Incidence of Sarcoma Histotypes and Molecular
Subtypes in a Prospective Epidemiological Study with
Central Pathology Review and Molecular Testing
Franc ¸oise Ducimetie `re1*, Antoine Lurkin1, Dominique Ranche `re-Vince2, Anne-Vale ´rie Decouvelaere2,
Michel Pe ´oc’h3, Luc Istier4, Philippe Chalabreysse5, Christine Muller6, Laurent Alberti7, Pierre-Paul
Bringuier8, Jean-Yves Scoazec8, Anne-Marie Schott9, Christophe Bergeron10, Dominic Cellier11, Jean-
Yves Blay7, Isabelle Ray-Coquard1
1Universite ´ de Lyon, Cancer Centre Leon Berard, EA 4129, Lyon, France, 2Universite ´ de Lyon, Cancer Centre Leon Berard, Department of Pathology, Lyon, France,
3Universite ´ de Saint-Etienne, Centre Hospitalier Universitaire, Department of Pathology, Saint-Etienne, France, 4Laboratory of Pathology, Pringy, France, 5Laboratory of
Pathology, Cypath, Lyon, France, 6Laboratory of Pathology, Grenoble, France, 7Universite ´ de Lyon, Cancer Centre Leon Berard, INSERM U590, Lyon, France, 8Universite ´
de Lyon, Hospices Civils de Lyon, Ho ˆpital Edouard Herriot, Department of Pathology, Lyon, France, 9Universite ´ de Lyon, Hospices Civils de Lyon, Po ˆle IMER, Lyon, France,
10Institut d’He ´matologie et d’Oncologie Pe ´diatrique, Department of Paediatrics, Lyon, France, 11Merck Serono, Scientific Relation, Lyon, France
Background: The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present
population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants,
based on a central pathological review of the cases.
Methodology/Principal Findings: From March 2005 to February 2007, pathology reports and tumor blocks were
prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma
were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health
Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the
study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year.
Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent
histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000),
liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000).
Conclusions/Significance: The observed incidence of sarcomas was higher than expected. This study is the first detailed
investigation of the crude incidence of histological and molecular subtypes of sarcomas.
Citation: Ducimetie `re F, Lurkin A, Ranche `re-Vince D, Decouvelaere A-V, Pe ´oc’h M, et al. (2011) Incidence of Sarcoma Histotypes and Molecular Subtypes in a
Prospective Epidemiological Study with Central Pathology Review and Molecular Testing. PLoS ONE 6(8): e20294. doi:10.1371/journal.pone.0020294
Editor: Joseph Najbauer, City of Hope National Medical Center and Beckman Research Institute, United States of America
Received October 30, 2010; Accepted April 28, 2011; Published August 3, 2011
Copyright: ? 2011 Ducimetiere et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work is financially supported by Merck Serono (http://www.merckserono.fr/fr/index.html), Conticanet (European Connective Tissue Cancer
Network FP6-018806, http://www.conticanet.eu/html/), INCa (French National Cancer Institute, http://www.e-cancer.fr/) and the French national cancer league
(Ain and Rhone committees, http://www.ligue-cancer.net/). Merck-Serono provided intellectual and administrative support and helped the authors organize
steering committees. It is an Academic/Industrial partnership. The study described here is a descriptive and exhaustive epidemiological study about collection of
sarcoma cases and it does not concern an industrial product. The other funders had no role in study design, data collection and analysis, decision to publish or
preparation of the manuscript.
Competing Interests: The authors would like to specify that Dr. Dominic Cellier is the scientific relationship director of Merck-Serono. Merck-Serono provides
financial support. The authors confirm that this does not alter their adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
Sarcomas are a heterogeneous group of rare malignant tumors
of connective tissues, capable of differentiation into many different
cell types such as connective tissues (lipocytes, fibrous supporting
structures, muscle, etc.), visceral tissues and bone. These tumors
can occur in almost any anatomic site, although they are reported
to be more frequent in the extremities . In most comprehensive
reviews, soft tissue sarcomas (STS) are reported to account for
respectively 0.7–1% and 4–8% of all adult and pediatric malignant
tumors, and bone sarcomas for respectively 0.2% and 5% [2–4].
More than fifty histological subtypes were described in the
classification of the World Health Organization (WHO) updated
in 2002 , and further refinements have been made since with
the publication of molecular classification studies identifying
distinct molecular subtypes .
The exact overall incidence of sarcomas is unknown and the
incidence of the different histological and molecular subtypes has
not been determined precisely . Most studies consider adults
and children, or soft tissue and bone sarcomas separately. Results
of population studies indicate that the incidence of sarcomas may
actually be underestimated, possibly because of diagnostic
confusion with carcinomas of the same organ. Recent reports of
a 1.1–1.5/100,000/year incidence of gastrointestinal stromal
PLoS ONE | www.plosone.org1 August 2011 | Volume 6 | Issue 8 | e20294
tumors (GIST)  suggest that the overall incidence rates of 1 to
3/100,000/year generally reported are likely underestimated .
In addition, sarcomas encompass a wide variety of histotypes and
molecular subtypes and are categorized in rapidly evolving
phenotypic and molecular subgroups now used for sarcoma
diagnosis with a growing impact on the management of patients
The aim of the present study was to describe the overall
incidence of sarcoma and the precise incidence of the different
histological and molecular subtypes in a given European region.
Materials and Methods
This prospective study involves the exhaustive collection of all
incident cases of sarcoma in the French Rhone-Alpes (RA) region
(6,021,352 inhabitants, 2006 census, 10% of the French
population) over a two-year period (March 2005 to March 2007).
Inclusion and exclusion criteria
All Rhone-Alpes patients with a diagnosis of primary sarcoma
made by any public or private pathology laboratory of the region
between March 1, 2005 and February 28, 2007, were included in
the study. All subtypes of sarcoma were eligible: soft tissue, bone,
or visceral tumors (GIST, gynecological sarcomas), Kaposi
sarcomas, etc. Relapsing patients were excluded. Other exclusion
criteria were date of initial diagnosis outside the registration
period, patients living outside the region at the date of diagnosis
(selected based on postal code), and no evidence of sarcoma upon
histological review. All patients’ medical records were reviewed for
All 43 pathology laboratories (N=158 pathologists) of the RA
region agreed to participate in the study. They prospectively
reported all newly suspected cases and provided paraffin-
embedded blocks for systematic review. Onsite monitoring visits
were conducted to ensure exhaustiveness of registration. The
pathologists were given financial compensation for each case they
reported. Two pathologists of the comprehensive cancer centre,
Dominique Ranche `re-Vince (DRV) and Anne-Valerie Decouve-
laere (AVD), established a list of ADICAP codes corresponding to
subtypes of sarcoma to be used by the pathology laboratories for
patient registration. The French ADICAP coding system is an
accurate mnemonic alphanumeric thesaurus, currently in use in
France to classify histological subtypes and is equivalent to the
International Classification of Diseases for Oncology (ICDO)
codes (Figure 1). Pathologists were also required to report tumors
with uncertain diagnosis or ambiguous subtype, so that sarcomas
initially misdiagnosed as benign lesions or categorized into
different subsets (carcinomas) would not be missed.
Control of exhaustiveness
To ensure exhaustive collection, the list of patients with sarcoma
included in the study was checked against different sources: the list
of pediatric patients with sarcoma obtained from the Rhone-Alpes
children’s tumor registry (ARCERRA) , the list of patients
treated for a sarcoma at the comprehensive cancer centre, the list
of patients whose diagnosis was reviewed by the sarcoma expert
pathologist of the Comprehensive Cancer Centre (for second
opinion) and the list of patients whose management was discussed
by the multidisciplinary sarcoma tumor board within the RA
Central pathology review and molecular characterization
of the tumors
All suspicious pediatric or adult connective tissue samples were
centrally reviewed by the two expert pathologists (DRV, AVD) at
the Comprehensive Cancer Center of Lyon to confirm the
diagnosis. Immunohistochemical analysis was repeated and
completed. Sarcomas were graded according to the grading
systems used in the French sarcoma group and to the 2002 WHO
classification. When representative material was available for
examination, STS were graded using the three-tiered grading
system proposed by the Sarcoma Group of the French Federation
of Cancer Centers (FNCLCC) . Chondrosarcomas were
graded according to the classification of O’Neal and Ackerman,
whereas the grade of osteosarcoma (OS) was determined as a
function of the subtype (high grade for conventional OS, low grade
for parosteal OS). GIST were classified using the risk stratification
system published by Fletcher following the international consensus
conference , and the more recent classification proposed by
Soft tissue and bone sarcomas were classified using morphologic
and immunohistochemical criteria according to the 2002 WHO
classifications . Cutaneous and visceral sarcomas were catego-
rized under three different WHO groups: skin tumors, tumors of
the digestive system, and tumors of the breast and female genital
organs [15,16]. In cases where no consensus could be achieved,
diagnosis was reviewed collectively by the pathologists of the
French sarcoma group.
