Annals of Oncology 21 (Supplement 5): v198–v203, 2010
doi:10.1093/annonc/mdq209clinical practice guidelines
Soft tissue sarcomas: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
P. G. Casali1 & J.-Y. Blay2
On behalf of the ESMO/CONTICANET/EUROBONET Consensus Panel of experts*
1Department of Cancer Medicine, Istituto Nazionale dei Tumori, Milan, Italy; 2INSERM U590, Claude Bernard University and Department of Oncology, Edouard Herriot
Hospital, Lyon, France
The following recommendations apply to adult-type soft tissue
sarcomas arising from limbs and superficial trunk.
Recommendations on retroperitoneal sarcomas, desmoid-
type fibromatosis, uterine sarcomas head and neck sarcomas
and breast sarcomas are provided separately at the end of the
chapter with regard to those main aspects by which they differ
from more frequent soft tissue sarcomas.
In general, the main principles of diagnosis and treatment
may well apply to all soft tissue sarcomas, including the
rarest presentations [e.g. visceral sarcomas other than
gastrointestinal stromal tumours (GISTs)], which therefore are
not specifically covered. Specific histological types, however,
may deserve specific approaches, not necessarily covered
hereafter, given the scope of these Recommendations.
Extraskeletal Ewing sarcoma as well as embryonal and alveolar
rhabdomyosarcoma are covered by other ESMO Clinical
Practice Guidelines, inasmuch as they need completely different
approaches. The same applies to GIST. Kaposi’s sarcoma is
excluded from this chapter.
incidence
Adult soft tissue sarcomas are rare tumours, with an estimated
incidence averaging 5/100 000/year in Europe.
diagnosis
Soft tissue sarcomas are ubiquitous in their site of origin,
and are often treated with multimodality treatment. A
multidisciplinary approach is therefore mandatory in all cases
(involving pathologists, radiologists, surgeons, radiation
therapists, medical oncologists and paediatric oncologists if
applicable). This should be carried out in reference centres
for sarcomas and/or within reference networks sharing
multidisciplinary expertise and treating a high number of
patients annually. These centres are involved in ongoing clinical
trials, in which sarcoma patients’ enrolment is highly
encouraged. This centralized referral should be pursued from
the time of the clinical diagnosis of a suspect sarcoma. In
practice, referral of all patients with a lesion likely to be
a sarcoma would be recommended. This would mean referring
all patients with an unexplained deep mass of soft tissues,
or with a superficial lesion of soft tissues having a diameter
of >5 cm, or arising in paediatric age.
In soft tissue tumours, MR is the main imaging modality,
although radiographs should be the first step to rule out a bone
tumour, to detect a bone erosion with a risk of fracture and
to show calcifications. CT has a role in calcified lesions to rule
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: August 2003, last update March
2010. This publication supercedes the previously published version—Ann Oncol 2009;
20 (Suppl 4): iv132–iv136.
Conflict of interest: Dr Casali has reported that he is currently conducting research
sponsored by Amgen Dompe´, Merck SD, Glaxo SK, Lilly, Novartis, Pfizer, PharmaMar,
Sanofi-Aventis and Schering Plough. He had a consultancy role with and/or received
honoraria for lectures from Merck SD, Novartis, Pfizer, PharmaMar, Sanofi-Aventis. He
has received travel coverage for medical meetings from Novartis and PharmaMar; Prof.
Blay has reported that he is a consultant for Pfizer, Novartis, GSK, Roche and
Pharmamar. Consensus panel’s conflict of interest: Prof. Aglietta has reported that he
has received research grants from Bayer, Amgen, Roche and Novartis; Prof. Alvega˚rd
has reported no conflicts of interest; Dr Athanasou has reported no conflicts of interest;
Dr Bihn has not reported any conflicts of interest; Dr Bonvalot has reported that she has
received honoraria from Novartis and grants from Pharmamar; Dr Boukovinas has
reported that he is a member of the speakers’ bureau for Novartis; Prof. De Alava has
reported no conflicts of interest; Dr Dei Tos has reported no conflicts of interest; Dr Dileo
has reported no conflicts of interest; Dr Eriksson has reported that he has received
honoraria from Novartis, MSD, Pfizer, Swedish Orphan and GSK; Dr A. Ferrari has
reported no conflicts of interest; Dr S. Ferrari has reported that he has participated in
researches sponsored by Pharmamar and Ariad; Dr Garcia Del Muro has reported no
conflicts of interest; Dr Gronchi has reported no conflicts of interest; Dr Hall has reported
no conflicts of interest; Prof. Hassan has reported that at present he has no conflicts of
interest, but he is planning trials with Takeda and Pharmamar; Prof. Hogendoorn has
reported no conflicts of interest; Dr Hohenberger has not reported any conflicts of
interest; Dr Gelderblom has reported no conflicts of interest; Dr Grimer has reported no
conflicts of interest; Prof. Issels has reported no conflicts of interest; Dr Joensuu has
reported no conflicts of interest; Dr Jost has reported no conflicts of interest; Prof.
