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.
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).
Citation: Ducimetière F, Lurkin A, Ranchère-Vince D, Decouvelaere A-V, Péoc'h M, Istier L, 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. https://doi.org/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.
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% –. 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 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 exclusion criteria.
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 Ranchère-Vince (DRV) and Anne-Valerie Decouvelaere (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 region.
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 Miettinen .
Soft tissue and bone sarcomas were classified using morphologic and immunohistochemical criteria according to the 2002 WHO classifications . Cutaneous and visceral sarcomas were categorized under three different WHO groups: skin tumors, tumors of the digestive system, and tumors of the breast and female genital organs , . 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 problematic 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 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 Libertés (CNIL, protection of individuals with regard to the processing of personal data). This was a descriptive epidemiological 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 study.
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 sarcomas.
Crude and age-adjusted incidence of histological subtypes
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 angiosarcomas, 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 sarcoma), each having a specific distribution (Fig. 3B). Age-specific 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.
(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 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 osteosarcomas, 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 subtypes
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 sarcomas and rhabdomyosarcomas). Table 8 describes the predominant 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. Angiosarcoma affected more frequently elderly mainly due to secondary angiosarcoma (44%) diagnosed after radiation treatment 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, duplication) 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 characterization.
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 immunohistochemistry, 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 , . 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 , . 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.
The work presented here differs from previous large retrospective 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 , , the European database of the Automated Childhood Cancer Information 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 , . 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 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 ,  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 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 regions with the youngest population (Source INSEE) though the age 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 known to be higher among African Americans than among Caucasian patients ,  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 in the 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 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 , , 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, liposarcoma and fibrosarcoma. In the present study, the main histological types were GIST, unclassified sarcoma, liposarcoma and leiomyosarcoma. 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 incidence of GIST has increased from 0.2 to more than 1/100,000 in several European countries after the introduction in 2001 of anti-CD117 antibody for immunohistochemical staining , , . 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 diagnostic markers.
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 characterization 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) –, 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 rhabdomyosarcoma 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 receptors) .
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 referents.
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 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 ,  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 Léonie 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 Fouchardière, 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 Péoc'h, G Perrot, J Pialat, E Piaton, N Picchetti Mayer, N Pinet Briquet, M Plenier Maisonneuve, P Pocachard, G Pugens, I Remy, D Ranchère-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-Béjui, 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.MA ClarkC. FisherI. JudsonJM Thomas2005Soft-tissue sarcomas in adults.N Engl J Med35370111
- 2. Jemal A, Siegel R, Ward E, Murray T, Xu J, et al. (2006) Cancer statistics, 2006. CA Cancer J Clin 56: 106–30.A. JemalR. SiegelE. WardT. MurrayJ. Xu2006Cancer statistics, 2006.CA Cancer J Clin5610630
- 3. Parkin DM, Stiller CA, Nectoux J (1993) International variations in the incidence of childhood bone tumours. Int J Cancer 53: 371–6.DM ParkinCA StillerJ. Nectoux1993International variations in the incidence of childhood bone tumours.Int J Cancer533716
- 4. Stiller CA, Parkin DM (1994) International variations in the incidence of childhood soft-tissue sarcomas. Paediatr Perinat Epidemiol 8: 107–19.CA StillerDM Parkin1994International variations in the incidence of childhood soft-tissue sarcomas.Paediatr Perinat Epidemiol810719
- 5. Fletcher CDM, Unni KK, Mertens F (2002) World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and Bone. CDM FletcherKK UnniF. Mertens2002World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and Bone.IARC Press: Lyon. 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.CL CorlessA. SchroederD. GriffithA. TownL. McGreevey2005PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.J Clin Oncol23535764
- 7. De Vita V, Lawrence T, Rosenberg S (2008) V. De VitaT. LawrenceS. Rosenberg2008DeVita, Hellman and Rosenberg's Cancer: Principles and Practice of Oncology, Eighth ed. 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.B. NilssonP. BummingJM Meis-KindblomA. OdenA. Dortok2005Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden.Cancer1038219
- 9. Zahm SH, Fraumeni JF Jr (1997) The epidemiology of soft tissue sarcoma. Semin Oncol 24: 504–14.SH ZahmJF Fraumeni Jr1997The epidemiology of soft tissue sarcoma.Semin Oncol2450414
- 10. Antonescu CR (2006) The role of genetic testing in soft tissue sarcoma. Histopathology 48: 13–21.CR Antonescu2006The role of genetic testing in soft tissue sarcoma.Histopathology481321
- 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.C. BergerB. Trombert-PaviotN. MittonD. FrappazC. Galambrun2006[Childhood cancer incidence and survival rates in the Rhone-Alpes regional paediatric registry 1987–1999].Arch Pediatr131219
- 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.L. GuillouJM CoindreF. BonichonBB NguyenP. Terrier1997Comparative 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 Oncol1535062
- 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: 459–65.CD FletcherJJ BermanC. CorlessF. GorsteinJ. Lasota2002Diagnosis of gastrointestinal stromal tumors: A consensus approach.Hum Pathol3345965
- 14. Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23: 70–83.M. MiettinenJ. Lasota2006Gastrointestinal stromal tumors: pathology and prognosis at different sites.Semin Diagn Pathol237083
- 15. Hamilton SR, Aaltonen LA (2000) World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Digestive System. SR HamiltonLA Aaltonen2000World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Digestive System.IARC Press: Lyon. IARC Press: Lyon.