The molecular characterization of the tumors was established
from biopsy or surgical specimens. Specific translocations, gene
amplifications and mutations were detected using polymerase
chain reaction (PCR), fluorescent in situ hybridization (FISH) and
sequencing. Multiplex PCR was also used for analyzing problem-
atic round cell tumors .
After central pathology review, all poorly differentiated tumors
and sarcomas with strong differential diagnoses and negative
molecular results were reviewed again by the national reference
pathologists from the French sarcoma group. Decision to finally
Figure 1. The French ADICAP coding system (http://www.adicap.asso.fr/).
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org2 August 2011 | Volume 6 | Issue 8 | e20294
include or not the cases in the study was based on criteria such as
tumor localization and depth.
Statistical analysis was performed with SPSS 12.0 statistical
software (SPSS Inc., Chicago, IL). Incidence rates were based on
the January 1, 2006 census of Rhone-Alpes obtained from the
Institut National de Statistiques Et d’Evaluation (INSEE). Age-
adjusted rates were estimated by direct standardization. To allow
comparison with previous and future studies, we used data from
the French, the European (Scandinavian), the Segi world and the
new WHO world standard populations .
Ethics, patient information and follow-up
The study received approval from the French national ethics
committee and from the Commission Nationale de l’Informatique
et des Liberte ´s (CNIL, protection of individuals with regard to the
processing of personal data). This was a descriptive epidemiolog-
ical study, with no human experimentation and no consequences
on patient management; therefore, no institutional review board
review was required. Following approval by the French ethics
committee, all surgeons in the region received an information
letter about the study and were asked to inform their patients with
sarcoma that their medical records would be reviewed for the
From March 1, 2005 to February 28, 2006, 1287 suspected
sarcoma cases were reported by RA pathologists and 748 (58%)
patients were found eligible for inclusion. Figure 2 itemizes the
reasons for non inclusion. Twenty-eight private and 15 public
pathology laboratories diagnosed respectively 62% (n=466) and
38% (n=282) of the cases. The characteristics of the patients are
described in table 1. The sex ratio (male/female) was 1.1 and
varied with the type of sarcoma. The median age was 60 years,
ranging from 0 to 92; 8% (n=57) of the patients were under 18
years of age and 28% (n=210) were older than 70 years. The
median tumor size was 6 cm for both soft tissue (range=0.3–
40 cm) and visceral (range=0.3–45 cm) tumors and 7.5 cm for
bone tumors (range=1.3–25 cm). Fifteen tumors (2%) were less
than one centimeter in diameter (six GIST, five Kaposi sarcomas,
two unclassified sarcomas and two leiomyosarcoma). The tumors
were located in all sites of the body (Table 2): 58% (n=433) in the
trunk, 34% (n=258) in the limbs and 8% (n=57) in the head and
neck. The thigh was the most frequent site for STS and bone
Crude and age-adjusted incidence of histological
Of the 748 sarcoma cases included, 98% (n=732) were
reviewed by the expert pathologists. Review was impossible for
the other 16 patients (2%) because there was no tumor tissue
available for analysis (three unclassified sarcomas, three angiosar-
comas, two leiomyosarcomas, two GIST, two liposarcomas, one
DFSP, one Kaposi sarcoma, one osteosarcoma and one epithelioid
hemangioendothelioma). Seventy-six percent of the diagnoses
(n=568) were made from surgical specimens and 24% (n=180)
from biopsy samples. Immunohistochemistry was performed
whenever necessary, except for two small tumors with limited
tissue availability (two unclassified sarcoma).
Figure 3 shows age-specific incidence rates. The overall sarcoma
incidence peaked at 19 per 100,000 in the 80–89 age group
(Fig. 3A). Age-specific rates for soft tissue and visceral sarcomas
increased regularly up to the oldest age groups. Bone sarcomas
presented a biphasic profile with a first peak in young people
between 10 and 30 years of age and a second peak in adults
between 60 and 90 years of age. Nevertheless this bimodal
distribution reflected the combined influence of the three most
occurent histotypes (osteosarcoma, chondrosarcoma, Ewing sar-
coma), each having a specific distribution (Fig. 3B). Age-specific
Figure 2. Selection of patients eligible for inclusion.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org3 August 2011 | Volume 6 | Issue 8 | e20294
incidence rates of the different subtypes showed also variation
within a histological type (Fig. 3C). The four liposarcomas
subtypes showed peaks of incidence in different decades, with
myxoid-round cell liposarcoma occurring in patients younger than
those affected by dedifferentiated liposarcoma.
Table 3 describes sarcoma incidence rates in the Rhone-Alpes
region. The crude and world age standardized incidence rates
were respectively 6.2 and 4.8 per 100,000 for the whole sample.
Incidence rates for the two histotypes of GIST and unclassified
sarcomas reached 1 per 100,000. Fifty-nine percent of visceral
sarcomas (140/237) were diagnosed in women, whereas 57% of
soft tissue sarcomas (245/433) and 63% of bone sarcomas (49/78)
were diagnosed in men.
Four percent (n=28) of sarcomas occurred in previous radiation
fields (13 unclassified sarcomas, 11 angiosarcomas, 3 osteosarco-
mas, and 1 leiomyosarcoma).
Results of tumor grading and specific risk stratification for GIST
are shown in tables 4 and 5. Fifty-six percent (n=420) of the
tumors were graded. Thirty-five percent (n=147) were classified
as low grade, 28% (n=116) as intermediate grade and 37%
(n=157) as high grade.
Crude incidence of histological subtypes and molecular
The total numbers of cases in each histological type and subtype
are described in tables 6 and 7, regardless of the primary site (soft
tissue, viscera or bone). The four most frequent histotypes
represented 60% of all sarcomas. As expected, each histological
type had a specific epidemiological profile regarding age and
gender; some were more frequent in women (e.g., GIST,
leiomyosarcomas and angiosarcomas) and others in men (e.g.,
unclassified sarcomas, liposarcomas, osteosarcomas, Kaposi sar-
comas and rhabdomyosarcomas). Table 8 describes the predom-
inant histotypes for children, adolescents and young adults, adults
and the elderly. Most histotypes occurred at any ages, although
they are mainly divided in pediatric-type sarcomas occurring in
early stage of life and presenting sporadic cases in adults and
elderly (e.g. rhabdomyosarcoma, Ewing sarcoma, osteosarcoma)
and adult-type sarcomas which emerged in 30- to 49-year-old age
group (e.g. GIST, liposarcoma, leiomyosarcoma). Bone sarcoma
(osteosarcoma, PNET-Ewing) predominated in adolescents and
young adults while dermatofibrosarcoma, Kaposi sarcoma and
uterine leiomyosarcoma peaked in 30- to 49-year-old age group.
Table 1. General characteristics of sarcoma patients in the Rhone-Alpes region, France, 2005–2006.
