1471-2407-10-1501471-2407 Research article <p>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</p> LurkinAntoinelurkin@lyon.fnclcc.fr DucimetièreFrancoiseducimeti@lyon.fnclcc.fr VinceRanchèreDominiquerancherd@lyon.fnclcc.fr DecouvelaereAnne-Valériedeouvel@lyon.fnclcc.fr CellierDominicdominic.cellier@merck.fr GillyNFrançoisfrancois.gilly@chu-lyon.fr SalameireDimitriDSalameire@chu-grenoble.fr BironPierrebiron@lyon.fnclcc.fr de LarocheGuyguy.delaroche@icloire.fr BlayYvesJeanblay@lyon.fnclcc.fr Ray-CoquardIsabelleray@lyon.fnclcc.fr

Centre Léon Bérard, 28 rue Laennec - 69008 Lyon; France

INSERM EA 4129 « SIS », 28 rue Laennec - 69008 Lyon, France

ONCORA network, Réseau Oncologie Rhône-Alpes BIOPARC/ADENINE - 60 Avenue Rockefeller, 69373 LYON Cedex 08, France

CONCORDE network, Réseau Oncologie Rhône-Alpes BIOPARC/ADENINE - 60 Avenue Rockefeller, 69373 LYON Cedex 08, France

ARC'ALPIN network, Unité de Concertation et de Recherche pour le Traitement des Affections Cancéreuses, CHU A. Michallon BP217 38043 GRENOBLE, France

Institut de Cancerologie de la Loire, 108 Bis av. Albert Raimond 42270 Saint Priest en Jarez, France

Merck Serono, 37 rue Saint Romain - 69008 Lyon, France

INSERM U590 Cytokine et Cancer, 28 rue Laennec - 69008 Lyon, France

 BMC Cancer 1471-2407 2010 10 1 150 http://www.biomedcentral.com/1471-2407/10/150 2040316010.1186/1471-2407-10-150 249200919420101942010 2010Lurkin et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Sarcomas are rare malignant tumors. Accurate initial histological diagnosis is essential for adequate management. We prospectively assessed the medical management of all patients diagnosed with sarcoma in a European region over a one-year period to identify the quantity of first diagnosis compared to central expert review (CER).

Methods

Histological data of all patients diagnosed with sarcoma in Rhone-Alpes between March 2005 and Feb 2006 were collected. Primary diagnoses were systematically compared with second opinion from regional and national experts.

Results

Of 448 patients included, 366 (82%) matched the inclusion criteria and were analyzed. Of these, 199 (54%) had full concordance between primary diagnosis and second opinion (the first pathologist and the expert reached identical conclusions), 97 (27%) had partial concordance (identical diagnosis of conjonctive tumor but different grade or subtype), and 70 (19%) had complete discordance (different histological type or invalidation of the diagnosis of sarcoma). The major discrepancies were related to histological grade (n = 68, 19%), histological type (n = 39, 11%), subtype (n = 17, 5%), and grade plus subtype or grade plus histological type (n = 43, 12%).

Conclusions

Over 45% of first histological diagnoses were modified at second reading, possibly resulting in different treatment decisions. Systematic second expert opinion improves the quality of diagnosis and possibly the management of patients.

Background

Sarcomas are malignant tumors developing in soft tissue, bone, skin or internal organs. The large majority of soft tissue tumors are benign and 100 times more common than malignant lesions 1 2 . Because there are more than 50 histological subtypes of soft tissue sarcoma (STS) identified in the 2002 WHO classification, accurate diagnosis is difficult 3 . Given the rarity of the disease, inappropriate medical management has been reported in more than 70% of patients with sarcomas 4 . Careful pre-treatment evaluation is therefore essential for accurate diagnosis and appropriate treatment decision making 5 6 . Discrepancies between pathologists have been reported frequently 7 8 9 10 . Although immunohistochemistry, Fluorescence In Situ Hybridization (FISH) and molecular biology can facilitate diagnosis, these techniques are not routinely available in all laboratories and their use requires experienced pathologists with expertise in molecular biology.