Judson has reported that he has received honoraria for participation in advisory boards
meetings from Novartis, Pfizer, PharmaMar and Ariad; Dr Juergens has reported no
conflicts of interest; Dr Le Cesne has reported that he has received honoraria from
Novartis, Pfizer and PharmaMar; Dr Leyvraz has not reported any conflicts of interest; Dr
Martin-Broto has reported no conflicts of interest; Dr Montemurro has reported no
conflicts of interest; Prof. Nishida has reported that he is currently conducting research
partly funded by Novartis Pharma; Dr Shreyaskumar has reported no conflicts of
interest; Dr Reichardt has reported that he is a member of the speakers’ bureau and
Advisory Board for PharmaMar; Dr Robinson has reported no conflicts of interest; Dr
Rutkowski has reported that he has received honoraria from and that he is a member of
the speakers’ bureau of Novartis; Prof. Scho¨ffski has reported that he is conducting
research sponsored by Novartis, Pfizer, PharmaMar, Eisai, GlaxoSmithKline, Infinity and
Genentech and that he is a member of the speakers’ bureau for Novartis, Pfizer,
PharmaMar, Eisai, GlaxoSmithKline; Dr Schlemmer has reported that he is currently
conducting research funded by Novartis; Dr Sleijfer has reported no conflicts of interest;
Dr Van der Graaf has reported no conflicts of interest; Dr Vanel has reported no conflicts
of interest; Prof. Verweij has reported no conflicts of interest; Dr Wardelmann has not
reported any conflicts of interest; Dr Whelan has reported no conflicts of interest.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
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out a myositis ossificans, and in retroperitoneal tumours,
where the performance is identical to MR.
Following proper imaging assessment, the standard
approach to diagnosis consists of multiple core needle
biopsies (by using needles >16G). However, an excisional
biopsy may be the most practical option for superficial lesions
of <5 cm. An open biopsy may be another option in selected
cases. Immediate evaluation of tissue viability may be
considered, to make sure the biopsy is adequate at the time
it is done. However, a frozen-section technique for immediate
diagnosis is not encouraged, because generally it does not
allow a complete diagnosis, especially when a preoperative
treatment is planned. Fine-needle aspiration is used only in
some institutions, which have developed specific expertise on
this procedure, and is not recommended outside these centres.
A biopsy may underestimate the tumour malignancy grade,
so that, when preoperative treatment is an option, radiological
imaging may add to pathology in providing the clinician with
information that helps to estimate the malignancy grade
(e.g. necrosis). The biopsy should be performed by a surgeon
or a radiologist, after interdisciplinary discussion, as needed.
It should be planned in such a way that the biopsy pathway
and the scar can be safely removed on definitive surgery.
The biopsy entrance point is preferably tattooed. The tumour
sample should be fixed in formalin in due time (Bouin
fixation should be banned, since it prevents molecular
analysis).
Histological diagnosis should be made according to the latest
World Health Organization (WHO) classification.
A pathological expert second opinion is recommended in
all cases where the original diagnosis was made outside
reference centres.
The malignancy grade should be provided in all cases in
which this is feasible based on available systems. The Federation
Nationale des Centres de Lutte Contre le Cancer (FNCLCC)
grading system is generally used, which distinguishes three
malignancy grades based on differentiation, necrosis and
mitotic rate. Whenever possible, the mitotic rate should be
provided independently. An effort should be made to improve
the reliability of mitotic count as actually recorded.