Years Type of sarcoma
Total patients748 (100%) 378 (100%)370 (100%) 433 (58%)237 (32%) 78 (10%)
Male 391 (52%)195 (52%) 196 (53%) 245 (57%)97 (41%)49 (63%)
Female 357 (48%) 183 (48%)174 (47%)188 (43%) 140 (59%) 29 (37%)
Age at diagnosis (years)
Mean 5656 575661 41
Median60 606161 6240
Range0–92 0–920–91 0–920–91 6–84
0–925 (3%)12 (3%) 13 (3%)17 (4%)2 (1%) 6 (8%)
10–1935 (5%) 18 (5%)17 (5%)19 (4%) 3 (1%)13 (17%)
20–29 39 (5%)24 (6%)15 (4%)20 (5%)4 (2%)15 (19%)
30–2959 (8%) 34 (9%) 25 (7%)38 (9%) 16 (7%)5 (6%)
40–4974 (10%)40 (11%) 34 (9%)43 (10%) 25 (10%) 6 (8%)
50–59133 (18%)60 (16%)73 (20%)70 (16%) 52 (22%)11(14%)
60–69 161 (21%)74 (20%)87 (24%) 99 (23%) 52 (22%)10 (13%)
70–79 133 (18%)65 (17%) 68 (18%) 70 (16%)55 (23%) 8 (10%)
80–89 84 (11%) 47 (12%) 37 (10%)53 (12%)27 (11%) 4 (5%)
5 (1%)4 (1%)1 (,1%)4 (1%)1 (1%)-
Tumor size, cm1
#5 278 (37%) 151 (40%) 127 (34%)176 (41%)88 (37%) 14 (18%)
5,#10 211 (28%)108 (29%) 103 (28%)100 (23%)82 (35%) 29 (37%)
.10 188 (25%)87 (23%)101 (27%)116 (27%) 50 (21%)22 (28%)
Not available 71 (10%)32 (8%)39 (11%) 41 (9%) 17 (7%)13 (17%)
Deep 615 (82%)297 (79%) 318 (86%)300 (69%) 237 (100%)78 (100%)
Superficial133 (18%)81 (21%) 52 (14%) 133 (31%)--
1According to pathology report n=535 (71%), to imaging n=133 (18%) or to physical examination n=9 (1%).
2Above or under superficial fascia.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org4 August 2011 | Volume 6 | Issue 8 | e20294
Angiosarcoma affected more frequently elderly mainly due to
secondary angiosarcoma (44%) diagnosed after radiation treat-
ment for another cancer. A large proportion of sarcomas (8 to
21%) remained unclassified in each age group.
Of the 748 cases studied, 48% (n=362) had known molecular
alterations: 56% (32/57) of the tumors diagnosed in patients under
19 years of age versus 48% (330/691) in adult patients. Molecular
characterization was performed in 85% (n=306) of these 362
tumors. The remaining 15% (n=56) could not be analyzed, either
because the tumor material had been fixed in Bouin’s solution
(n=22), or there was insufficient material for analysis (n=20) or
the technique was not available in France (n=14). Table 9
presents the distribution and the crude incidence of molecular
subtypes in the Rhone-Alpes region. Sarcomas with specific
translocations, with point mutations (deletion, insertion, duplica-
tion) or with gene amplifications represented respectively 35%,
38% and 27% of all cases with known molecular alterations.
Population of GIST was more detailed by Cassier et al. .
The objective of the present study was to determine the overall
incidence of sarcoma as well as the incidence of histological and
molecular subtypes in a typical European region of 6 million
inhabitants. This involved the collection of all cases diagnosed in
the region, as well as the central review and molecular testing of
these rare tumors. Patient data collected through a systematic
review of patients’ medical records were centrally reviewed. To
our knowledge, although many studies have reported on the
incidence of primary bone and soft tissue lesions, this is the first
exhaustive collection of cases on a regional basis, with
centralized pathology review coupled with molecular character-
The present study identified 748 new cases of sarcoma over a
two-year period instead of the 200 per year expected. Of these,
98% were reviewed by regional and national experts in sarcoma
pathology, all diagnoses were confirmed by immunohistochemis-
try, and 85% of cases with molecular alterations could be
characterized using molecular techniques. On the basis of these
numbers, the French and world age-standardized incidence rates
were respectively 6.4 and 4.8 per 100,000 population, which is
higher than the rates reported in previous publications, either in
the USA or in Europe (between 1 and 3 per 100,000), even though
some studies have reported higher results [20,21]. In children
under 15 years of age, the incidence of STS and bone tumors was
estimated to be respectively 0.9 and 0.6 per 100,000 per year
[22,23]. In 2005, the number of new cases of cancer of all sites was
estimated to 27,869 in the Rhone-Alpes region . With a mean
annual rate of 374 new cases in this study, sarcoma thus represents
1.3% of all new cancer cases in the region.
Table 2. Primary tumor site according to the type of sarcoma (two-year period).
Soft tissue sarcomas
tumor siteN (%)
tumor siteN (%)
tumor site N (%)
Trunk173 (40)Abdomen 161 (68) Limbs 43 (55)
Abdomen 26 (6) Stomach 85 (36)Lower limbs31 (40)
Retroperitoneum41 (9) Small intestine 42 (18) Femur21 (27)
Thorax73 (17)Colon6 (2) Tibia8 (10)
Pelvis33 (8)Rectum 4 (2)Fibula1 (1)
Omentum4 (2) Metatarsus1 (1)
Limbs214 (49) Peritoneum5 (2) Upper limbs12 (15)
Lower limbs155 (36)Kidney6 (2) Humerus 5 (6)
Thigh88 (20)Liver 2 (1) Scapula 3 (4)
Leg 23 (5)Spleen2 (1) Clavicle2 (2)
Pelvic girdle23 (5) Other abdomen5 (2)Hand 2 (2)
Foot 8 (2)
Knee 9 (2)Thorax 22 (9)Head and Neck 10 (13)
Ankle 4 (1)Lung 9 (4)Skull3(4)
Upper limbs 59 (14) Pleura 5 (2)Orbit 2 (2)
Shoulder girdle22 (5)Heart 4 (2)Mandible 1 (1)
Arm7 (2) Other Thorax4 (2) Other 4 (5)
Forearm 20 (5)
Elbow 5 (1) Pelvis54 (22) Pelvis 11 (14)
Hand5 (1) Uterine 42 (18)Thorax7 (9)
Ovary 3 (1)Rib 6 (8)
Head and neck 46 (11)Bladder 3 (1) Sternum1 (1)
Spermatic cord3 (1)Spine 7 (9)
Other pelvis 3 (1)
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org5August 2011 | Volume 6 | Issue 8 | e20294
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org6 August 2011 | Volume 6 | Issue 8 | e20294
The work presented here differs from previous large retrospec-
tive studies which have used a different methodology, and from
results published by cancer registries, from which incidence data
have been extrapolated. Age-standardized incidence rates of STS
are fairly constant in most areas covered by cancer registration,
and range from 1–3 per hundred thousand population .
However, because of the rarity and heterogeneity of primary sites
and presentations of STS, general registries do not provide routine
data about their incidence. The main sources of incidence data for
sarcoma are the world databases of the International Agency for
Research on Cancer (IARC) , the American Surveillance,
Epidemiology and End Results (SEER) Program [21,26], the
European database of the Automated Childhood Cancer Infor-
mation System (ACCIS)  and the national coverage registry of
the Nordic countries .
Because of the great number of cases recorded, diagnosis is not
always reviewed by pathology experts, which is a serious limitation
in the case of sarcomas, given the frequency of misdiagnosis with
carcinoma, melanoma or benign tumor, or even between
histological subtypes [29,30]. The reproducibility of sarcoma
diagnosis, and particularly of soft tissue sarcoma, is relatively poor
across pathologists who are not familiar with these lesions, and the
histopathological classification of this cancer in cancer registries is
often inconsistent. Epidemiological studies have suffered from this
misclassification of histology. A concordance study performed in
Rhone-Alpes comparing primary diagnosis and systematic review
by expert showed that 46% of diagnoses were modified at second
reading and that in 19% of cases there was a discordance in the
histological type .
In addition, the design of registries is not always suitable for
sarcomas. The data collected are incomplete, mainly because
of the broad diversity of morphological entities and of the
classification of data per anatomic site which does not
distinguish visceral sarcomas (e.g., GIST are counted with
‘‘digestive cancers’’, uterine sarcomas with ‘‘uterine cancers’’).