Second opinion in diagnostic pathology has recently received considerable attention as a result of efforts to enhance institutional performance and reduce medical errors 11 . However, the mechanisms by which second opinion is obtained greatly influence the results 12 . Second opinions given by another institution or a specialty panel at the time of patient referral produce highly discordant rates as compared to analysis of cases referred to experts for review 13 . In the case of expert review, discrepancies are not viewed as "errors" but as a reflection of the acknowledged need for assistance. For this we initiated an exhaustive, prospective study involving the systematic comparison of initial histological diagnosis by a first ('non-expert') pathologist and second opinion (SO) from regional and/or national experts of the disease in a comprehensive population of patients diagnosed in a precise geographical region over a one-year period.

Methods

Objectives

The main objective of the present work was to evaluate the benefit of systematic central review by regional and national experts of all sarcoma cases diagnosed in the Rhône-Alpes region (RA). All sarcoma cases diagnosed by pathologists of the region were reported, and data were statistically analyzed to quantify inter-observer differences and determine their nature.

Description of the Region

RA is the second largest region in France, with nearly 6 million inhabitants and 8 departements (i.e. the administrative and geographical unit in France). It has 15 public structures (3 university hospitals, 1 cancer center, 11 general hospitals) with 59 pathologists and 28 private structures with 80 pathologists.

Patient selection

To be eligible, patients had to meet the following inclusion criteria: first diagnosis of connective tissue tumor, according to the 2002 WHO definition, and no previous treatment, first sarcoma diagnosis between March 1, 2005 and February 28, 2006 in RA region, all disease stages, and age ≥ 15 years. Exclusion criteria were as follows: diagnosis of relapse or a diagnosis other than sarcoma (i.e. low grade phyllodes tumor). Similarly, patients were not included when primary diagnosis had been established in the reference center (Leon Berard Cancer Center) by one of the 'experts' or if the tumor specimen was not sent to the expert or when there was not enough tumor material. In order to include patients and assess the concordance our study obtained an ethical approval by a review board (CNIL: Commission Nationale de l'information et des libertés. Independent administrative authority protecting privacy and personal data). The evaluation of medical records has been made through clinical audit

Study design

The goal of this study was to compare initial histological evaluation by the diagnostic pathologist (generally not an expert on these diseases) and results of the central expert review (CER) by two regional and national exclusively soft tissue experts. These two experts, members of the French Sarcoma Group (FSG), were selected by the EMS project scientific committee. All pathologists working in the region agreed to cooperate. All suspected cases of sarcoma (soft tissue, bone and visceral tissue sarcoma; n = 671) diagnosed during the reference period were collected 14 .

For each patient, a copy of the original histology report and histopathological specimens (Hemalin Eosin Safran (HES) and paraffin-embedded tissue) representative of the tumor sample were provided.

The diagnostic pathologist was offered financial compensation for each patient included (50 euros). For all included patients, immunohistochemistry (and/or molecular biology analysis) was performed by the referent pathologist.

Exhaustiveness control

To ensure exhaustiveness, several controls were established throughout the study by comparing the registered patients with the complete list of: 1) sarcomas reviewed by the expert pathologist every two months during the inclusion period; 2) medical files of the multidisciplinary sarcoma committee and patients obtained from the Medical Information Department of the reference center; 3) pediatric patients with sarcoma to confirm the number of patients aged 15-18 and obtained from the pediatric registry of the RA region; 4) all sarcomas diagnosed by initial pathologists; then we excluded patients with exclusion criteria. After cross validation, only 5 additional patients were identified as missing and included 15 16 .

Main outcome measure

Differences between the first diagnosis established by the non-expert pathologist and the second opinion given by experts were evaluated and scored on a three-point scale: The two experts evaluated in same time the diagnosis.

Zero agreement corresponded to cases where initial diagnosis was benign and final diagnosis was malignant (sarcoma) or conversely, or where the tumor was classified in different histological subtypes (i.e. synovialosarcoma vs. liposarcoma).

Partial agreement corresponded to cases where both pathologists diagnosed a sarcoma but with different histopathological grades, or with a different subtype (i.e. dedifferentiated liposarcoma vs. myxoid round cell liposarcoma).

Full agreement corresponded to cases where both observers gave identical diagnoses.

To define this score, the two experts must conclude to the same diagnose. In some rare cases and when the two experts did not have the same conclusion or if the diagnose was difficult the diagnosis was reexamined either by another expert (international expert Pr Fletcher) or/and discussed at monthly FSG pathologist meetings and a final consensus was determinated.

