Review Article
Factors Predictive of Survival in Synovial Sarcoma; a Review of the Literature
Sharp SJE1 and Choong PFM2,3*
1University of Melbourne, Australia
2Department of Orthopaedics, St. Vincent’s Hospital Melbourne, Australia
3Department of Surgery, St. Vincent’s Hospital Melbourne, University of Melbourne, Australia
*Corresponding author: Choong PFM, Department of Surgery,
St. Vincent’s Hospital Melbourne,
University of Melbourne, Australia
Published: 29 Jul 2016
Cite this article as: Sharp SJE, Choong PFM. Factors
Predictive of Survival in Synovial
Sarcoma; a Review of the Literature.
Clin Oncol. 2016; 1: 1051.
Abstract
Background: Synovial sarcomas are a rare malignant mesenchymal soft tissue tumour, with
generally poor prognosis due to a high degree of local invasiveness and propensity to metastasise.
Despite sharing a common translocation signature, tumour behaviour is highly variable with wide
heterogeneity in patient outcomes. Limited data exists in the literature regarding prognostic factors
and treatment modalities. This review aims to summarise current literature findings to help better
prognosticate patients and evaluate treatment modalities.
Methods: A critical literature review of the English language literature from 2000 was conducted
utilising MEDLINE (via OVID) software and searching the terms “synovial sarcoma” alone or in
combination with “prognosis”, “radiotherapy”, “chemotherapy” and “neoadjuvant therapy”. 331
articles were retrieved; full-text articles specifically evaluating outcomes in synovial sarcoma were
included; unavailable full texts (68) case reports (113) and non-synovial sarcoma related (73)
articles were excluded. Further articles (20) were identified by cross referencing the bibliographies
of relevant papers; in total 97 papers remained eligible for analysis.
Conclusion: Adverse prognostic factors include: increasing age at diagnosis, male gender, increasing
tumour size, deep sited tumours, monophasic and poorly differentiated subtypes, increasing
necrosis, increasing mitotic activity, higher genomic complexity, non-specialist treatment centre
and inadequate margins. New immunohistochemical markers are emerging that may also assist
with prognostication. Radiotherapy improves local control and may offer further survival benefits.
Chemotherapy should be reserved for high risk patient groups.
Introduction
Synovial sarcomas (SS) are rare malignant mesenchymal soft tissue tumours(STS), accounting for approximately 6-8% of all malignant STS [1,2]. They are considered high grade with poor prognosis, due to a high degree of local invasiveness and propensity to metastasise [1]. It commonly occurs in adolescents and young adults, mostly within the age range of 15-40 years [3]. Contemporary 5-year overall survival (OS) rates for SS have been reported as ranging from 61% to 73% [1,3-6]. Thetranslocation of (X;18)(p11;q11), results in either of three possible gene fusions, SYT-SSX1, SYTSSX2 or rarely SYT-SSX4 and is highly specific for SS, present in 95% cases. Despite this common translocation, SS interestingly displays various histological subtypes. SS may be characterised by epithelial-like and spindle cell components arranged in either a monophasic pattern, composed entirely of spindle cells; biphasic pattern, composed of both spindle cells and epithelial cells; or poorly differentiated form. SS demonstrate highly diverse clinical and biological behaviours, with substantial heterogeneity in patient outcome. Various prognostic factors and treatment modalities have been described, however due to the rarity of the tumour, high level evidence remains lacking. In recent years, many new studies have emerged proposing various prognostic factors in patients with SS; while some findings are consistent with previously published findings, others remain contentious. The purpose of this review is to summarise recent literature findings to facilitate better prognostication of patients, which may then help inform treatment choices.
Predicting Survival Outcome
Gender
The effect of gender on survival outcome has been variably reported. Some early studies found
that gender had nosignificant effect on overall survival [7-9]. A number of more recent studies have reported male gender to have inferior survival outcomes on
significant on univariate analysis [10-13]. These studies have all
been limited by relatively small sample sizes (n=42-165) and lack of
multivariate analysis concordance. Most recently, a large analysis of
the Surveillance, Epidemiology and End Results (SEER) database
from North America found that male gender on multivariate
analysis conferred an adverse survival outcome, with a hazard ratio
(HR) compared to female gender for OS of 1.63 (P< 0.001, n=1189)
[6].Validation of the SEER findings are needed from other large
population studies before male gender can be completely described
as an adverse prognosticator. Despite this gender effect seems likely,
given that to date all studies that have reported gender to have
significant survivorship influence haveimplicated male gender with
worse outcomes. It has been speculated that differences in survival by
gender may relate to male sex having a higher incidence of SYT-SSX1
fusion which has been associated with worse survival [14].