Very few registry studies have focused and produced data on
Figure 3. Age-specific incidence rates (per 100,000). (A) Age-specific rates by sarcoma type. (B) Age-specific rates within bone sarcomas, for
the 3 most important histotypes. (C) Age-specific rates for liposarcoma subtypes.
Table 3. Crude and age-standardized incidence rates of the main histological subtypes.
Crude incidence rates/100,000/
year Age-standardized incidence rates/100,000/year
N (%) TotalMen Women FranceEurope World (Segi) World (WHO)
All sarcomas748 (100)6.2 6.7 5.8 6.4 5.64.5 4.8
Without Kaposi sarcoma723 (97) 6.06.3 5.7 6.1 5.4 4.4 4.6
Age group, years
Children 0–1444 (6)1.9 2.61.2 1.9 1.9 1.9 1.9
Adults 15–69 482(64) 5.8 6.35.3 5.9 5.8 5.2 5.1
222 (30) 15.818.3 14.215.8 15.7 15.415.7
Soft tissue sarcoma 433(58) 3.6 4.2 3.03.73.2 2.6 2.8
Visceral sarcoma 237 (32)2.0 1.72.3 2.0 1.7 1.3 1.4
Bone sarcoma 78 (10) 0.6 0.8 0.5 0.70.6 0.6 0.6
GIST135(18)1.1 1.0 1.2 188.8.131.52 0.7
Unclassified sarcoma 117 (16)1.0 1.20.8 1.0 0.8 0.60.7
Liposarcoma112 (15) 0.9 1.2 0.7 1.00.8 0.60.7
Leiomyosarcoma85 (11) 0.7 0.5 0.9 0.70.6 0.5 0.5
Dermatofibrosarcoma38 (5)0.3 0.40.3 0.30.3 0.30.3
Osteosarcoma 31 (4)0.3 0.40.2 0.3 0.3 0.3 0.3
Chondrosarcoma29 (4) 0.2 0.3 0.2 0.20.20.20.2
Ewing sarcoma/PNET 27(4) 0.20.2 0.2 0.20.2 0.3 0.3
Rhabdomyosarcoma 26(3) 0.20.3 0.10.2 0.20.3 0.3
Kaposi sarcoma 25 (3)0.20.4 0.10.2 0.20.10.2
Angiosarcoma 25 (3)0.2 0.1 0.3 0.2 0.10.10.1
Myxofibrosarcoma17(2) 0.10.1 0.10.1 0.10.10.1
Synovial sarcoma16 (2)0.10.10.2 0.10.1 0.10.1
Endometrial stromal sarcoma14 (2)0.1- 0.20.10.10.1 0.1
1Histological types with fewer than ten cases per year are not shown.
2006 Rhone-Alpes population: 6,021,352 inhabitants (Male: 2,932,105; Female: 3,089,247).
2006 French population: 61,399,719 inhabitants (Source INSEE).
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org7 August 2011 | Volume 6 | Issue 8 | e20294
Table 4. Description of tumor grade.
Tumor grade N, (%)
Low IntermediateHigh Not done1
FNCLCC WHO grading
Pleomorphic cell sarcoma2 (4)13 (24)28(51)12 (22)55
Spindle cell sarcoma1 (2)11 (27)18(44) 11 (27)41
Round cell sarcoma----7 (64)4 (36) 11
Sarcoma not otherwise specified1 (10)2 (20)2 (20)5(50) 10
Well differentiated liposarcoma 71(100)------ 71
Dedifferentiated liposarcoma4 (15) 13 (48)9 (33)1 (4)27
Myxoid-round cell liposarcoma8 (67)4 (33)---- 12
Pleomorphic liposarcoma--1 (50)1 (50)--2
Non uterine leiomyosarcoma15(24) 25(40) 15(24)7 (11)62
Angiosarcoma3 (12) 11 (44)9 (36)2 (8)25
Myxofibrosarcoma2 (12)8 (47)7 (41)-- 17
Monophasic synovial sarcoma--7 (54)6 (46)-- 13
Biphasic synovial sarcoma--2 (67)1 (33)--3
MPNST2 (40)1 (20)2 (40)--5
Epithelioid sarcoma--2 (40)2 (40)1 (20)5
Low grade fibromyxoid sarcoma4 (100)------4
Fibrosarcoma1 (33)--2 (67)--3
Myxoinflammatory fibroblastic sarcoma2 (100)------2
Composite hemangioendothelioma1 (100)------1
High-grade phyllodes tumor----1 (100)--1
Bone sarcoma grading
Conventional osteosarcoma---- 26(100)-- 26
Soft tissue osteosarcoma--1 (34)2(66)--3
Osteosarcoma grade 2--1 (100)----1
Chondrosarcoma12 (41)13(45)4 (14)--29
Uterine sarcoma grading
Uterine leiomyosarcoma3 (13)1 (4) 10 (44)9 (39)23
Endometrial stromal sarcoma 14(100)------ 14
Undifferentiated endometrial sarcoma----3(100)--3
1Grade was not evaluated due to limited material or too undifferentiated tumor.
Table 5. Description of GIST stratification risk.
NIH criteria Very low riskLow riskIntermediate risk High riskNot done1
GIST 11 (8) 32(24) 45(33)37 (24)10 (7) 135
AFIP criteria None riskVery low risk Low risk Moderate risk High risk Not done1
Gastric 12(15) 23 (29)18(23) 11(14) 10 (12)6 (7)80
Other localization3 (5)-- 10(18) 14 (26)26 (47)2 (4)55
NIH, National Institutes of Health ; AFIP, Armed Forces Institute of Pathology.
1Grade was not evaluated due to limited material or too undifferentiated tumor.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org8 August 2011 | Volume 6 | Issue 8 | e20294
the histological classification of sarcomas; their results have
shown that failing to include tumors arising in specific organs
resulted in an underestimation of the overall incidence of
sarcoma by 50% . Pediatric registries have reported more
accurate data on incidence rates of sarcoma in children and
adolescents because the nosologic classifications for children
malignancies is primarily based on histology [32,33] and only
few cases of visceral sarcoma arise in children or adolescents
(two cases in our study).
Any comparisons with existing datasets may be affected by the
specific population under study, by changes in sarcoma incidence
over time, and by possible ascertainment biases. We excluded the
possibility of an ascertainment bias because of the reputation and
experience of the local clinician in the management of sarcoma.
The place of residence at the first suspicion of sarcoma was
collected for each patient and those who moved to Rhone-Alpes
after the first diagnosis of sarcoma were excluded from the
analysis. Moreover, our method of case ascertainment is likely to
Table 6. Crude incidence of histological subtypes.