For all sarcoma types with mutation, a molecular biology was systematically assessed (FISH technic, PCR or DNA sequencing) to characterize the genetic alteration and confirm the diagnose. The Immunomarques were systematically done again by the expert

Grading system

The grading system of the French Sarcoma Group of the French Federation of Cancer Centers (FNCLCC) was used in this study as now proposed in the WHO classification 17 . Grade was rated 'not applicable' for some specific histological types (e.g. Kaposi sarcoma) or when the grade could not be determined (biopsy specimen).

Subgroup analysis

For all included cases, the pathologist investigators were systematically offered an expert second opinion and the discrepancies were analyzed. However, two groups of patients were distinguished. The first one ("requested SO" group) corresponded to patients examined by a "non expert" pathologist who requested a second opinion from experts to confirm initial diagnosis. The second group ("control" group) included patients whose tumor samples were analyzed by a 'non expert' pathologist who did not request confirmation of diagnosis by experts and whose findings were reviewed only in the context of the present project but the results were not disclosed.

Statistical analysis

To evaluate patient characteristics and diagnostic concordance, categorical data were analyzed using Pearson's χ2-test or Fisher's exact test, as appropriate. Continuous data were analyzed with Student's t-test. The statistical significance level was set at p = 0.05 in a two-sided test.

Comparisons were also made between the "requested SO" group and controls. The χ2 test was used to determine the rate of concordance and the types of discordance. Correlations between the most frequent causes of error and groups were analyzed using the Kappa test. For grading evaluation, a two by two table was constructed to compare original diagnosis against final diagnosis, both subsets being partitioned according to whether or not the diagnosis was the type of sarcoma under consideration. A Kappa test was used to measure agreement between initial diagnosis and expert review as compared to what would be expected by chance alone 18 19 . All analyses were performed using SPSS® (version 12.0) and SAS® softwares.

Results

All values reported hereafter for grade, histology and type or site of sarcoma are those obtained after expert review.

Characteristics of selected patients and tumors

Of 671 patients initially screened by pathology laboratories, 220 (33%) were excluded, either because of patient age < 15 (n = 26, 4%), local relapse (n = 92, 14%), metastatic relapse (n = 40, 6%), or because the patient had not been firstly diagnosed in RA (n = 36, 5%) or had not been diagnosed between March 2005 and Feb 2006 (n = 26, 4%). Among the 451 selected patients, 52 (12%) were further excluded because initial diagnosis had been established in the reference center by one of the experts. Of the 399 remaining patients, 29 (7%) were excluded because there was no or not enough tumor tissue available for a second histological analysis and 4 (1%) because the initial histological report was not available. Finally, 366 (92%) patients were eligible for final analysis (Figure 1). The first diagnosis of sarcoma was performed in private practice for 265 (72%) patients and in public laboratories for 101 (28%) patients. Only 2 laboratories did not recruit any patient.

<p>Figure 1</p>

Patient selection

Patient selection.

Characteristics of included patients and tumors

Patients' characteristics are reported in Table 1. Among the 366 analyzed patients, 184 were males (50%) and 182 were females (50%). Median age was 61 years (range, 15-92): 60 (range, 15-92) for males and 63 (range, 16-91) for females.

<p>Table 1</p>

Characteristics of included patients

Number

%

Included patients

366

100%

Types of sarcoma

Soft tissue

215

59

Visceral tissue

130

35

Bone tissue

21

6

Tumor site

Abdomen

101

27.6

Lower limb

76

20.8

Thorax

54

14.8

Pelvis

45

12.3

Upper limb

34

9.3

Head and Neck

29

7.9

Retroperitoneum

21

5.7

Multiple localizations

5

1.4

Axial skeleton

1

0.3

Histological subtype

GIST

65

17.8

Liposarcoma

56

15.3

NOS Sarcoma *

52

14.2

Other **

38

10.3

Leiomyosarcoma

26

7.1

Dermatofibrosarcoma protuberans

20

5.5

Kaposi sarcoma

18

4.9

Uterine leiomyosarcoma

12

3.3

Myxofibrosarcoma

12

3.3

Osteosarcoma

11

3.0

Angiosarcoma

10

2.7

Chondrosarcoma

9

2.5

PNET/Ewing sarcoma

8

2,2

Rhabdomyosarcoma

8

2.2

Synovial sarcoma

7

1,9

Unclassified malignant connective tumors

14

3.8

Grade

I

85

23.2

II

77

21.0

III

97

26.5

Not applicable***

103

28.1

Unknown

4

1.1

* NOS = not otherwise specified.