Age at diagnosis
Presenting age at diagnosis is a very important determinant of
survival outcome. Most studies have found age at diagnosis to be
significantly correlated with survival outcome on univariate analysis,
with younger patients having improved survival compared to those
of older age [1,3,5,6,11,15-25]. This has also been demonstrated by
various large studies on multivariate analysis [5,6,16,18,19]. The effect
of age on survival outcome is striking. Sultan et al in a large analysis
from the SEER database reported that the 5-year cancer specific
survival was 83% for children/adolescents compared to 62% for adults
(P< 0.001, n=1268) [18]. This finding has been recently corroborated
by another large analysis from the Netherlands Cancer Registry
[19]. Vlenterie et al. [18], recently reportedsignificantly different
(P< 0.001, n=461) survivals of various age groups with localised
SS at diagnosis; children had the best 5-year OS outcome (89.3%),
followed by adolescents and young adults (73%), adults (54.7%) and
elderly (43%). The effect of age was maintained on their multivariate
analysis, with adults having a HR of 4.10 relative to children (P< 0.001,
n=613) [19]. Age at diagnosis therefore appears to be an important
prognosticator in SS.
Tumour size
Of all the prognostic factors evaluated in this review, tumour size
was found to be the prognostic factor most consistently predictive
of OS, event free survival (EFS) and metastases free survival on
univariate analysis(MFS) [3,4,6,11,14,16,20,22,26-41]. Although
increasing tumour size likely reflects underlying disease aggression,
tumour size is also likely to be confounded in part by other variables
such as tumour location and delayed time to presentation. Despite
this, a number of large studies have conducted extensive multivariate
analysis and found tumour size to be an independent prognostic
factor when adjusted for various variables [6,14,19,20,28,33,41]. The
effect to which tumour size affects survival has been variably reported.
Generally, it appears that larger tumour size, especially ≥5cm
predicts poor outcome, whilst size < 5cm is linked to more favourable
outcome. Canter et al. [14] reported that tumours 5-10cm conferred
a HR of 2.75 relative to ≤5cm (P=0.01, n=255). Similarly, Palmerini
et al. [23], found tumours >5cm to confer a RR of 2.20 compared to
≤5cm (P=0.002, n=250) [41]. In the large study by Naing et al. larger
tumour size conferred a HR of 1.13 (P < 0.001, n=1189); however
the threshold and relationship between size and HR was unclear [6].
To date it appears tumour size may reliably be used in prognostic
stratifications, and while the precise relationship between size and
outcome is unclear, tumour size ≥5cm is likely to represent a poorer
prognosis.
Tumour depth
Depth of tumour has also been shown to be predictive of
outcome, with superficial SS conferring better prognosis than deep on
univariate analyses [31]. In the study by Stanelle et al. [28], superficial
SS were associated with significantly better 5-year OS; 90% compared
to 68% deep (P = 0.03, n=111) [28]. Yaser et al. [1], also reported a
survival benefit with superficial tumours, with a 5-year OS of 86% for
superficial tumours compared to 45% deep tumours (P=0.012, n=51)
[1]. Both of these studies have been limited by small study numbers
and univariate analyses. A more recent study by Vlenteri et al. [19], in
a larger cohort (n=461) also found tumour depth to be an important
factor on univariate analysis, however this lost significance on
multivariate analysis [19]. The effect of tumour depth on survival may
beconfounded by difficulty in achieving adequate surgical margins
and possible delays in diagnosis, and further robust validationon
multivariate analyses are needed to adjust for these variables.