Histological types and subtypes
Number Sex ratioAge
Total% 20052006 (M/F) MedianRange
GIST135 (18) 70 65 0.8 65 (34–91)1.12
117(16) 57601.4 66(3–92)0.97
Pleomorphic cell sarcoma 55(7) 2728 1.467(18–91)0.46
Spindle cell sarcoma41 (5)15 261.6 67 (27–92)0.34
Round cell sarcoma11 (1)74 0.425(3–83) 0.09
Sarcoma not otherwise specified10(1)82 4.0 68 (49–84)0.08
Liposarcoma112 (15)56 561.761 (26–88)0.93
Well differentiated liposarcoma71 (9) 3635 1.860 (32–88) 0.59
Dedifferentiated liposarcoma27 (4)14 131.2 72(47–84)0.22
Myxoid-round cell liposarcoma12(2)57 2.0 47(26–81) 0.10
Pleomorphic liposarcoma2(,1)11 1.0 78(72–85) 0.02
Leiomyosarcoma 85 (11)40450.5 62(28–87) 0.71
Non uterine leiomyosarcoma62 (8)2834 0.962(28–87) 0.51
Uterine leiomyosarcoma 23(3)12 11- 53 (40–84)0.20
Dermatofibrosarcoma protuberans 38(5)2216 1.237 (8–91) 0.32
Osteosarcoma31 (4) 19122.136 (6–80) 0.26
Conventional osteosarcoma26 (4) 179 3.3 32 (6–80) 0.22
Soft tissue osteosarcoma3(,1)12 0.5 60 (30–67)0.02
Parosteal osteosarcoma1(,1)10- 25(25) 0.01
Osteosarcoma grade 21(,1)01- 49 (49)0.01
Chondrosarcoma 29 (4)1118 1.259 (20–83)0.24
Ewing sarcoma/PNET 27 (4) 1314 0.923 (1–83) 0.22
Rhabdomyosarcoma 26(3)13 133.3 12(1–83) 0.22
Embryonal rhabdomyosarcoma 12(2)57 3.0 11(2–25)0.10
Alveolar rhabdomyosarcoma8 (1)44 3.07 (1–34) 0.07
Pleomorphic rhabdomyosarcoma4(,1)22 3.0 64(38–82) 0.03
Spindle cell rhabdomyosarcoma2(,1)20- 76(70–83) 0.02
Kaposi sarcoma 25(3)1411 5.3 59 (30–90)0.21
Angiosarcoma 25(3)1312 0.5 75(39–84)0.21
Myxofibrosarcoma17 (2)98 0.963 (37–84) 0.14
Synovial sarcoma 16 (2)88 0.635 (13–87)0.13
Monophasic synovial sarcoma13(2)76 0.432(13–87) 0.11
Biphasic synovial sarcoma3(,1)12 2.041 (26–43) 0.02
Endometrial stromal sarcoma 14 (2)68- 49 (23–71)0.12
Malignant solitary fibrous tumor8 (1)351.7 71(61–77)0.07
Other43 (6)24 191.1-- 0.36
TOTAL748 (100) 378 3701.1 60 (1–92)6.21
GIST, gastrointestinal stromal tumor; PNET, primitive neuroectodermal tumor.
1Crude incidence rate/100,000/year.
2Unclassified sarcomas were divided in subtypes according to morphological features based on experts’ advice.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org9 August 2011 | Volume 6 | Issue 8 | e20294
have missed some false negatives (i.e., sarcomas misdiagnosed as
other cancer types) and the true incidence of sarcoma incidence
might be higher.
Concerning the specific population under study, the overall
distribution of sarcoma in Rhone-Alpes is not considered different
from the rest of France . Rhone-Alpes is one of the French
demographics are older than in the European and North American
reference populations. Ethnic differences might account for some of
the variance with published data. The overall incidence of STS is
Table 7. Rare histological types of sarcoma.
Crude incidence rate/million/year
Total% 2005 2006
5 (0.7)32 0.42
Epithelioid sarcoma5 (0.7)23 0.42
Low grade fibromyxoid sarcoma4 (0.5)22 0.33
Desmoplastic small round cell tumor4 (0.5)31 0.33
Undifferentiated endometrial sarcoma4 (0.5)22 0.33
Rhabdoid tumor3 (0.4)21 0.25
Epithelioid hemangioendothelioma3 (0.4)21 0.25
Fibrosarcoma3 (0.4)12 0.25
Intimal sarcoma2 (0.3)20 0.17
Malignant inflammatory myofibroblastic tumor2 (0.3)20 0.17
Myxoinflammatory fibroblastic sarcoma2 (0.3)11 0.17
2 (0.3)11 0.17
Composite hemangioendothelioma1 (0.1)10 0.08
High grade phyllodes tumor1 (0.1)01 0.08
Alveolar soft part sarcoma1 (0.1)01 0.08
Clear cell sarcoma of kidney1 (0.1)01 0.08
1MPNST, malignant peripheral nerve sheath tumor.
2PEComa, neoplasm with perivascular epithelioid cell differentiation.
Table 8. Sarcoma types by percentage of cases for age groups.
(n=44 ; 6%)
and young adults
(n=55 ; 7%)
(n=133 ; 18%)
(n=294 ; 39%)
Age 70+ +
(n=222 ; 30%)
Rhabdomyosarcoma 36Osteosarcoma 20 DFSP14GIST 22GIST 24
PNET/Ewing20 PNET/Ewing18Liposarcoma 14 Liposarcoma 19 Unclass. sarcoma 21
Unclass. sarcoma9 DFSP11GIST 13Unclass. sarcoma 17Liposarcoma15
Osteosarcoma7 Unclass. sarcoma 11Unclass. sarcoma8 Leiomyosarcoma 11Leiomyosarcoma10
Rhabdoid tumor7Synovial sarcoma9 Kaposi sarcoma7 Chondrosarcoma4 Angiosarcoma7
DFSP5 Chondrosarcoma5 Uterine LMS6 DFSP3 Chondrosarcoma3
Synovial sarcoma5 Rhabdomyosarcoma5 Chondrosarcoma5Uterine LMS3 Kaposi sarcoma3
DSRCT5 Leiomyosarcoma4 Leiomyosarcoma5Osteosarcoma3Myxofibrosarcoma3
Other6Liposarcoma4 ES sarcoma5 Kaposi sarcoma3 Uterine LMS3
Epithelioid sarcoma4Myxofibrosarcoma5 ES sarcoma2 Mal. solit. fibr. tumor2
DSRCT4 Angiosarcoma3 Angiosarcoma2Osteosarcoma2
MIM Tumor4Osteosarcoma3 PNET/Ewing2 Rhabdomyosarcoma2
ES sarcoma2 Synovial sarcoma3 Synovial sarcoma1 Other5
PNET, primitive neuroectodermal tumor; Unclass. sarcoma, unclassified sarcoma; DFSP, dermatofibrosarcoma protuberans; DSRCT, desmoplastic small round cell tumor;
Other, other sarcoma; MIM tumor, malignant inflammatory myofibroblastic tumor; ES sarcoma, endometrial stromal sarcoma; GIST, gastrointestinal stromal tumor;
Uterine LMS, uterine leiomyosarcoma; Mal. solit. Fibr. tumor, malignant solitary fibrous tumor.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org 10August 2011 | Volume 6 | Issue 8 | e20294
known to be higher among African Americans than among
Caucasian patients [9,21] while Ewing sarcoma showed a striking
incidence by race with the great majority of cases occurring in white
patients . The Rhone-Alpes population is principally Caucasian,
however,no ethnic information was recorded inthe study. The bone
sarcoma incidence rates reported in the present study and their age-
specific distribution were similar to those recently reported in other
countries with Caucasian population .
The time period under question may also account for the
differences with published data. The obvious point of concern is
the incidence of Kaposi’s sarcoma, which has clearly varied with
HIV prevalence over time and across the country. When
excluding patients with Kaposi’s sarcoma, the crude and world
age-standardized incidence rates in our study were respectively 6.0
and 4.6 per 100,000/year. Previous reported incidence rates of
soft tissue sarcoma were different amongst countries, even in
Table 9. Distribution of molecular subtypes for sarcoma with specific gene abnormality (N=362).
Histological types No.
TypeInvolved gene(s)No. (%) CIR1
GIST 135119 (88) 85/14/20Mutation C-kit exon 11 55 (56)0.46
C-kit exon 9 10 (10)0.08
C-kit exon 134 (4)0.03
C-kit exon 171 (1)0.01
PDGFRA exon 1814 (14)0.12
PDGFRA exon 12 1 (1)0.01
Wild type14 (14)0.12
Well differentiated liposarcoma7164 (90) 52/3/9 Amplification MDM2 and CDK4 42 (80)0.35
MDM2 only9 (18) 0.07
MDM2 and HMGA2 1 (2)0.01
Dedifferentiated liposarcoma27 23 (85)20/1/2 Amplification MDM2 and CDK419 (95) 0.16
MDM2 only1 (5) 0.01
Myxoid/Round cell liposarcoma12 12 (100) 7/1/4Fusion transcriptFUS-CHOP3 (43) 0.02
EWS-CHOP 1 (14)0.01
Dermatofibrosarcoma protuberans3825 (66) 19/2/4 Fusion transcriptCOL1A1-PDGFB19 (100)0.16
Ewing/PNET27 26 (96) 23/0/3 Fusion transcriptMultiplex5
EWSR1-FLI18 (35) 0.07
EWSR1-ERG2 (9) 0.02
Synovial sarcoma16 16 (100)16/0/0 Fusion transcriptSYT-SSX1 9 (56)0.07
SYT-SSX26 (38) 0.05
Multiplex 1 (6) 0.01
Endometrial stromal sarcoma2
14 0 (0)-Fusion transcript--
Alveolar rhabdomyosarcoma8 8 (100)7/1/0 Fusion transcriptPAX3-FKHR 3 (42)0.02
2 (29) 0.02
Desmoplastic small round cell tumor4 4 (100)4/0/0 Fusion transcriptEWSR1-WT1 4 (100)0.03
Low grade fibromyxoid sarcoma4 4 (100)4/0/0 Fusion transcriptFUS-CREB3L24 (100)0.03
Rhabdoid tumor3 3 (100) 3/0/0Mutation hSNF5-INI13 (100)0.02
2 1 (50)0/0/1Fusion transcript-
Alveolar soft part sarcoma1 1 (100)1/0/0 Fusion transcriptASPL-TFE3 1 (100)0.01
Total 362306 (84)241/22/43
GIST, gastrointestinal stromal tumors; PNET, primitive neuroectodermal tumor.