- 16. Tavassoli FA, Devilee P (2003) World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and female genital organs. FA TavassoliP. Devilee2003World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and female genital organs.IARC Press: Lyon. 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.M. PeterE. GilbertO. Delattre2001A multiplex real-time pcr assay for the detection of gene fusions observed in solid tumors.Lab Invest8190512
- 18. Ahmad O, Boschi-Pinto C, Lopez AD, Murray CJL, Lozano R, et al. (2001) O. AhmadC. Boschi-PintoAD LopezCJL MurrayR. Lozano2001Age standardization of rates: a new WHO standard. Geneva, World Health Organization, 2001 (GPE Discussion Paper No. 31). 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.PA CassierF. DucimetiereA. LurkinD. Ranchere-VinceJY Scoazec2010A 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 Cancer10316570
- 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.F. LeviC. La VecchiaL. RandimbisonVC Te1999Descriptive epidemiology of soft tissue sarcomas in Vaud, Switzerland.Eur J Cancer3517116
- 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.JR ToroLB TravisHJ WuK. ZhuCD FletcherSS Devesa2006Incidence 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 Cancer119292230
- 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 Information System project. Eur J Cancer 42: 2136–49.G. PastoreR. Peris-BonetM. CarliC. Martinez-GarciaJ. Sanchez de Toledo2006Childhood soft tissue sarcomas incidence and survival in European children (1978–1997): report from the Automated Childhood Cancer Information System project.Eur J Cancer42213649
- 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 42: 2124–35.CA StillerSS BielackG. JundtE. Steliarova-Foucher2006Bone tumours in European children and adolescents, 1978–1997. Report from the Automated Childhood Cancer Information System project.Eur J Cancer42212435
- 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.M. ColonnaN. BossardN. MittonL. RemontetA. Belot2008[Some interpretation of regional estimates of the incidence of cancer in France over the period 1980–2005].Rev Epidemiol Sante Publique5643440
- 25. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, et al. (2007) MP CuradoB. EdwardsHR ShinH. StormJ. Ferlay2007Cancer Incidence in Five Continents, Vol. IX. IARC Scientific Publications No.160,Lyon, IARC. Cancer Incidence in Five Continents, Vol. IX. IARC Scientific Publications No.160,Lyon, IARC.
- 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. LAG RiesMA SmithJG GurneyM. LinetT. Tamra1999Cancer 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. 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.K. Pritchard-JonesP. KaatschE. Steliarova-FoucherCA StillerJW Coebergh2006Cancer in children and adolescents in Europe: developments over 20 years and future challenges.Eur J Cancer42218390
- 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. G. EngholmJ. FerlayN. ChristensenML GjerstorffA. Klint2010NORDCAN: 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). 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.ZK ArbiserAL FolpeSW Weiss2001Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations.Am J Clin Pathol1164736
- 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.JM Meis-KindblomB. BjerkehageT. BohlingH. DomanskiTB Halvorsen1999Morphologic review of 1000 soft tissue sarcomas from the Scandinavian Sarcoma Group (SSG) Register. The peer-review committee experience.Acta Orthop Scand Suppl2851826
- 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.A. LurkinF. DucimetiereVD RanchereAV DecouvelaereD. Cellier2010Epidemiological 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 Cancer10150
- 32. Kramarova E, Stiller CA (1996) The international classification of childhood cancer. Int J Cancer 68: 759–65.E. KramarovaCA Stiller1996The international classification of childhood cancer.Int J Cancer6875965
- 33. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P (2005) International Classification of Childhood Cancer, third edition. Cancer 103: 1457–67.E. Steliarova-FoucherC. StillerB. LacourP. Kaatsch2005International Classification of Childhood Cancer, third edition.Cancer103145767
- 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.F. MenegozRJ BlackP. ArveuxV. MagneJ. Ferlay1997Cancer incidence and mortality in France in 1975–95.Eur J Cancer Prev644266
- 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.J. WorchKK MatthayJ. NeuhausR. GoldsbySG DuBois2010Ethnic and racial differences in patients with Ewing sarcoma.Cancer1169838
- 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.R. EyreRG FeltbowerPW JamesK. BlakeyE. Mubwandarikwa2010The epidemiology of bone cancer in 0–39 year olds in northern England, 1981–2002.BMC Cancer10357:357