Tumour site
Various studies have investigated the impact of SS tumour site on
survival. Location has been demonstrated to be important, with axial
sites conferring the worst prognosis [16], and distal extremity sites
conferring more favourable outcomes [34]. A small study by Paulino
et al. [17] noted that extremity sites had better local control rates than
non-extremity sites, with non-extremity sites treated with wide local
excision conferring a HR of death of 10.14 times the HR of extremity
sites treated with wide local excision (P=0.001, n=44) [17]. A more
modest finding by Orbach et al in contrast found on multivariate
analysis that non-limb site conferred a HR of 2.5 compared to limb
location (P=0.04, n=88) [39]. Ferrari et al. [41], in a pooled study of
STS, of which 107 patients had SS, found that head-neck sites versus
extremity sites conferred a HR of 2.0 (P = 0.001, n=301) [16], Naing et
al. [6], also found similar results with head-neck sites conferring a HR
of 1.88 (P = < 0.001, n=1189) and thoracic sites conferring a HR of 2.66
(P = < 0.001, n=1189) [6]. This relationship between site and outcome
has been corroborated by most studies, and non-extremity tumour
location has demonstrably worse survival outcomes [1,6,11,15-
17,19,28,30,39,42].
Tumour stage/grouping
Tumour stage unsurprisingly has also been found to be predictive
of OS, with higher stage at diagnosis linked to worse OS [8,13,20,39].
Naing et al. [6], found that regional staging compared to localised
staging conferred a HR of 1.61 (P < 0.001, n=1189) [6]. Okcu et al.
[43], found that Intergroup Rhabdomyo sarcoma Study Group (IRS)
group III and IV had particularly poor prognosis; IRS group III had a
HR of 2.7 of whilst IRS group IV conferred a HR of 14.1 [43]. An early
study by Trassard et al also found on multivariate analysis that higher
American Joint Committee on Cancer (AJCC) stage was associated
with less favourable prognosis [13]. A problem with staging tools is
that different institutions utilise different tools; from the previous
examples, Naing et al. [6], utilised a SEER staging tool, Okcu et al.
[43,44], utilised the IRS grouping method and Trassard et al assigned
AJCC stages [13]. It seems likely that higher stage, regardless of
grouping tool utilised, is associated with inferior outcome, however
more consistent use of grouping tools by varying institutions would
help to evaluate this prognostic tool further and enable easier
comparison of results.
Histologic subtype
Conflicting results regarding the effect of histological subtype
on survival outcome have been published. In this review, a number
of studies found that monophasic histology conferred adverse
survival outcome compared to biphasic histology [1,17,45,46], with
one study by Koh et al. [30], even finding that monophasic subtype
was the single most important prognostic factor after metastasis at
presentation, with a HR of 5.714 (P=0.00247, n=41) [30]. Not all
studies have been concordant; Okcu et al. [43] noted a non-significant
trend of patients with biphasic histology having reduced progression
free survival compared to monophasic histology (P=0.14, n=42) [44].
Furthermore, an earlier study by Hasegawa et al found that poorly
differentiated SS conferred a HR of 1.94 compared to monophasic
or biphasic histology subtype (P=0.0095, n=44) [4], a similar finding
was later found by De Silva et al in their analysis of the Scottish Bone
Tumour Registry, with the presence of poorly differentiated areas
conferring a HR of 8 on multivariate analysis relative to no poorly
differentiated areas (P=0.004, n=51).These studies have mostly been
limited by relatively small sample sizes and heterogenous study
groups. A recent large analysis of the National Cancer Data Base of
the American College of Surgeons revealed new observations, with
biphasic histology demonstrated a better 5-year survivorship (65%)
compared to monophasic SS (56%) (P< 0.031, n=3756) [45]. Poorly
differentiated SS was found to the worst prognosis compared to
other histology subtypes, with a 5-year survivorship of 52% (P< 0.001,
n=3756) [45]. From these results, it therefore seems probable that
monophasic, and in particularly, poorly differentiated SS subtypes
confer a worse prognosis than the biphasic subtype.