1CIR: Crude incidence rate/100,000/year.
2Molecular biology analysis not performed in France.
3Detection of rearrangement of ALK gene.
4Possible fusion transcript: TLS-CHOP; EWS-CHOP.
5Possible fusion transcript: EWS-FLI1; EWS-ERG; EWS-FEV; EWS-EIAF; EWS-ETV1.
6Possible fusion transcript: PAX3-FKHR; PAX7-FKHR.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org 11August 2011 | Volume 6 | Issue 8 | e20294
neighbored European countries, with different distribution of the
most common histological subtypes . This was due to different
inclusion criteria considering or not sarcoma of intermediate
malignancy (e.g. dermatofibrosarcoma), to the small absolute
number of cases and to inherent classifications. In the present
study, we included GIST (a type of sarcoma with a specific
biology) and all histological types of sarcoma described in 4
different WHO groups.
Because of changes and evolutions in the histological
classifications of sarcoma, it is not really possible to compare
the data collected over the decades. Whether the incidence of
sarcoma increases worldwide is unclear: increased rates have
been reported, sometimes due to increased incidence of Kaposi
sarcoma [20,38], but such increase was also observed in patients
without Kaposi sarcoma . Similar controversial findings are
reported in childhood cancer, with some studies reporting
increased sarcoma incidence rates  not confirmed by others
. It is yet unclear whether the incidence of sarcoma increases
because of environmental or other behavioral changes, or
whether there is only an apparent increase due to modifications
in the registration process. Moreover, epidemiological studies are
limited by the histopathological misclassification of these rare
tumors in cancer registries, both between histotypes (sarcoma vs.
other) and among histological subtypes (e.g., leiomyosarcoma vs.
other). To test hypotheses regarding risk factors, one must be able
to accurately measure disease incidence by age and by
histological type. In parallel to the data collected by registries
in large patient series, an exhaustive regional study based on
morphological criteria is needed.
In addition to describing the overall incidence of sarcoma (all
types, all ages), the present study also helps to further refine the
estimation of the incidence of the different subsets. GIST was the
more frequent histotype reported with a predominance in women,
while other published series indicate a more mixed population or
even sometimes a male predominance . The incidence of
dermatofibrosarcoma protuberans was unexpectedly high (5%)
whereas that of synovial sarcoma was lower than expected (2%). In
our study, 49% of all STS occurred in the limbs, which is consistent
with results of previous site distribution studies. However, if all
sarcoma subsets are taken into account, this site distribution
changes, with the trunk becoming the primary site of occurrence
(58%). The most common histological types in previous series were
malignant fibrous histiocytoma (MFH), leiomyosarcoma, liposarco-
ma and fibrosarcoma. In the present study, the main histological
types were GIST, unclassified sarcoma, liposarcoma and leiomyo-
sarcoma. These type distribution differences may be due to recent
advances in immunohistochemistry, cytogenetic and molecular
biology. With the development of numerous new antibodies since
the 1980s, immunohistochemistry has become the most accurate
and reproducible tool for sarcoma diagnosis and has provided
pathologists with new tests to distinguish between the different
histotypes of sarcoma . The distribution of sarcoma subtypes
has significantly evolved since the publication of the latest WHO
histological classification in 2002 which took into account the results
of immunohistochemistry. Two large categories that existed before
2002, MFH and fibrosarcoma, have now become much rarer .
Furthermore, the incidenceof GIST has increased from0.2to more
than 1/100,000inseveralEuropeancountriesafterthe introduction
in 2001 of anti-CD117 antibody for immunohistochemical staining
[8,41,44]. Rates seem to have remained stable since then ,
which tends to prove that the higher number of GIST was due to
the change in diagnostic methods and to the reclassification of many
mesenchymal gastrointestinal tumors previously diagnosed as
smooth-muscle tumors like leiomyosarcomas .
The development of molecular biology has also proven essential
for the diagnosis of sarcoma subtypes and for the refined
classification of sarcomas . This technique is suitable for use
in about 50% of sarcomas with specific known genomic
abnormality. In addition to clinical presentation and morphology,
molecular testing also contributes to distinguishing between
malignant and benign tumors (e.g., liposarcomas and lipomas) or
between sarcomas of similar morphology (e.g., round cell tumors).
Molecular diagnosis has been used for several years in routine for
pediatric round cell tumors, specific translocations being used as
Molecular biology has a growing impact and in the future, the
molecular-based classification of sarcoma should be as important
as the classification in histological subtypes. Molecular charac-
terization already has clinical implications for some subtypes of
sarcoma, either for prognosis (e.g., poor prognosis for patients
with KIT exon 11 deletion in GIST, FKHR-PAX3 expression in
metastatic rhabdomyosarcoma and SYT-SSX1 fusion type in
synovial sarcoma) [47–49], treatment (adjuvant radiotherapy), or
response to treatment (e.g. better response to imatinib for GIST
with exon 11 mutation than with exon 9 mutation) . In our
population-based study, the incidence of PDGFRA mutated
GIST was higher than previously reported in patients with
advanced disease  indicating that tumors bearing mutant
PDGFRA have a more indolent behaviour . Moreover,
Williamson et al. demonstrated that rather than histology, the key
factor in terms of biology and clinical progression of rhabdo-
myosarcoma was the presence or absence of a fusion gene .
The molecular profiling approach used in our study was relatively
standard and the technology evolves rapidly . Novel
molecular karyotyping techniques, such as array comparative
genomic hybridization (aCGH) or gene expression analysis led to
improve sarcoma classification by defining tumor-specific clusters
that have potential value for resolution of differential diagnoses
(e.g. wide separation of GIST from leiomyosarcoma)  and led
to the identification of new diagnostic markers as well (e.g.
DOG1 helpful in recognizing KIT-negative GIST) . Full
transcriptome sequencing and other genomic, proteomic and
epigenetic profiling approaches should become available in the
near future and will allow to better characterize the different
histotypes of sarcoma and to better understand their complex
genetic structure with numerous rearrangements. Anyway,
molecular techniques have yet revealed that sarcomas were
different entities with different biologies  and have allowed a
better understanding of the pathogenesis of some types of
sarcomas (e.g. initiating role of mutation of KIT or PDGFRA
This study was based on the voluntary participation of the
different pathology laboratories and the first data source was their
spontaneous notifications. All efforts were made to ensure the
accuracy of the results and the exhaustiveness of the collection. No
list can be totally exhaustive and all offer different levels of quality,
but the different cross-checks between lists tend to indicate that we
have collected all the sarcoma cases diagnosed in the region during
the study period. These good results can be attributed to the
effective collaboration between the different specialists and
Soft tissue, visceral and bone sarcoma represent three
heterogeneous groups of mesenchymal neoplasms, with different
methods of diagnosis, different classifications, different staging and
treatment approaches and different management. Nevertheless,
we have deliberately collected and grouped all histological types
because only this accurate collection can ensure exhaustiveness.
For example, the collection of all histological types of bone
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org 12 August 2011 | Volume 6 | Issue 8 | e20294
sarcoma allowed to collect cases of extraskeletal bone sarcoma (e.g.
Ewing sarcoma) that would have been missed otherwise.