**The 'other' category included sarcoma subtypes with less than 5 patients and tumors initially described as sarcomas and reclassified by the experts as carcinomas or sarcomatoid carcinomas

**Not applicable (Kaposi sarcoma, for instance)

Concordance analysis

Concordance analysis was performed on 93 (25%) sarcoma biopsy specimens and 273 (75%) surgical samples. Concordance data regarding grade, type of tumor sample (biopsy vs. surgery) and type of laboratory (private vs. public) are given in Table 2. Concordance analysis showed 70 cases of zero agreement (19%), 97 partial agreements (27%) and 199 full agreements (54%). The rate of discordance was higher in grade II-III than in grade I tumors (p = 0.012). On the other hand, no significant differences were reported according to type of tumor sample, type of laboratory and molecular biology examination (yes vs. no) (Table 2). The molecular biology techniques used were the Fluorescence in situ hybridization (FISH), the PCR and DNA sequencing.

<p>Table 2</p>

Concordance analysis

Concordance

Zero

Partial

Full

p

Included tumors

70 (100%)

97 (100%)

199 (100%)

Type of laboratory

Public

17 (16.8%)

28 (27.7%)

56 (55.4%)

0.78

Private

53 (20%)

69 (26.%)

143 (54%)

Concordance

Zero

Partial

Full

p

Included tumors

70

97

97

Type of tumor sample

Biopsy

16 (17.2%)

23 (24.7%)

54 (58.1%)

0.70

Surgical specimen

54 (19.8%)

74 (27.1%)

145 (53.1%)

Concordance

Zero

Partial

Full

p

Included tumors

44

81

134

Grade

I

9 (10.6%)

21 (24.7%)

55 (64.7%)

0.01

II-III

35 (20.1%)

60 (34.5%)

79 (45.4%)

Concordance

Zero

Partial

Full

p

Included tumors

67

97

199

Molecular biology study

No

45 (20%)

61 (26.%)

127 (54%)

0.84

Yes

23(17.6%)

36 (27.5%)

72 (55.0%)

Causes of non-concordance are presented in Table 3. Discrepancies between initial diagnosis and review were essentially related to grade and histological subtype. Details of zero and partial agreements are given in Table 4 and Additional File 1, respectively. More precisely, in the zero concordance group, the diagnoses were changed from benign to malignant for 7 patients. The modification of diagnosis between malignant tumor and benign have been concerning 3 patients. The most frequent discrepancy was related to the grade of the tumor: either no grading by the diagnostic pathologist while the expert attributed grade 3 (n = 33, 20%), or misinterpretation of the grading with grade 3 attributed by the diagnostic pathologist and grade 1 by the expert (n = 3, 2%). Other (n = 131, 78%) discrepancies were related to the grade (0 vs. I, I vs. II, II vs. III) and histological subtype. We measured the chance-corrected agreement on grade between groups using the Kappa test. The Kappa coefficient was 0.7857 (p < 0.0001), which reflected a high level of agreement. The major cause of discrepancies was the very high proportion (n = 85, 66%) of tumors not graded by diagnostic pathologists. However, when diagnostic pathologists did grade the tumors, their grading was generally correct (Additional File 1).

<p>Table 3</p>

Reasons for non-concordance

Reasons for non-concordance

Frequency

%

Grade

68

18.5

Histological type

39

10.7

Grade and Histological type

30

8.2

Subtype

17

4.6

Grade and subtype

13

3.6

SUB-TOTAL

167

45.6

Patient with total agreement

199

54.4

TOTAL

366

100

<p>Table 4</p>

Diagnostic differences in cases with zero concordance

Expert diagnosis

Initial diagnosis

Frequency

(n = 70)