Tumour site should be properly recorded. Tumour size and
tumour depth (in relation to the muscular fascia) should be
recorded, since they entail a prognostic value, along with
malignancy grade. The pathology report after definitive surgery
should mention whether the tumour was intact and should
include an appropriate description of tumour margins (i.e. the
status of inked margins and the distance between tumour
edge and the closest inked margins). This allows assessment
of marginal status (i.e. whether the minimum margin is
intralesional, marginal, wide and distances from surrounding
tissues). The pathological assessment of margins should be
made in collaboration with the surgeon.
If preoperative treatment was carried out, the pathology
report should include a tumour response assessment. In
contrast to osteosarcoma and Ewing sarcoma, however, no
validated system is available at present in this regard, and no
percentage of residual ‘viable cells’ is considered to have
a specific prognostic significance. This depends on several
factors, including the presence of non-treatment-related
necrosis and haemorrhage and the heterogeneity of post-
treatment changes. A multidisciplinary judgement is
recommended, involving the pathologist and the radiologist.
Pathological diagnosis relies on morphology and
immunohistochemistry. It should be complemented by
molecular pathology [fluorescent in situ hybridization (FISH),
reverse transcription–polymerase chain reaction (RT–PCR)],
especially when: (i) the clinical pathological presentation is
unusual; (ii) the specific histological diagnosis is doubtful;
(iii) it may have prognostic/predictive relevance.
External quality assurance programmes are encouraged for
laboratories performing molecular pathology assessments.
Collection of fresh frozen tissue and tumour imprints (touch
preps) is encouraged, because new molecular pathology
assessments could be made at a later stage in the patient’s
interest. Informed consent for tumour banking should be
sought enabling later analyses and research, as long as this is
allowed by local and international guidelines.
stage classification and risk
assessment
The American Joint Committee on Cancer (AJCC)/
International Union against Cancer (UICC) stage classification
system stresses the importance of the malignancy grade in
sarcoma. However, its use in routine practice is limited. In
addition to grading, other prognostic factors are tumour size
and tumour depth. Of course, tumour resectability is also
important.
staging procedures
The surgical report, or patient chart, should provide details on:
the preoperative and intraoperative diagnosis; the surgical
conduct, including possible contamination (i.e. it should
mention whether the tumour was opened, was ‘seen’ during the
excision, etc.); surgical actual completeness vis-a`-vis planned
quality of margins.
A chest spiral CT scan is mandatory for staging purposes.
Depending on the histological type and other clinical
features, further staging assessments may be recommended
(i.e. regional lymph node clinical assessment for synovial
sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear
cell sarcoma; abdominal CT scan for myxoid liposarcoma, etc.).
treatment
limited disease
Surgery is the standard treatment for all patients with adult-
type, localized soft tissue sarcomas. It must be performed by
a surgeon specifically trained in the treatment of this disease.
The standard surgical procedure is a wide excision with
negative margins (R0). This implies removing the tumour with
a rim of normal tissue around. One centimetre has been
selected as a cut-off in some studies, but it is important to
realize that the margin can be minimal in the case of resistant
anatomical barriers, such as muscular fasciae, periostium and
perineurium. A marginal excision may be acceptable as an
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individualized option in highly selected cases, in particular for
extracompartmental atypical lipomatous tumours.
Wide excision followed by radiation therapy is standard
treatment in high-grade, deep lesions, >5 cm. Radiation therapy
is not given in the case of a truly compartmental resection of
a tumour entirely contained within the compartment. With
exceptions to be discussed in a multidisciplinary setting, and in
the face of a lack of consensus across reference centres, also
high-grade, deep, <5 cm lesions are treated with surgery
followed by radiation therapy. Radiation therapy is added in
selected cases in the case of low-grade, superficial, >5 cm,
and low-grade, deep, <5 cm soft tissue sarcoma. In the case
of low-grade, deep, >5 cm soft tissue sarcoma, radiation
therapy should be discussed in a multidisciplinary fashion,
considering the anatomical site and the related expected
sequelae versus the histological aggressiveness. Overall,
radiation therapy has been shown to improve local control,
but not overall survival. Radiation therapy should be
administered postoperatively, with the best technique available,
at a dose of 50–60 Gy, with fractions of 1.8–2 Gy, possibly
with boosts up to 66 Gy, depending on presentation and quality
of surgery. Alternatively, radiotherapy may be carried out
preoperatively, normally using a dose of 50 Gy. Intraoperative
radiation therapy (IORT) and brachytherapy are options in
selected cases.