Tumour necrosis
A number of studies have reported that the presence of
spontaneous tumour necrosis in SS affects survival outcome
[4,11,42,46-48]. Increasing tumour necrosis especially confers worse
outcome; this was demonstrated in a recent study by Setsu et al. which
found varying 5-year OS rates for no necrosis (81.9%), ≤50% necrosis
(35.9%) and >50% necrosis (37%) (P< 0.0001, n=112) [11]. De Silva et
al. [46], also found that higher percentage tumour necrosis resulted
in an increased likelihood of metastases on multivariate analysis, with
a HR of 5.06 conferred (P=0.016, n=51) [46]. Although these studies
are of modest sizes, increased tumour necrosis may reflect increasing
underlying tumour aggression and may assist prognostication.
Mitotic activity and genomic complexity
Increasing mitotic activity has been implicated as conferring
worse outcome in a number of studies [22,38,49]. Although a
component of the FNCLCC grading system, mitotic activity has
recently been demonstrated to be an independent prognostic factor
on multivariate analyses by Song et al (mitoses ≥10 per high powered
field HR 9.182 (P=0.004, n=103) and Tarkan et al. [49]. (mitoses ≥10
per high powered DFS HR 0.3; P=0.017, n=96). Chakiba et al. [50],
recently found that genomic complexity is significantly associated
with MFS, with higher genomic index complexity conferring a HR
of 3.79 (P=0.02, n=65) [50]. Gene expression profiling by Przybyl
et al. [51], in a small group (n=54) has demonstrated that AURKA
and KIF18A are significantly upregulated in SS patients that develop
metastasis/local recurrence or present with metachronous metastatic
disease, compared to patients that do not develop local recurrence
or metastasis [51]. Further work is needed in this area, however it
appears differences in biological behaviour and clinical outcome may
be attributed to significant differences in genomic composition.
Tumour grade
SS has conventionally been considered a high-grade sarcoma [9].
Notwithstanding, SS may be graded according to the published criteria
of Fedération Nationale des Centres de Lutte le Cancer (FNCLCC)
as either Grade II or Grade III [52]. Mounting evidence supports
utilising this approach, with a number of studies finding that Grade
III confers a worse prognosis than Grade II SS [4,5,9,21,40,42,53].`
Indeed, Guillou et al. [9], found that histologic grade III was the
most significant prognostic factor for both disease specific survival
(RR 3.77; P< 0.0001, n=130) and metastases free survival (RR 3.56;
P< 0.0001, n=130) on multivariate analysis [9]. Despite this, until
further research is forthcoming it is best to consider SS as high grade
until the prognostic importance of grading in SS is resolved [54].
Immunohistochemical markers
A number of other immunohistochemical markers have been
explored. Palmerini et al recently found on multivariate analysis that
nuclear expression of CXCR4 (negative expression 5-year OS HR
0.3; P=0.003, n=88) and IGF-1R (negative expression 5-year OS HR
0.4; P=0.04, n=88) are independent adverse prognostic factors for
patient survival [23]. Other antibodies suggested to be of prognostic
value include secernin-1[55], FGFR3[56], surviving [57], EZH2
[58], dysadherin [59] and HER-2 [60]. This area is clearly evolving
and further work is needed, but such research may offer unique
prognostication tools and development of targeted therapies.
Surgical setting
Multiple studies have found on review that unplanned biopsy
and surgical treatment at centres other than tertiary cancer care
centres result in worse oncological outcomes and increased risk of
mismanagement and worsened prognosis [4,53,61,62]. An early study
by Choong et al. [7], found a significantly higher rate of local recurrence
(LR) in patients with SS treated outside their own institution, with
11 of 13 patients who developed LR treated by definitive surgery
outside of their own institution (P< 0.0001, n=113) [7]. A later study
by Ipach et al. [29], found that patients treated with STS at external
centres had twice the rate of local recurrence (LR) compared to their
own specialist cancer centre institution (45.7% at 5 years v 21.2%; P
= 0.013, n=118) [29]. This was further corroborated by Yaser et al.
[1], who also found reduced local recurrence free survival (LRFS)
for externally treated patients; with 5-year LRFS rates of 80% v 21%
(P=0.001, n=51); 5-year OS was also significantly adversely affected
(0% v 78%; P=0.003, n=51) [1]. Difference in survival outcomes
and local recurrence rates likely reflect better planned surgery and
multidisciplinary care and highlight the importance for treatment at
specialist centres where possible.