NOS Sarcoma

MPNST

1

NOS Sarcoma

Angiosarcoma

1

NOS Sarcoma

Unclassified malignant tumor

6

NOS Sarcoma

Leiomyosarcoma

1

NOS Sarcoma

GIST

1

NOS Sarcoma

Chondrosarcoma

1

NOS Sarcoma

Embryonic Rhabdomyosarcoma

1

NOS Sarcoma

Benign Tumor

1

NOS Sarcoma

Liposarcoma

1

NOS Sarcoma

Leiomyosarcoma

2

Leiomyosarcoma

Benign Tumor

2

Leiomyosarcoma

NOS Sarcoma

1

Osteosarcoma

NOS Sarcoma

1

Osteosarcoma

Unclassified malignant tumor

1

Osteosarcoma

Melanoma

1

Lipoma-like Liposarcoma

Benign Tumor

1

Lipoma-like Liposarcoma

Fibrosarcoma

1

Lipoma-like Liposarcoma

Unclassified malignant tumor

1

Liposarcoma

Benign Tumor

1

Liposarcoma

NOS Sarcoma

2

Dedif. Liposarcoma

Leiomyosarcoma

2

Dedif. Liposarcoma

Unclassified malignant tumor

1

Dedif. Liposarcoma

NOS Sarcoma

1

Myxofibrosarcoma

Liposarcoma

1

Myxofibrosarcoma

NOS Sarcoma

3

Myxofibrosarcoma

Sarcomatoid Carcinoma

1

Myxofibrosarcoma

Chondrosarcoma

1

Sarcomatoid Carcinoma

Leiomyosarcoma

1

Sarcomatoid Carcinoma

NOS Sarcoma

3

Angiosarcoma

Unclassified malignant tumor

1

Angiosarcoma

Synovial sarcoma

1

Benign Tumor

Inflammatory MyxofibroSarcoma

1

Benign Tumor

Leiomyosarcoma

1

Benign Tumor

Well-differenciated lipoma-like Liposarcoma

1

Epithelioid Sarcoma

Unclassified malignant tumor

1

Epithelioid Sarcoma

Synovial sarcoma

1

PNET/Ewing sarcoma

Carcinoma

2

PNET/Ewing sarcoma

Unclassified malignant tumor

3

Rhabdomyosarcoma

Leiomyosarcoma

1

GIST

NOS Sarcoma

1

Carcinoma

Phyllodes Tumor

1

Carcinoma

NOS Sarcoma

1

Solitary fibrosis/malignant Tumor

GIST

1

Uterine Leiomyosarcoma

Benign Tumor

1

PEComa

Unclassified malignant tumor

1

Fibrosarcoma

Unclassified malignant tumor

1

Endometrial Stromal Sarcoma

Leiomyosarcoma

1

Epithelioid Hemangioendothelioma

Carcinoma

1

Inflammatory Myxofibrosarcoma

Epithelioid Sarcoma

1

Unclassified malignant tumor

Carcinoma

1

Low grade fibromyxoid Sarcoma

Benign Tumor

1

Kaposi sarcoma

NOS Sarcoma

1

Synovial sarcoma

Benign Tumor

1

Dermatofibrosarcoma protuberans

Benign Tumor

1

NOS: not otherwise specified

PNET: primitive neuroectodermal tumor

GIST: gastrointestinal stromal tumor

PEComa: malignant perivascular epithelioid cell tumor

MPNST: malignant peripheral nerve sheath tumor

 <p>Additional file 1</p>

Table S1: Grade concordance between groups using the Kappa test (n = 157).

Click here for file

The second most frequent discrepancy was related to the histological type (Table 4). In 22 (31%) patients the diagnosis reviewed and modified by the expert concerned benign tumor or sarcomatoid carcinoma.

Diagnosis was confirmed by molecular biology (RT-PCR, FISH) in 131 (36%) patients: 72 (55%) in the "requested SO" group and 59 (45%) in the control group at the request of the expert reviewer. Seventy-two (55%) tests were performed in the group with full concordance, 36 (27%) with partial concordance and 23 (18%) with zero concordance. Eighty-seven (66%) of these 131 molecular biology tests were positive, 32 (24%) were negative and 12 (9%) were non significant. They were performed essentially in patients with GIST (n = 41, 31%), liposarcoma (n = 39; 30%) and dermatofibrosarcoma protuberans (n = 11, 8%). Final diagnosis could not be established by the first expert for 20 (5%) patients, and the case was submitted to other sarcoma experts for second opinion (French sarcoma group).

Requested SO group versus control group

For the two groups of patients distinguished, the characteristics are compared in Tables 5 and Additional File 2.