Sarcomas represent a heterogeneous group of malignancies
which may occur at any site and any age. All types occur across
the age spectrum  but distribution of histotypes during
childhood is striking different with what is described in adults or in
adolescent and young adult. Specific molecular events defined
sarcoma histological types: most pediatric-type sarcoma are
associated with translocation due to the high incidence of genetic
factors unlike adult-type sarcoma, with more complexe karyotypes,
for which environmental factors will tend to influence more often.
Adult sarcomas have different prognostic factors  and
significantly worse outcomes than children sarcomas [56,58] due
to inherent biological differences. Sarcomas present a specific
epidemiology per histological and molecular subtypes leading to
the conclusion that they comprise multiple aetiologically distinct
entities rather than a single disease.
This study allowed to detect and overcome the low frequency of
sarcoma. The world age-standardized incidence rate of sarcomas
taken as a whole is 5 per 100,000 population per year. This is the
first prospective and exhaustive study of sarcoma in Europe, with
complete pathological review and updated tumor classification
using immunohistochemistry and molecular biology. Our results
should prove useful for the development of future targeted
treatments since the figures presented here are more accurate
than those described in the literature.
We thank Marie-Dominique Reynaud for editing assistance and Philippe
Cousin, Magali Bousquet, Muriel Rogasik and Christine Rodriguez for
data management. We thank the ARCERRA Registry: Claire Berger,
Fernand Freycon and Le ´onie Casagranda. We thank all the pathologists of
the Rhone-Alpes region for their active collaboration in the study:
C Agard, F Allias-Montmayeur, R Angonin, M Augros-Monavon, C
Bailly, B Balme, B Bancel, R Barnoud, N Ben-Lagha, L Bensaadi, F
Berger, N Berger Dutrieux, I Beschet, F Billard, V Blanc, AM Bonin, N
Bottero, J Bourloux, J Boutonnat, R Bouvier, C Bozon, E Brambilla, B
Bringeon, A Buenemd, M Buyck-Mabrut, B Cantero, C Cavailles, L
Chalabreysse, P Chalabreysse, ML Chambonniere, J Chanoz, G Chanoz-
Poulard, C Chassagne-Clement, M Chevalier, B Chouvet, A Ciapa, C
Claret-Tourner, A Clemenson, S Collardeau Frachon, A Corrand-Faure,
L Corsois, F Crozes, I Cruel, R Dardelin, C David, M Decaussin, AV
Decouvelaere, A De La Fouchardie `re, J-F Denier, J Depardon-Dolce, P
Der Garabedian, P Derolland, B Descombes-Thivolet, M Devouassoux, A
Dieny, F Dijoud, C Donne, A-V Donsbeck, J-P Donzel, C Douchet, JM
Dumollard, A Economides, N Elbaz, B Fabre, M Faisant, C Faure, M
Faysse, P Felman, C Feutry, M Ffrench, M Fior-Golzan, L Frappart, F
Gasnier, A Gentil-Perret, A Glehen, W Godard, J Godeneche, C
Gouarderes, F Gouzy-Grosjean, A Griot, C Guillaubey, C Guillaud, C
Herve-Nicollet, V Hervieu, S Isaac-Pinet, L Istier, M Jouffre-Cottier, A
Jouvet, J Kanitakis, P Kermanac’h, A Khaddage, J-F Knopf, M-H Koeb,
M Labadie, B Lamouliatte, S Lantuejoul, I Laurent, C Lauro-Colleaux,
M-H Laverriere, F Le Breton, F Le Marc’hadour, P Lucht-Versini, B Mac
Gregor, J-P Machayekhi, D Maisonneuve-Gilly, H Martin, F Mege
Lechevallier, P Mesguich, D Meyronet, I Morand-Dusserre, J-L Morcillo,
F Morel, A Morens, B Muller, C Muller, M Ney, M Neyra, B Pasquier, D
Pasquier, C Paulin, M Pe ´oc’h, G Perrot, J Pialat, E Piaton, N Picchetti
Mayer, N Pinet Briquet, M Plenier Maisonneuve, P Pocachard, G Pugens,
I Remy, D Ranche `re-Vince, J Richard, V Rouault-Plantaz, J-J Roux, M-G
Roux-Gilly, L Saint-Genis, G Saint-Pierre, D Salameire, M Salle, C Salon,
JY Scoazec, D Seigneurin, F Serain, L Siche, M-S Soubeyrand, N
Streichenberger, N Sturm, Y Suignard, P Terdjman, F Thivolet-Be ´jui, I
Treilleux, S Vancina, B Vaunois, A Vercherin, F Vittetat, D Vitrey, M
Vock-Bonnet, L Zappatini.
Conceived and designed the experiments: DR-V DC J-YB IRC. Performed
the experiments: FD AL DR-V A-VD MP LI PC CM LA P-PB J-YS.
Analyzed the data: FD AL DR-V A-VD A-MS CB J-YB IR-C.
Contributed reagents/materials/analysis tools: DR-V A-VD MP LI PC
CM LA P-PB J-YS. Wrote the paper: FD AL DR-V A-VD J-YB IR-C.
1. Clark MA, Fisher C, Judson I, Thomas JM (2005) Soft-tissue sarcomas in adults.
N Engl J Med 353: 701–11.
2. Jemal A, Siegel R, Ward E, Murray T, Xu J, et al. (2006) Cancer statistics, 2006.
CA Cancer J Clin 56: 106–30.
3. Parkin DM, Stiller CA, Nectoux J (1993) International variations in the
incidence of childhood bone tumours. Int J Cancer 53: 371–6.
4. Stiller CA, Parkin DM (1994) International variations in the incidence of
childhood soft-tissue sarcomas. Paediatr Perinat Epidemiol 8: 107–19.
5. Fletcher CDM, Unni KK, Mertens F (2002) World Health Organization
Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and
Bone. IARC Press: Lyon.
6. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, et al. (2005)
PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and
in vitro sensitivity to imatinib. J Clin Oncol 23: 5357–64.
7. De Vita V, Lawrence T, Rosenberg S (2008) DeVita, Hellman and Rosenberg’s
Cancer: Principles and Practice of Oncology, Eighth ed.
8. Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, et al. (2005)
Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and
prognostication in the preimatinib mesylate era–a population-based study in
western Sweden. Cancer 103: 821–9.
9. Zahm SH, Fraumeni JF, Jr. (1997) The epidemiology of soft tissue sarcoma.
Semin Oncol 24: 504–14.
10. Antonescu CR (2006) The role of genetic testing in soft tissue sarcoma.
Histopathology 48: 13–21.
11. Berger C, Trombert-Paviot B, Mitton N, Frappaz D, Galambrun C, et al. (2006)
[Childhood cancer incidence and survival rates in the Rhone-Alpes regional
paediatric registry 1987–1999]. Arch Pediatr 13: 121–9.
12. Guillou L, Coindre JM, Bonichon F, Nguyen BB, Terrier P, et al. (1997)
Comparative study of the National Cancer Institute and French Federation of
Cancer Centers Sarcoma Group grading systems in a population of 410 adult
patients with soft tissue sarcoma. J Clin Oncol 15: 350–62.
13. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, et al. (2002) Diagnosis
of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 33:
14. Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and
prognosis at different sites. Semin Diagn Pathol 23: 70–83.
15. Hamilton SR, Aaltonen LA (2000) World Health Organization Classification of
Tumors. Pathology and Genetics of Tumors of the Digestive System. IARC
16. Tavassoli FA, Devilee P (2003) World Health Organization Classification of
Tumors. Pathology and Genetics of Tumors of the Breast and female genital
organs. IARC Press: Lyon.
17. Peter M, Gilbert E, Delattre O (2001) A multiplex real-time pcr assay for the
detection of gene fusions observed in solid tumors. Lab Invest 81: 905–12.
18. Ahmad O, Boschi-Pinto C, Lopez AD, Murray CJL, Lozano R, et al. (2001) Age
standardization of rates: a new WHO standard. Geneva, World Health
Organization, 2001 (GPE Discussion Paper No. 31). 2001.