Surgical margins
Several studies have found that surgical margins are an
important prognostic factor, with inadequate margins conferring
higher risk of LR and metastases compared to clear wide margins
[5,6,11,21,27,35,40,63]. Control of margin status is also important in
improving survival outcomes. A reasonably large study by Italiano
et al. found margin status on multivariate analysis to be significant
for both OS and LRFS, with uncertain margins conferring a HR for
OS of 2.43 (P=0.005, n=237) and a HR for LRFS of 2.43 (P=0.027,
n=237) [5]. More recent studies by Yaser et al. [1] and Stanelle
et al. [28], have also found similar findings. Yaser et al. [1], found
a significant difference (P = 0.001, n=51) in 5-year local recurrence
free survival (LRFS) between negative margins (92%) and positive margins (45%) and 5-year OS (86.5% v 50.3%, P = 0.009) [1]. Stanelle
et al. [28], also found that margin status significantly correlated with
LR (but not metastasis), with negative margins having a LR rate of
16.3% compared to 47.6% in patients who had positive margins (P =
0.002, n=111) [28]. Recently, Tarkan et. [49] alfurther demonstrated
in their cohort that achieving adequate margins significantly affected
both 5-year OS (74% v 28%; P=0.003, n=69) and 3-year disease free
survival (47% v 21%; P=0.005, n=69) [49]. Despite this, some studies
have also found that clear margins did not affect event free survival or
OS [32,64]. For instance, Brecht et al. [33] found that margin status
did not significantly affect OS (P=0.36, n=150) or LRFS (P=0.42,
n=150) [65]. It seems probable that surgical margins significantly
affect the likelihood of LR, however further studies are required to
elucidate to what extent margins must be obtained to offer survival
benefit, particularly in the setting of attempted limb salvage where
patients may be more acceptable of higher level of LR rates if the risk
is low.
Chemotherapy
SS is regarded as a relatively chemo-sensitive subset of STS, and
a recent assessment of use in extremity sarcomas in the United States
found that patients with SS were more likely (OR 1.48; P< 0.001,
n=8649) to receive post-operative chemotherapy than other extremity
sarcomas [66]. Despite this, the role of neoadjuvant chemotherapy
in SS is controversial. Some studies have found improved OS and
metastases free survival [21,36,61,67], whilst others have found it
does not affect OS or metastases rate [8,26,68]. Regimes are typically
ifosfamide based and use appears to be more established in paediatric
patients with SS. An early study by Ferrari et al. [67], in a cohort of
271 mixed adult and paediatric patients with SS found that among
patients treated with surgery, the 5-year MFS was 60% for those
treated with chemotherapy compared to 48% for those who were
not [67]. This benefit of chemotherapy appeared to be greatest for
patients age > 17 years who had tumours measuring > 5 cm (MFS,
47% [chemotherapy] vs. 27% [no chemotherapy]. The conclusions by
Ferrari et al. [67], were however limited in that they reported raw
data findings (n=271) only and did not attempt any univariate or
multivariate analysis; and may further be confounded by selection
bias as benefit was greatest for patients at higher risk [67]. Eilber et al.
[36], later evaluated the use of ifosfamide chemotherapy for high risk
(median tumour size 7cm, monophasic histology 70%) adult patients
with SS. They demonstrated an independently improved (HR 0.4;
P=0.03, n=101) distant-recurrence free survival (DRFS) compared to
patients who did not receive chemotherapy. A later study by Chen et al.
