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.
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.
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).
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.
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
The exact overall incidence of sarcomas is unknown and the incidence of the different histological and molecular subtypes has not been determined precisely
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.
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).
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 (
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)
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)
Soft tissue and bone sarcomas were classified using morphologic and immunohistochemical criteria according to the 2002 WHO classifications
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
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.
Characteristic | Total | Years | Type of sarcoma | |||
2005 | 2006 | STS | Visceral | Bone | ||
|
748 (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%) |
|
||||||
Mean | 56 | 56 | 57 | 56 | 61 | 41 |
Median | 60 | 60 | 61 | 61 | 62 | 40 |
Range | 0–92 | 0–92 | 0–91 | 0–92 | 0–91 | 6–84 |
Age group | ||||||
0–9 | 25 (3%) | 12 (3%) | 13 (3%) | 17 (4%) | 2 (1%) | 6 (8%) |
10–19 | 35 (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%) |
30–29 | 59 (8%) | 34 (9%) | 25 (7%) | 38 (9%) | 16 (7%) | 5 (6%) |
40–49 | 74 (10%) | 40 (11%) | 34 (9%) | 43 (10%) | 25 (10%) | 6 (8%) |
50–59 | 133 (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%) |
90+ | 5 (1%) | 4 (1%) | 1 (<1%) | 4 (1%) | 1 (1%) | - |
|
||||||
≤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%) |
Superficial | 133 (18%) | 81 (21%) | 52 (14%) | 133 (31%) | - | - |
According to pathology report n = 535 (71%), to imaging n = 133 (18%) or to physical examination n = 9 (1%).
Above or under superficial fascia.
Soft tissue sarcomas(n = 433) | Visceral sarcomas(n = 237) | Bone sarcomas(n = 78) | |||
Primarytumor site | N (%) | Primarytumor site | N (%) | Primarytumor site | N (%) |
|
|
|
|
|
|
Abdomen | 26 (6) | Stomach | 85 (36) | Lower limbs | 31 (40) |
Retroperitoneum | 41 (9) | Small intestine | 42 (18) | Femur | 21 (27) |
Thorax | 73 (17) | Colon | 6 (2) | Tibia | 8 (10) |
Pelvis | 33 (8) | Rectum | 4 (2) | Fibula | 1 (1) |
Omentum | 4 (2) | Metatarsus | 1 (1) | ||
|
|
Peritoneum | 5 (2) | Upper limbs | 12 (15) |
Lower limbs | 155 (36) | Kidney | 6 (2) | Humerus | 5 (6) |
Thigh | 88 (20) | Liver | 2 (1) | Scapula | 3 (4) |
Leg | 23 (5) | Spleen | 2 (1) | Clavicle | 2 (2) |
Pelvic girdle | 23 (5) | Other abdomen | 5 (2) | Hand | 2 (2) |
Foot | 8 (2) | ||||
Knee | 9 (2) |
|
|
|
|
Ankle | 4 (1) | Lung | 9 (4) | Skull | 3(4) |
Upper limbs | 59 (14) | Pleura | 5 (2) | Orbit | 2 (2) |
Shoulder girdle | 22 (5) | Heart | 4 (2) | Mandible | 1 (1) |
Arm | 7 (2) | Other Thorax | 4 (2) | Other | 4 (5) |
Forearm | 20 (5) | ||||
Elbow | 5 (1) |
|
|
|
|
Hand | 5 (1) | Uterine | 42 (18) |
|
|
Ovary | 3 (1) | Rib | 6 (8) | ||
|
|
Bladder | 3 (1) | Sternum | 1 (1) |
Spermatic cord | 3 (1) |
|
|
||
Other pelvis | 3 (1) |
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).