- 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. C. WibmerA. LeithnerN. ZielonkeM. SperlR. Windhager2009Increasing 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: 486–90.JA RossRK SeversonS. DavisJJ Brooks1993Trends in the incidence of soft tissue sarcomas in the United States from 1973 through 1987.Cancer7248690
- 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: 1961–71.P. KaatschE. Steliarova-FoucherE. CrocettiC. MagnaniC. Spix2006Time trends of cancer incidence in European children (1978–1997): report from the Automated Childhood Cancer Information System project.Eur J Cancer42196171
- 40. Linabery AM, Ross JA (2004) Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer 112: 416–32.AM LinaberyJA Ross2004Trends in childhood cancer incidence in the U.S. (1992–2004).Cancer11241632
- 41. Tryggvason G, Gislason HG, Magnusson MK, Jonasson JG (2005) Gastrointestinal stromal tumors in Iceland, 1990–2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer 117: 289–93.G. TryggvasonHG GislasonMK MagnussonJG Jonasson2005Gastrointestinal stromal tumors in Iceland, 1990–2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study.Int J Cancer11728993
- 42. Coindre JM (2003) Immunohistochemistry in the diagnosis of soft tissue tumours. Histopathology 43: 1–16.JM Coindre2003Immunohistochemistry in the diagnosis of soft tissue tumours.Histopathology43116
- 43. Daugaard S (2004) Current soft-tissue sarcoma classifications. Eur J Cancer 40: 543–8.S. Daugaard2004Current soft-tissue sarcoma classifications.Eur J Cancer405438
- 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.WG GoettschSD BosN. Breekveldt-PostmaM. CasparieRM Herings2005Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study.Eur J Cancer41286872
- 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.EA PerezAS LivingstoneD. FranceschiC. Rocha-LimaDJ Lee2006Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors.J Am Coll Surg2026239
- 46. Lazar AJ, Trent JC, Lev D (2007) Sarcoma molecular testing: diagnosis and prognosis. Curr Oncol Rep 9: 309–15.AJ LazarJC TrentD. Lev2007Sarcoma molecular testing: diagnosis and prognosis.Curr Oncol Rep930915
- 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.J. AnderssonP. BummingJM Meis-KindblomH. SihtoN. Nupponen2006Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis.Gastroenterology130157381
- 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 20: 2672–9.PH SorensenJC LynchSJ QualmanR. TiraboscoJF Lim2002PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group.J Clin Oncol2026729
- 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.M. LadanyiCR AntonescuDH LeungJM WoodruffA. Kawai2002Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients.Cancer Res6213540
- 50. Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22: 3813–25.CL CorlessJA FletcherMC Heinrich2004Biology of gastrointestinal stromal tumors.J Clin Oncol22381325
- 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.D. WilliamsonE. MissiagliaA. de ReyniesG. PierronB. Thuille2010Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.J Clin Oncol2821518
- 52. Vauhkonen H, Savola S, Kaur S, Larramendy ML, Knuutila S (2006) Molecular karyotyping in sarcoma diagnostics and research. Adv Exp Med Biol 587: 53–63.H. VauhkonenS. SavolaS. KaurML LarramendyS. Knuutila2006Molecular karyotyping in sarcoma diagnostics and research.Adv Exp Med Biol5875363
- 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: 1301–7.TO NielsenRB WestSC LinnO. AlterMA Knowling2002Molecular characterisation of soft tissue tumours: a gene expression study.Lancet35913017
- 54. Nielsen TO, West RB (2010) Translating gene expression into clinical care: sarcomas as a paradigm. J Clin Oncol 28: 1796–805.TO NielsenRB West2010Translating gene expression into clinical care: sarcomas as a paradigm.J Clin Oncol281796805
- 55. Miettinen M (2006) From morphological to molecular diagnosis of soft tissue tumors. Adv Exp Med Biol 587: 99–113.M. Miettinen2006From morphological to molecular diagnosis of soft tissue tumors.Adv Exp Med Biol58799113
- 56. Wolden SL, Alektiar KM (2010) Sarcomas across the age spectrum. Semin Radiat Oncol 20: 45–51.SL WoldenKM Alektiar2010Sarcomas across the age spectrum.Semin Radiat Oncol204551
- 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.A. FerrariM. CasanovaP. ColliniC. MeazzaR. Luksch2005Adult-type soft tissue sarcomas in pediatric-age patients: experience at the Istituto Nazionale Tumori in Milan.J Clin Oncol23402130
- 58. Soliman H, Ferrari A, Thomas D (2009) Sarcoma in the young adult population: an international view. Semin Oncol 36: 227–36.H. SolimanA. FerrariD. Thomas2009Sarcoma in the young adult population: an international view.Semin Oncol3622736