcoma
In the last 10 years, significant achievements have been made in the diagnostic approach and molecular
biology of the well-differentiated/dedifferentiated liposarcoma category. Well-differentiated
liposarcomas can easily be confused with benign lesions (lipoma with myxoid changes, spindle
cell/pleomorphic lipoma, lipoblastoma, angiomyolipoma, etc.) whereas dedifferentiated liposarcomas are
often confused with spindle cell/pleomorphic sarcomas such as so-called MFH, fibrosarcoma, MPNST,
leiomyosarcoma, myxofibrosarcoma and even myxoid liposarcoma, if myxoid changes predominate. The
distinction between dedifferentiated liposarcoma and other sarcoma subtypes is of import, since the
clinical course of the former is much more indolent, with a high risk of local recurrence but low risk
for metastatic dissemination (15-20%). Karyotypically, well-diff/dediff LPS harbour characteristically
supernumerary ring and/or giant chromosomes composed of 12q13-15 amplicons Several genes situated in this
region can be amplified including HMG-A2 (HMGI-C), MDM2 (murine double minute-2), CDK4 (cyclin dependent
kinase 4), SAS (sarcoma amplified sequence), GLI, CHOP, etc... [reviewed in ref 47 and 51]. In contrast
to well-differentiated LPS, dedifferentiated LPS show additional chromosomal abnormalities especially in
the 1p32, 12q24 et 6q23 regions which might correlate with loss of lipogenic differentiation and
increased aggressiveness . Mdm2 and cdk4 amplifications/overexpression, which can be detected using
FISH, quantitative PCR or immunohistochemistry are seldom observed in other sarcoma types [reviewed in
ref 51], and, thus, can be used as a diagnostic tool to identify the well-diff/dediff liposarcoma
category. As a matter of fact, it appeared that many spindle cell and pleomorphic sarcomas of the
retroperitoneum and of the inguinal/paratesticular region called "MFH" were actually unrecognized
Areas of heterologous differentiation in dedifferentiated
liposarcomas are consistently positive for mdm2 and/or cdk4. Crucially, whereas pure myogenic sarcomas
(leiomyosarcoma, rhabdomyosarcoma) display aggressive clinical behaviour, dedifferentiated liposarcomas
showing myogenic (i.e. smooth muscle or skeletal muscle) heterologous differentiation have the same
indolent clinical course as conventional dedifferentiated liposarcomas.
Sarcomas with Myogenic Differentiation
In a recent re-evaluation of 100 so-called MFH, Fletcher et al.  observed that pleomorphic
sarcomas which showed myogenic differentiation (i.e leiomyosarcoma, rhabdomyosarcoma and myogenic sarcoma
NOS) were associated with a more aggressive behavior, higher metastatic rate and shorter time to
metastasis than those lacking myogenic differentiation. Although the minimum quantity of cells positive
for myogenic markers and the intensity of staining required for a tumor to be classified as "myogenic"
were not clearly stated in their paper, it was the first time that myogenic differentiation, as a whole,
was shown to be an adverse prognostic factor. This was confirmed subsequently by other studies
Deyrup et al.  showed that this negative effect was maintained even after adjusting for tumor grade,
tumor size, tumor extent, and patient age, and that increasing myoid differentiatioin correlated with
worse survival (additive effect of myoid differentiation). Thus, patients with pleomorphic sarcomas that
express myoid antigens might benefit from the development of better adjuvant therapies.
Many sarcomas bear histotype-specific chromosomal abnormalities, including reciprocal translocations.
These abnormalities are currently used as diagnostic markers but can also be of value in assessing the
prognosis of a given neoplasm, in detecting residual disease after treatment, or for early detection of
infraclinical relapse. In terms of prognosis, Ewing sarcoma, alveolar rhabdomyosarcoma, and GIST have
benefited most from molecular advances, whereas the prognostic value of fusion transcripts in synovial
sarcoma is still under discussion. New techniques such as gene expression profiling will provide us with
new insights in the pathogenesis, maintenance, and outcome of soft tissue sarcomas, allowing the
development of more specific therapies.
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Table 1 : Main chromosomal abnormalities that can be used for the diagnosis and/or prognosis of soft tissue sarcomas
|Sarcoma type ||Chromosomal Abboldities ||Genes Involved ||Prevalence|
|Ewing sarcoma/PNET ||t(11;22) (q24;q12)|
|Synovial sarcoma ||t(X;18) (p11;q11) ||SYT(SS18)-SSX1|
|Myxoid liposarcoma ||t(12;16) (q13;p11)|
|Alveolar rhabdomyosarcoma ||t(2;13) (q35;q14) |
|Clear cell sarcoma ||t(12;22) (q13;q12)|
|Extraskeletal myxoid chondrosarcoma ||t(9;22) (q22;q12) |
t(9 ;17) (q22;q11)
t(9 ;15) (q22;q21)
|Desmoplastic small round cell tumor ||t(11;22) (p13;q12) ||WT1-EWS ||>90%|
|Low-grade fibromyxoid sarcoma ||t(7;16) (q32-34;p11)|
|Dermatofibrosarcoma protuberans /giant cell fibroblastoma ||t(17 ;22) (q22;q13)|
ring 17q, ring 22q, der(22)
|Alveolar soft part sarcoma ||t(X ;17) (p11.2;q25) ||ASPL-TFE3 ||>90%|
|Infantile fibrosarcoma (cell. mesoblastic nephroma) ||t(12 ;15) (p13;q25) ||ETV6(TEL)-NTRK3(TRKC) ||80-90%|
|Well-differentiated / dediff. liposarcoma ||giant chromosomes / ring chromosomes (12q14-15) ||MDM2, CDK4 amplified ||80%|
|Inflammatory myofibroblastic tumor ||t(2;19) (p23;p13.1)|
other 2p23 rearrangements
|Rhabdoid tumor || -22q11.2 ||INI1 (hSNF5/SMARCB1) loss ||70%|