[36] in a cohort of 76 patients also found thatchemotherapy benefited
patients with stage IIB/III SS in disease specific survival (73% with
chemotherapy v 31% with no chemotherapy, P = 0.001), 5-year MFS
(62% with chemotherapy v 19% with no chemotherapy, P = 0.008)
and a prolonged time to metastases (25 months with chemotherapy
v 9 months with no chemotherapy, P = 0.001) [21]. A later multiinstitutional
study by Ferrari et al. [67] demonstrated good response
to neoadjuvant ifosfamide-doxorubicin chemotherapy with 3-year
event free survival rates of 91.2% and 74.4% for intermediate and
high risk groups respectively, compared to 91.7% for low risk patients
who received surgery alone [69]. Other groups have published
opposing findings. Italiano et al found that neither neoadjuvant or
adjuvant chemotherapy had significant impact on OS, LRFS or DRFS
(P>0.05, n=237) [5]. Stanelle et al.[28], in a retrospective review of
111 patients with SS finding that chemotherapy (using doxorubicin,
a combination of doxorubicin and ifosfamide, or a combination of
ifosfamide and etoposide) did not correlate with improved 5-year
survival in any patient group (however the authors do note that the
lack of chemotherapy-associated benefit may represent a selection
bias for patients who were administered chemotherapy) [28]. An
additional study by Al-Hussaini et al. [26], in a mixed study of adult
and paediatric patients also found similar 5-year event free survival
outcomes between patients who received chemotherapy to those who
did not (62.6% v 71.5%; P=0.48, n=102), with no statistical difference
in outcome [26]. Some of these discrepancies may be accounted for
by different chemotherapy regime protocols and different patient
selection criteria; studies with positive findings have mostly selected
high risk patients. Currently insufficient evidence exists to support
the routine use of chemotherapy in SS, and use is better restricted for
higher risk patient populations. Further study, particularly in adult
populations is required to elucidate which patients should receive
adjuvant chemotherapy.
Radiotherapy
For localised disease, surgical resection is frequently combined
with radiotherapy. This was shown by Sherman et al in a large
retrospective study (n=1242) where in addition to surgical resection;
7% patients with SS were treated with neoadjuvant radiotherapy, 25%
with post-operative radiotherapy and 22% with both radiotherapy
and chemotherapy [66][66].Many studies have evaluated the role
of radiotherapy. Most have found that routine use of radiotherapy
results in betteroutcome, especially demonstrated by improved
local control rates [1, 6, 16, 29, 31, 68]. Cumulative doses >60 Gy
have been demonstrated in STS to have the best impact on local
control (P=0.003, n=155) and OS(P=0.048, n=155) compared to
≤60 Gyin one study by Laskar et al.[31]. Interestingly, Ipach et al.
found that the risk of death doubled if no adjuvant chemotherapy
or radiotherapy was provided, although the effect of chemotherapy
from radiotherapy was unclear [29]. A study by Italiano et al. found
that while radiotherapy did not improve DRFS or OS, it significantly
improved LRFS, with a HR of 0.43 in favour of use (P=0.026, n=237)
[5]. Comparable results were found by Palmerini et al, who found a
RR of 1.86 for LRFS when radiotherapy was omitted (P=0.02, n=250)
[41]. Similarly, Song et al found the use of radiotherapy to confer a
LRFS benefit, with a HR of 0.195 in favour of use (P=0.0028, n=103); a
benefit in progression-free survival was also demonstrated with a HR
of 0.248 (P=0.006,n=103)[38].Most recently, Naing et al.evaluatedthe
use of radiotherapy in SS in their large SEER database [6]. They found
that radiotherapy provided significant improvement to OS (HR
= 0.65; P=0.005, n=1189) and disease specific survival (HR = 0.62;
P=0.003, n=1189); with a benefit maintained at 5-years [6]. These
and other studies provide strong evidence for the use of RT in the
treatment of localised SS, due toboth improved local control rates and
potential OS benefit.
Conclusion
Despite their rarity, emerging research is assisting in the development of improved prognostic tools for patients and clinicians. This has been assisted by multi-institutional collaboration and data from large national registries. Although sharing a common fusion translocation, synovial sarcomas are a heterogenous subset of soft tissue sarcomas. Adverse prognostic factors include increasing age at diagnosis, male gender, increasing tumour size, deep sited tumours, monophasic and poorly differentiated subtypes, increasing necrosis, increasing mitotic activity, higher genomic complexity, non-specialist treatment centre and inadequate margins. New immunohistochemical markers are emerging that may also assist with prognostication. Surgical resection with wide margins provides the mainstay of treatment; radiotherapy improves local control and may offer further survival benefits. Chemotherapy should be reserved for high risk patient groups until further research emerges.It is imperative that sarcoma centres collaborate to form multi-institutional randomised trials to raise the quality of evidence available to improve patient outcomes.
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