Re-operation in reference centres must be considered in the
case of R1 resections, if adequate margins can be achieved
without major morbidity, taking into account tumour extent
and tumour biology (e.g. it may be spared in
extracompartmental atypical lipomatous tumours, etc.). In the
case of R2 surgery, re-operation is mandatory, possibly with
preoperative treatments if adequate margins cannot be
achieved, or surgery is mutilating. In the latter case, the use of
multimodal therapy with less radical surgery requires shared
decision-making with the patient under conditions of
uncertainty. Plastic repairs and vascular grafting should be used
as needed, and the patient should be properly referred if
necessary. Radiation therapy will obviously follow marginal or
R1–R2 excisions, if these cannot be rescued through re-excision,
even outside the usual indications (see above). In non-resectable
tumours, or those amenable only to mutilating surgery (in
this case, on an individualized basis after sharing the decision
with the patient in conditions of uncertainty), chemotherapy
and/or radiotherapy, or isolated hyperthermic limb perfusion
with tumour necrosis factor-a (TNFa) + melphalan, if the
tumour is confined to an extremity, or regional hyperthermia
combined with chemotherapy, are options.
Regional lymph node metastases should be distinguished
from soft tissue metastases involving lymph nodes. They are
rare, and constitute an adverse prognostic factor in adult-type
soft tissue sarcomas. More aggressive treatment planning is
therefore felt to be appropriate for these patients, although
there is a lack of formal evidence to indicate that this improves
clinical results. Surgery through wide excision (mutilating
surgery is exceptionally done given the prognosis of these
patients) may be coupled with adjuvant radiation therapy and
adjuvant chemotherapy for sensitive histological types, as
standard treatment for these presentations. Chemotherapy may
be administered as preoperative treatment, at least in part.
These treatment modalities adding to surgery should not be
viewed as truly ‘adjuvant’, the context being in fact that of
a likely systemic disease. In one large randomized phase III
study (in patients with G2–3, deep, >5 cm soft tissue sarcomas),
regional hyperthermia in addition to systemic chemotherapy
was associated with a local and disease-free survival advantage.
Isolated limb perfusion may be an option in this patient
population, along with chemotherapy and radiation therapy.
Data have been provided that adjuvant chemotherapy might
improve, or at least delay, distant and local recurrence in
high-risk patients. A meta-analysis found a statistically
significant, limited benefit in terms of both survival and
relapse-free survival. However, studies are conflicting, and
a final demonstration of efficacy is lacking. It is also unknown
whether adjuvant chemotherapy may be especially beneficial
in specific subgroups. Therefore, adjuvant chemotherapy is not
standard treatment in adult-type soft tissue sarcomas, and
can be proposed as an option to the high-risk individual patient
(having a >G1, deep, >5 cm tumour) for shared decision-
making with the patient [II, C]. Adjuvant chemotherapy is not
used in histologies known to be insensitive to chemotherapy.
If the decision is made to use chemotherapy as upfront
treatment, it may well be used preoperatively, at least in part.
A local benefit may be gained, facilitating surgery. In one large
randomized phase III study (in patients with G2–3, deep, >5 cm
soft tissue sarcomas), regional hyperthermia in addition
to systemic chemotherapy was associated with a local and
disease-free survival advantage (no survival benefit
demonstrated). If used, adjuvant chemotherapy should consist
of the combination chemotherapy regimens proven to be
most active in the advanced disease.
The standard approach to local relapse parallels the approach
to primary local disease, except for a wider resort to
preoperative or postoperative radiation therapy, if not
previously performed.
extensive disease
Metachronous resectable lung metastases without
extrapulmonary disease are managed with complete excision
of all lesions as standard treatment [IV, B]. Chemotherapy may
be added as an option, taking into account the prognostic
factors (a short previous free interval and a high number of
lesions are adverse factors, encouraging the addition of
chemotherapy), although there is a lack of formal evidence
that this improves results. Chemotherapy is preferably given
before surgery, in order to assess tumour response and thus
modulate the length of treatment. In the case of lung metastases
being synchronous, in the absence of extrapulmonary disease,
standard treatment is chemotherapy [IV, B]. Especially when
a patient benefit is achieved, surgery of completely resectable
lung metastases may be offered as an option.
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