<p>Table 5</p>

Patient characteristics per subgroup

Patient characteristics.

requested SO group

Control group

p

Included patients

188 (100%)

178 (100%)

Sex

Males

102 (54.3%)

82 (46.1%)

0.117

Females

86 (45.7%)

96 (53.9%)

Age (years)

Mean

57.9

59.6

Median

62

61

0.359

Range

[15-86]

[18-92]

Types of tumor

Soft tissue

117 (62.2%)

98 (55.1%)

Bone tissue

13 (6.9%)

8 (4.5%)

0.128

Visceral tissue

58 (30.9%)

72 (40.4%)

Localization

Upper limb

15 (8.%)

19 (10.7%)

Lower limb

45 (23.9%)

31 (17.4%)

Abdomen

44 (23.4%)

57 (32%)

Thorax

31 (16.5%)

23 (12.9%)

0.313

Head and Neck

16 (8.5%)

13 (7.3%)

Pelvis

25 (13.3%)

20 (11.2%)

Retroperitoneum

10 (5.3%)

11 (6.2%)

Axial skeleton

1 (0.5%)

0 (0%)

Multiple localizations

1 (0.5%)

4 (2.2%)

Grade

Grade I

47 (25%)

38 (21.3%)

Grade II

36 (19.1%)

41 (23%)

Grade III

50 (26.6%)

47 (26.4%)

0.716

Non applicable

52 (27.2%)

51 (28.7%)

Unknown

3 (1.6%)

1 (0.6%)

Histological subtypes

Liposarcoma

37 (19.7%)

19 (10.7%)

NOS Sarcoma

32 (17.0%)

20 (11.2%)

GIST

23 (12.2%)

42 (23.6%)

Myxofibrosarcoma

9 (4.8%)

3 (1.7%)

Leiomyosarcoma

7 (3.7%)

19 (10.7%)

PNET/Ewing

6 (3.2%)

2 (1.1%)

Rhabdomyosarcoma

6 (3.2%)

2 (1.1%)

< 0.001.

Chondrosarcoma

6 (3.2%)

3 (1.7%)

Dermatofibrosarcoma

4 (2.1%)

16 (9.0%)

protuberans

Uterine Leiomyosarcoma

5 (2.7%)

7 (3.9%)

Osteosarcoma

5 (2.7%)

6 (3.4%)

Kaposi Sarcoma

5 (2.7%)

13 (7.3%)

Synovialosarcoma

5 (2.7%)

2 (1.1%)

Angiosarcoma

3 (1.6%)

7 (3.9%)

Unclassified malignant tumor

7 (3.7%)

7 (3.9%)

Other

28 (14.9%)

10 (5.6%)

<p>Additional file 2</p>

Table S2: Characteristics of patients per type of laboratory and type of tumor sample.

Click here for file

Only three items seemed different between subgroups: type of samples, type of laboratory and histological subtype. The patients for whom initial diagnosis had been made from biopsy specimens were most frequently not proposed for a SO. Likewise, the majority of patients included in the group without SO were first diagnosed in public laboratories. For all other factors no differences were noted. In fact, non expert pathologists asked for a second expert opinion principally for difficult diagnoses or cases requiring molecular analysis (n = 188). Sex, age, type of tumor, or tumor localization and grade did not influence the decision of the first pathologist to request a second opinion (Table 5).

Concordance results in the two subgroups of patients

The concordance observed between the two groups of patients is described in Table 6. Not surprisingly, concordance was significantly better in cases where the primary pathologist did not ask for a second opinion as compared to cases where an expert second opinion was requested spontaneously (66% vs. 44%) (p < 0.001). Reasons for non-concordance were tested in both groups. The type of sample and the type of laboratory were not found correlated to concordance, with respectively 40 (70%) vs. 77 (63%) (p = 0.62), and 82 (68%) vs. 35 (60%) (p = 0.39) full concordance in the group without SO. In the group with SO, full concordance results were 14 (39%) vs. 68 (44%) (p = 0.72) and 61 (42%) vs. 21 (48%) (p = 0.66).

<p>Table 6</p>

Comparison of concordance results in the two groups

Requested SO group

Control group

p

Included patients

188 (100%)

178 (100%)

Concordance

Zero

53 (28.2%)

17 (9.6%)

Partial

53 (28.2%)

44 (24.7%)

< 0.001.