(
Diagnostic Group | Patients | Crude incidence rates/100,000/year | Age-standardized incidence rates/100,000/year | ||||||
N | (%) | Total | Men | Women | France | Europe | World (Segi) | World (WHO) | |
|
748 | (100) | 6.2 | 6.7 | 5.8 | 6.4 | 5.6 | 4.5 | 4.8 |
Without Kaposi sarcoma | 723 | (97) | 6.0 | 6.3 | 5.7 | 6.1 | 5.4 | 4.4 | 4.6 |
|
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Children 0–14 | 44 | (6) | 1.9 | 2.6 | 1.2 | 1.9 | 1.9 | 1.9 | 1.9 |
Adults 15–69 | 482 | (64) | 5.8 | 6.3 | 5.3 | 5.9 | 5.8 | 5.2 | 5.1 |
Elderly 70+ | 222 | (30) | 15.8 | 18.3 | 14.2 | 15.8 | 15.7 | 15.4 | 15.7 |
|
|||||||||
Soft tissue sarcoma | 433 | (58) | 3.6 | 4.2 | 3.0 | 3.7 | 3.2 | 2.6 | 2.8 |
Visceral sarcoma | 237 | (32) | 2.0 | 1.7 | 2.3 | 2.0 | 1.7 | 1.3 | 1.4 |
Bone sarcoma | 78 | (10) | 0.6 | 0.8 | 0.5 | 0.7 | 0.6 | 0.6 | 0.6 |
|
|||||||||
GIST | 135 | (18) | 1.1 | 1.0 | 1.2 | 1.2 | 0.9 | 0.7 | 0.7 |
Unclassified sarcoma | 117 | (16) | 1.0 | 1.2 | 0.8 | 1.0 | 0.8 | 0.6 | 0.7 |
Liposarcoma | 112 | (15) | 0.9 | 1.2 | 0.7 | 1.0 | 0.8 | 0.6 | 0.7 |
Leiomyosarcoma | 85 | (11) | 0.7 | 0.5 | 0.9 | 0.7 | 0.6 | 0.5 | 0.5 |
Dermatofibrosarcoma | 38 | (5) | 0.3 | 0.4 | 0.3 | 0.3 | 0.3 | 0.3 | 0.3 |
Osteosarcoma | 31 | (4) | 0.3 | 0.4 | 0.2 | 0.3 | 0.3 | 0.3 | 0.3 |
Chondrosarcoma | 29 | (4) | 0.2 | 0.3 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
Ewing sarcoma/PNET | 27 | (4) | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.3 | 0.3 |
Rhabdomyosarcoma | 26 | (3) | 0.2 | 0.3 | 0.1 | 0.2 | 0.2 | 0.3 | 0.3 |
Kaposi sarcoma | 25 | (3) | 0.2 | 0.4 | 0.1 | 0.2 | 0.2 | 0.1 | 0.2 |
Angiosarcoma | 25 | (3) | 0.2 | 0.1 | 0.3 | 0.2 | 0.1 | 0.1 | 0.1 |
Myxofibrosarcoma | 17 | (2) | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
Synovial sarcoma | 16 | (2) | 0.1 | 0.1 | 0.2 | 0.1 | 0.1 | 0.1 | 0.1 |
Endometrial stromal sarcoma | 14 | (2) | 0.1 | - | 0.2 | 0.1 | 0.1 | 0.1 | 0.1 |
Histological 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).