19. Cassier PA, Ducimetiere F, Lurkin A, Ranchere-Vince D, Scoazec JY, et al.
(2010) A prospective epidemiological study of new incident GISTs during two
consecutive years in Rhone Alpes region: incidence and molecular distribution of
GIST in a European region. Br J Cancer 103: 165–70.
20. Levi F, La Vecchia C, Randimbison L, Te VC (1999) Descriptive epidemiology
of soft tissue sarcomas in Vaud, Switzerland. Eur J Cancer 35: 1711–6.
21. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS (2006) Incidence
patterns of soft tissue sarcomas, regardless of primary site, in the surveillance,
epidemiology and end results program, 1978–2001: An analysis of 26,758 cases.
Int J Cancer 119: 2922–30.
22. Pastore G, Peris-Bonet R, Carli M, Martinez-Garcia C, Sanchez de Toledo J,
et al. (2006) Childhood soft tissue sarcomas incidence and survival in European
children (1978–1997): report from the Automated Childhood Cancer Informa-
tion System project. Eur J Cancer 42: 2136–49.
23. Stiller CA, Bielack SS, Jundt G, Steliarova-Foucher E (2006) Bone tumours
in European children and adolescents, 1978–1997. Report from the
Automated Childhood Cancer Information System project. Eur J Cancer
24. Colonna M, Bossard N, Mitton N, Remontet L, Belot A, et al. (2008) [Some
interpretation of regional estimates of the incidence of cancer in France over the
period 1980–2005]. Rev Epidemiol Sante Publique 56: 434–40.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org13 August 2011 | Volume 6 | Issue 8 | e20294
25. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, et al. (2007) Cancer Download full-text
Incidence in Five Continents, Vol. IX. IARC Scientific Publications No.160,L-
26. Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, et al. (1999) Cancer
Incidence and Survival among Children and Adolescents: United States SEER
Program 1975–1995. National Cancer Institute, SEER Program. NIH Pub.
No. 99-4649. Bethesda MD.
27. Pritchard-Jones K, Kaatsch P, Steliarova-Foucher E, Stiller CA, Coebergh JW
(2006) Cancer in children and adolescents in Europe: developments over 20
years and future challenges. Eur J Cancer 42: 2183–90.
28. Engholm G, Ferlay J, Christensen N, Gjerstorff ML, Klint A, et al. (2010)
NORDCAN: Cancer Incidence, Mortality, Prevalence and Prediction in the
Nordic Countries, Version 3.6. Association of the Nordic Cancer Registries.
Danish Cancer Society. (http://www.ancr.nu).
29. Arbiser ZK, Folpe AL, Weiss SW (2001) Consultative (expert) second opinions in
soft tissue pathology. Analysis of problem-prone diagnostic situations. Am J Clin
Pathol 116: 473–6.
30. Meis-Kindblom JM, Bjerkehage B, Bohling T, Domanski H, Halvorsen TB,
et al. (1999) Morphologic review of 1000 soft tissue sarcomas from the
Scandinavian Sarcoma Group (SSG) Register. The peer-review committee
experience. Acta Orthop Scand Suppl 285: 18–26.
31. Lurkin A, Ducimetiere F, Ranchere VD, Decouvelaere AV, Cellier D, et al.
(2010) Epidemiological evaluation of concordance between initial diagnosis and
central pathology review in a comprehensive and prospective series of sarcoma
patients in the Rhone-Alpes region. BMC Cancer 10: 150.
32. Kramarova E, Stiller CA (1996) The international classification of childhood
cancer. Int J Cancer 68: 759–65.
33. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P (2005) International
Classification of Childhood Cancer, third edition. Cancer 103: 1457–67.
34. Menegoz F, Black RJ, Arveux P, Magne V, Ferlay J, et al. (1997) Cancer
incidence and mortality in France in 1975–95. Eur J Cancer Prev 6: 442–66.
35. Worch J, Matthay KK, Neuhaus J, Goldsby R, DuBois SG (2010) Ethnic and
racial differences in patients with Ewing sarcoma. Cancer 116: 983–8.
36. Eyre R, Feltbower RG, James PW, Blakey K, Mubwandarikwa E, et al. (2010)
The epidemiology of bone cancer in 0–39 year olds in northern England, 1981–
2002. BMC Cancer 10: 357:357.
37. Wibmer C, Leithner A, Zielonke N, Sperl M, Windhager R (2009) Increasing
incidence rates of soft tissue sarcomas? A population-based epidemiologic study
and literature review. Ann Oncol.
38. Ross JA, Severson RK, Davis S, Brooks JJ (1993) Trends in the incidence of soft
tissue sarcomas in the United States from 1973 through 1987. Cancer 72:
39. Kaatsch P, Steliarova-Foucher E, Crocetti E, Magnani C, Spix C, et al. (2006)
Time trends of cancer incidence in European children (1978–1997): report from
the Automated Childhood Cancer Information System project. Eur J Cancer 42:
40. Linabery AM, Ross JA (2004) Trends in childhood cancer incidence in the U.S.
(1992–2004). Cancer 112: 416–32.
41. Tryggvason G, Gislason HG, Magnusson MK, Jonasson JG (2005) Gastroin-
testinal stromal tumors in Iceland, 1990–2003: the icelandic GIST study, a
population-based incidence and pathologic risk stratification study. Int J Cancer
42. Coindre JM (2003) Immunohistochemistry in the diagnosis of soft tissue
tumours. Histopathology 43: 1–16.
43. Daugaard S (2004) Current soft-tissue sarcoma classifications. Eur J Cancer 40:
44. Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, et al.
(2005) Incidence of gastrointestinal stromal tumours is underestimated: results of
a nation-wide study. Eur J Cancer 41: 2868–72.
45. Perez EA, Livingstone AS, Franceschi D, Rocha-Lima C, Lee DJ, et al. (2006)
Current incidence and outcomes of gastrointestinal mesenchymal tumors
including gastrointestinal stromal tumors. J Am Coll Surg 202: 623–9.
46. Lazar AJ, Trent JC, Lev D (2007) Sarcoma molecular testing: diagnosis and
prognosis. Curr Oncol Rep 9: 309–15.
47. Andersson J, Bumming P, Meis-Kindblom JM, Sihto H, Nupponen N, et al.
(2006) Gastrointestinal stromal tumors with KIT exon 11 deletions are
associated with poor prognosis. Gastroenterology 130: 1573–81.
48. Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, et al. (2002) PAX3-
FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar
rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol
49. Ladanyi M, Antonescu CR, Leung DH, Woodruff JM, Kawai A, et al. (2002)
Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a
multi-institutional retrospective study of 243 patients. Cancer Res 62: 135–40.
50. Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal
tumors. J Clin Oncol 22: 3813–25.
51. Williamson D, Missiaglia E, de Reynies A, Pierron G, Thuille B, et al. (2010)
Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly
indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28: 2151–8.
52. Vauhkonen H, Savola S, Kaur S, Larramendy ML, Knuutila S (2006)
Molecular karyotyping in sarcoma diagnostics and research. Adv Exp Med Biol
53. Nielsen TO, West RB, Linn SC, Alter O, Knowling MA, et al. (2002) Molecular
characterisation of soft tissue tumours: a gene expression study. Lancet 359:
54. Nielsen TO, West RB (2010) Translating gene expression into clinical care:
sarcomas as a paradigm. J Clin Oncol 28: 1796–805.
55. Miettinen M (2006) From morphological to molecular diagnosis of soft tissue
tumors. Adv Exp Med Biol 587: 99–113.
56. Wolden SL, Alektiar KM (2010) Sarcomas across the age spectrum. Semin
Radiat Oncol 20: 45–51.
57. Ferrari A, Casanova M, Collini P, Meazza C, Luksch R, et al. (2005) Adult-type
soft tissue sarcomas in pediatric-age patients: experience at the Istituto Nazionale
Tumori in Milan. J Clin Oncol 23: 4021–30.
58. Soliman H, Ferrari A, Thomas D (2009) Sarcoma in the young adult population:
an international view. Semin Oncol 36: 227–36.
Incidence Sarcoma Histotypes
PLoS ONE | www.plosone.org14 August 2011 | Volume 6 | Issue 8 | e20294