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
Histological type | Tumor grade N, (%) | Total | |||||||
Low | Intermediate | High | Not done |
||||||
|
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Unclassified sarcoma | |||||||||
Pleomorphic cell sarcoma | 2 | (4) | 13 | (24) | 28 | (51) | 12 | (22) | 55 |
Spindle cell sarcoma | 1 | (2) | 11 | (27) | 18 | (44) | 11 | (27) | 41 |
Round cell sarcoma | - | - | - | - | 7 | (64) | 4 | (36) | 11 |
Sarcoma not otherwise specified | 1 | (10) | 2 | (20) | 2 | (20) | 5 | (50) | 10 |
Liposarcoma | |||||||||
Well differentiated liposarcoma | 71 | (100) | - | - | - | - | - | - | 71 |
Dedifferentiated liposarcoma | 4 | (15) | 13 | (48) | 9 | (33) | 1 | (4) | 27 |
Myxoid-round cell liposarcoma | 8 | (67) | 4 | (33) | - | - | - | - | 12 |
Pleomorphic liposarcoma | - | - | 1 | (50) | 1 | (50) | - | - | 2 |
Non uterine leiomyosarcoma | 15 | (24) | 25 | (40) | 15 | (24) | 7 | (11) | 62 |
Angiosarcoma | 3 | (12) | 11 | (44) | 9 | (36) | 2 | (8) | 25 |
Myxofibrosarcoma | 2 | (12) | 8 | (47) | 7 | (41) | - | - | 17 |
Synovial sarcoma | |||||||||
Monophasic synovial sarcoma | - | - | 7 | (54) | 6 | (46) | - | - | 13 |
Biphasic synovial sarcoma | - | - | 2 | (67) | 1 | (33) | - | - | 3 |
MPNST | 2 | (40) | 1 | (20) | 2 | (40) | - | - | 5 |
Epithelioid sarcoma | - | - | 2 | (40) | 2 | (40) | 1 | (20) | 5 |
Low grade fibromyxoid sarcoma | 4 | (100) | - | - | - | - | - | - | 4 |
Fibrosarcoma | 1 | (33) | - | - | 2 | (67) | - | - | 3 |
Intimal sarcoma | - | - | - | - | 2 | - | - | 2 | |
Myxoinflammatory fibroblastic sarcoma | 2 | (100) | - | - | - | - | - | - | 2 |
Composite hemangioendothelioma | 1 | (100) | - | - | - | - | - | - | 1 |
High-grade phyllodes tumor | - | - | - | - | 1 | (100) | - | - | 1 |
|
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Conventional osteosarcoma | - | - | - | - | 26 | (100) | - | - | 26 |
Soft tissue osteosarcoma | - | - | 1 | (34) | 2 | (66) | - | - | 3 |
Parosteal osteosarcoma | 1 | (100) | - | - | - | - | - | - | 1 |
Osteosarcoma grade 2 | - | - | 1 | (100) | - | - | - | - | 1 |
Chondrosarcoma | 12 | (41) | 13 | (45) | 4 | (14) | - | - | 29 |
|
|||||||||
Uterine leiomyosarcoma | 3 | (13) | 1 | (4) | 10 | (44) | 9 | (39) | 23 |
Endometrial stromal sarcoma | 14 | (100) | - | - | - | - | - | - | 14 |
Undifferentiated endometrial sarcoma | - | - | - | - | 3 | (100) | - | - | 3 |
Grade was not evaluated due to limited material or too undifferentiated tumor.
NIH criteria | Very low risk | Low risk | Intermediate risk | High risk | Not done |
Total | |||||
GIST | 11 | (8) | 32 | (24) | 45 | (33) | 37 | (24) | 10 | (7) | 135 |
AFIP criteria | None risk | Very low risk | Low risk | Moderate risk | High risk | Not done |
Total | ||||||
Gastric | 12 | (15) | 23 | (29) | 18 | (23) | 11 | (14) | 10 | (12) | 6 | (7) | 80 |
Other localization | 3 | (5) | - | - | 10 | (18) | 14 | (26) | 26 | (47) | 2 | (4) | 55 |
NIH, National Institutes of Health ; AFIP, Armed Forces Institute of Pathology.
Grade was not evaluated due to limited material or too undifferentiated tumor.
The total numbers of cases in each histological type and subtype are described in
Histological types and subtypes | Number | Sex ratio | Age | CIR |
||||
Total | % | 2005 | 2006 | (M/F) | Median | Range | ||
GIST | 135 | (18) | 70 | 65 | 0.8 | 65 | (34–91) | 1.12 |
Unclassified sarcoma |
117 | (16) | 57 | 60 | 1.4 | 66 | (3–92) | 0.97 |
Pleomorphic cell sarcoma | 55 | (7) | 27 | 28 | 1.4 | 67 | (18–91) | 0.46 |
Spindle cell sarcoma | 41 | (5) | 15 | 26 | 1.6 | 67 | (27–92) | 0.34 |
Round cell sarcoma | 11 | (1) | 7 | 4 | 0.4 | 25 | (3–83) | 0.09 |
Sarcoma not otherwise specified | 10 | (1) | 8 | 2 | 4.0 | 68 | (49–84) | 0.08 |
Liposarcoma | 112 | (15) | 56 | 56 | 1.7 | 61 | (26–88) | 0.93 |
Well differentiated liposarcoma | 71 | (9) | 36 | 35 | 1.8 | 60 | (32–88) | 0.59 |
Dedifferentiated liposarcoma | 27 | (4) | 14 | 13 | 1.2 | 72 | (47–84) | 0.22 |
Myxoid-round cell liposarcoma | 12 | (2) | 5 | 7 | 2.0 | 47 | (26–81) | 0.10 |
Pleomorphic liposarcoma | 2 | (<1) | 1 | 1 | 1.0 | 78 | (72–85) | 0.02 |
Leiomyosarcoma | 85 | (11) | 40 | 45 | 0.5 | 62 | (28–87) | 0.71 |
Non uterine leiomyosarcoma | 62 | (8) | 28 | 34 | 0.9 | 62 | (28–87) | 0.51 |
Uterine leiomyosarcoma | 23 | (3) | 12 | 11 | - | 53 | (40–84) | 0.20 |
Dermatofibrosarcoma protuberans | 38 | (5) | 22 | 16 | 1.2 | 37 | (8–91) | 0.32 |
Osteosarcoma | 31 | (4) | 19 | 12 | 2.1 | 36 | (6–80) | 0.26 |
Conventional osteosarcoma | 26 | (4) | 17 | 9 | 3.3 | 32 | (6–80) | 0.22 |
Soft tissue osteosarcoma | 3 | (<1) | 1 | 2 | 0.5 | 60 | (30–67) | 0.02 |
Parosteal osteosarcoma | 1 | (<1) | 1 | 0 | - | 25 | (25) | 0.01 |
Osteosarcoma grade 2 | 1 | (<1) | 0 | 1 | - | 49 | (49) | 0.01 |
Chondrosarcoma | 29 | (4) | 11 | 18 | 1.2 | 59 | (20–83) | 0.24 |
Ewing sarcoma/PNET | 27 | (4) | 13 | 14 | 0.9 | 23 | (1–83) | 0.22 |
Rhabdomyosarcoma | 26 | (3) | 13 | 13 | 3.3 | 12 | (1–83) | 0.22 |
Embryonal rhabdomyosarcoma | 12 | (2) | 5 | 7 | 3.0 | 11 | (2–25) | 0.10 |
Alveolar rhabdomyosarcoma | 8 | (1) | 4 | 4 | 3.0 | 7 | (1–34) | 0.07 |
Pleomorphic rhabdomyosarcoma | 4 | (<1) | 2 | 2 | 3.0 | 64 | (38–82) | 0.03 |
Spindle cell rhabdomyosarcoma | 2 | (<1) | 2 | 0 | - | 76 | (70–83) | 0.02 |
Kaposi sarcoma | 25 | (3) | 14 | 11 | 5.3 | 59 | (30–90) | 0.21 |
Angiosarcoma | 25 | (3) | 13 | 12 | 0.5 | 75 | (39–84) | 0.21 |
Myxofibrosarcoma | 17 | (2) | 9 | 8 | 0.9 | 63 | (37–84) | 0.14 |
Synovial sarcoma | 16 | (2) | 8 | 8 | 0.6 | 35 | (13–87) | 0.13 |
Monophasic synovial sarcoma | 13 | (2) | 7 | 6 | 0.4 | 32 | (13–87) | 0.11 |
Biphasic synovial sarcoma | 3 | (<1) | 1 | 2 | 2.0 | 41 | (26–43) | 0.02 |
Endometrial stromal sarcoma | 14 | (2) | 6 | 8 | - | 49 | (23–71) | 0.12 |
Malignant solitary fibrous tumor | 8 | (1) | 3 | 5 | 1.7 | 71 | (61–77) | 0.07 |
Other | 43 | (6) | 24 | 19 | 1.1 | - | - | 0.36 |
|
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|
|
GIST, gastrointestinal stromal tumor; PNET, primitive neuroectodermal tumor.
Crude incidence rate/100,000/year.
Unclassified sarcomas were divided in subtypes according to morphological features based on experts' advice.
Histological types | Number | Crude incidence rate/million/year | |||
Total | % | 2005 | 2006 | ||
MPNST |
5 | (0.7) | 3 | 2 | 0.42 |
Epithelioid sarcoma | 5 | (0.7) | 2 | 3 | 0.42 |
Low grade fibromyxoid sarcoma | 4 | (0.5) | 2 | 2 | 0.33 |
Desmoplastic small round cell tumor | 4 | (0.5) | 3 | 1 | 0.33 |
Undifferentiated endometrial sarcoma | 4 | (0.5) | 2 | 2 | 0.33 |
Rhabdoid tumor | 3 | (0.4) | 2 | 1 | 0.25 |
Epithelioid hemangioendothelioma | 3 | (0.4) | 2 | 1 | 0.25 |
Fibrosarcoma | 3 | (0.4) | 1 | 2 | 0.25 |
Intimal sarcoma | 2 | (0.3) | 2 | 0 | 0.17 |
Malignant inflammatory myofibroblastic tumor | 2 | (0.3) | 2 | 0 | 0.17 |
Myxoinflammatory fibroblastic sarcoma | 2 | (0.3) | 1 | 1 | 0.17 |
PEComa |
2 | (0.3) | 1 | 1 | 0.17 |
Composite hemangioendothelioma | 1 | (0.1) | 1 | 0 | 0.08 |
High grade phyllodes tumor | 1 | (0.1) | 0 | 1 | 0.08 |
Alveolar soft part sarcoma | 1 | (0.1) | 0 | 1 | 0.08 |
Clear cell sarcoma of kidney | 1 | (0.1) | 0 | 1 | 0.08 |
MPNST, malignant peripheral nerve sheath tumor.
PEComa, neoplasm with perivascular epithelioid cell differentiation.
Age 0–14Children(n = 44 ; 6%) | Age 15–29Adolescents and young adults(n = 55 ; 7%) | Age 30–49Adults(n = 133 ; 18%) | Age 50–69AdultsMiddle-aged(n = 294 ; 39%) | Age 70+Elderly(n = 222 ; 30%) | |||||
Rhabdomyosarcoma | 36 | Osteosarcoma | 20 | DFSP | 14 | GIST | 22 | GIST | 24 |
PNET/Ewing | 20 | PNET/Ewing | 18 | Liposarcoma | 14 | Liposarcoma | 19 | Unclass. sarcoma | 21 |
Unclass. sarcoma | 9 | DFSP | 11 | GIST | 13 | Unclass. sarcoma | 17 | Liposarcoma | 15 |
Osteosarcoma | 7 | Unclass. sarcoma | 11 | Unclass. sarcoma | 8 | Leiomyosarcoma | 11 | Leiomyosarcoma | 10 |
Rhabdoid tumor | 7 | Synovial sarcoma | 9 | Kaposi sarcoma | 7 | Chondrosarcoma | 4 | Angiosarcoma | 7 |
DFSP | 5 | Chondrosarcoma | 5 | Uterine LMS | 6 | DFSP | 3 | Chondrosarcoma | 3 |
Synovial sarcoma | 5 | Rhabdomyosarcoma | 5 | Chondrosarcoma | 5 | Uterine LMS | 3 | Kaposi sarcoma | 3 |
DSRCT | 5 | Leiomyosarcoma | 4 | Leiomyosarcoma | 5 | Osteosarcoma | 3 | Myxofibrosarcoma | 3 |
Other | 6 | Liposarcoma | 4 | ES sarcoma | 5 | Kaposi sarcoma | 3 | Uterine LMS | 3 |
Epithelioid sarcoma | 4 | Myxofibrosarcoma | 5 | ES sarcoma | 2 | Mal. solit. fibr. tumor | 2 | ||
DSRCT | 4 | Angiosarcoma | 3 | Angiosarcoma | 2 | Osteosarcoma | 2 | ||
MIM Tumor | 4 | Osteosarcoma | 3 | PNET/Ewing | 2 | Rhabdomyosarcoma | 2 | ||
ES sarcoma | 2 | Synovial sarcoma | 3 | Synovial sarcoma | 1 | Other | 5 | ||
Other | 9 | Myxofibrosarcoma | 1 | ||||||
Other | 7 |
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.
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).
Histological types | No. | Molecular biology analysis performed | Molecular abnormality | ||||
No. (%) | Results | Type | Involved gene(s) | No. (%) | CIR |
||
Positive/Negative/Failure | |||||||
GIST | 135 | 119 (88) | 85/14/20 | Mutation | C-kit exon 11 | 55 (56) | 0.46 |
C-kit exon 9 | 10 (10) | 0.08 | |||||
C-kit exon 13 | 4 (4) | 0.03 | |||||
C-kit exon 17 | 1 (1) | 0.01 | |||||
PDGFRA exon 18 | 14 (14) | 0.12 | |||||
PDGFRA exon 12 | 1 (1) | 0.01 | |||||
Wild type | 14 (14) | 0.12 | |||||
Well differentiated liposarcoma | 71 | 64 (90) | 52/3/9 | Amplification | MDM2 and CDK4 | 42 (80) | 0.35 |
MDM2 only | 9 (18) | 0.07 | |||||
MDM2 and HMGA2 | 1 (2) | 0.01 | |||||
Dedifferentiated liposarcoma | 27 | 23 (85) | 20/1/2 | Amplification | MDM2 and CDK4 | 19 (95) | 0.16 |
MDM2 only | 1 (5) | 0.01 | |||||
Myxoid/Round cell liposarcoma | 12 | 12 (100) | 7/1/4 | Fusion transcript | FUS-CHOP | 3 (43) | 0.02 |
Multiplex |
3 (43) | 0.02 | |||||
EWS-CHOP | 1 (14) | 0.01 | |||||
Dermatofibrosarcoma protuberans | 38 | 25 (66) | 19/2/4 | Fusion transcript | COL1A1-PDGFB | 19 (100) | 0.16 |
Ewing/PNET | 27 | 26 (96) | 23/0/3 | Fusion transcript | Multiplex |
13 (56) | 0.11 |
EWSR1-FLI1 | 8 (35) | 0.07 | |||||
EWSR1-ERG | 2 (9) | 0.02 | |||||
Synovial sarcoma | 16 | 16 (100) | 16/0/0 | Fusion transcript | SYT-SSX1 | 9 (56) | 0.07 |
SYT-SSX2 | 6 (38) | 0.05 | |||||
Multiplex | 1 (6) | 0.01 | |||||
Endometrial stromal sarcoma |
14 | 0 (0) | - | Fusion transcript | - | - | |
Alveolar rhabdomyosarcoma | 8 | 8 (100) | 7/1/0 | Fusion transcript | PAX3-FKHR | 3 (42) | 0.02 |
PAX7-FKHR | 2 (29) | 0.02 | |||||
Multiplex |
2 (29) | 0.02 | |||||
Desmoplastic small round cell tumor | 4 | 4 (100) | 4/0/0 | Fusion transcript | EWSR1-WT1 | 4 (100) | 0.03 |
Low grade fibromyxoid sarcoma | 4 | 4 (100) | 4/0/0 | Fusion transcript | FUS-CREB3L2 | 4 (100) | 0.03 |
Rhabdoid tumor | 3 | 3 (100) | 3/0/0 | Mutation | hSNF5-INI1 | 3 (100) | 0.02 |
Malignant inflammatory myofibroblastic tumor |
2 | 1 (50) | 0/0/1 | Fusion transcript | - | ||
Alveolar soft part sarcoma | 1 | 1 (100) | 1/0/0 | Fusion transcript | ASPL-TFE3 | 1 (100) | 0.01 |
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GIST, gastrointestinal stromal tumors; PNET, primitive neuroectodermal tumor.
CIR: Crude incidence rate/100,000/year.
Molecular biology analysis not performed in France.
Detection of rearrangement of ALK gene.
Possible fusion transcript: TLS-CHOP; EWS-CHOP.
Possible fusion transcript: EWS-FLI1; EWS-ERG; EWS-FEV; EWS-EIAF; EWS-ETV1.
Possible fusion transcript: PAX3-FKHR; PAX7-FKHR.
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
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
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
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%
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
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
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
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 development of molecular biology has also proven essential for the diagnosis of sarcoma subtypes and for the refined classification of sarcomas
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)
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
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.