Full

82 (43.6%)

117 (65.7%)

Included patients

106 (100%)

61 (100%)

Type of discordance

Subtype alone

10 (9.4%)

7 (11.5%)

Grade alone

31 (29.2%)

37 (60.7%)

Histological type alone

27 (25.5%)

12 (19.7%)

< 0.001

Grade + Subtype

13 (12.3%)

0 (0%)

Grade + Histological type

25 (23.6%)

5 (8.2%)

Discussion

Full concordance was reported for only 54% of cases included in this comprehensive cohort of sarcoma patients treated in RA in one year. Indeed, accurate diagnosis is essential to ensure appropriate management of patients with sarcoma, especially in the context of new targeted therapies. This study confirmed that centralized pathological review improves the quality of diagnosis in these rare tumors.

This study confirms that the diagnosis of sarcoma is very difficult to establish since more than 45% of first diagnoses were declared invalid by the panel of experts conducting the centralized pathological review. The major result was that concordance seems independent of the type of laboratory providing the primary diagnosis, the nature of the tumor samples or the tissue affected by the sarcoma (bone, soft tissue, viscera). The most frequent discrepancies identified were related to tumor grade and histological type. Exact determination of the tumor type and grade is crucial for making individual treatment decisions and subsequently improving patient outcome 20 21 . In fact, determining the grade of the tumor is essential to decide between adjuvant chemotherapy or not, neo-adjuvant chemotherapy or not, or radiotherapy or not. With the introduction of targeted treatments and the proliferation of clinical studies, patients whose grade has not been correctly evaluated may be excluded from trials 20 21 22 23 . Although the clinical practice recommendations published in France have confirmed that the tumor grade must be included in the histological report generated at the time of diagnosis, this information is not always given, as confirmed in other studies demonstrating that the reproducibility of grade is very difficult to achieve 20 23 24 25 . On the other hand, when non expert pathologists participating in the study did grade a tumor, their evaluation was generally correct. Pathologists may sometimes lack experience and would benefit from training sessions organized in the framework of continuous medical education 26 .

Accurate determination of the type of sarcoma lesion is also crucial for correct patient management especially for differentiating between benign and malignant tumors, or between the different subtypes 27 . Determining the grade of the tumor is more reproducible than characterizing its histological type which is the second cause of diagnostic discordance 8 . The second cause of discrepancies concerned the histological type, and the central question that arises is whether all sarcoma cases should be reviewed in a specialized center. Importantly, all pathologists evaluating sarcoma patients should be able to use immunohistochemistry for confirmation of diagnosis. For certain histological types (GIST, Dermatofibrosarcoma protuberans...), molecular biology can also contribute to the establishment and/or the confirmation of diagnosis 28 29 30 31 32 . Non concordance between first diagnosis and review seems very frequent for liposarcoma, PNET tumor and NOS sarcoma, and it is high for GIST and dermatofibrosarcoma protuberans for which specific markers are available. Similar results were reported by Harris et al, with a high degree of agreement for osteosarcoma and chondrosarcoma and low agreement for leiomyosarcoma and malignant fibrous histiocytoma 27 28 .

In the literature, the rate of diagnostic errors in patients with soft tissue sarcoma is between 25% and 40%. 6 7 8 9 10 33 34 35 36 37 , Surprisingly, since the first published reports on second opinion for sarcoma tumors in 1980, despite the introduction of new tools (immunochemistry, molecular biology etc.) and the development of educational workshops, the percentage of concordance has remained unchanged. Disagreements between diagnostic pathologists and expert panel members are inescapable (unrepresentative samples, heterogeneous tumors, misdiagnosis of grading...). In spite of the relatively high incidence of sarcoma, such variations in diagnosis will continue to occur and no significant convergence can be expected over time 14 . Our comprehensive prospective study confirmed the results of previous retrospective studies, with inconsistencies between primary diagnosis and histological review in 45% of all cases. Our results revealed that diagnostic pathologists were often lack expertise in this disease or in other rare tumors. Thus, systematic expert second opinion seems essential 35 . The inexperience of non-specialists with the multitude and complexity of soft tissue sarcomas is probably the most important factor accounting for diagnostic discrepancies 27 . Actually, this question of centralized diagnosis is less relevant for tumors with more "standardized" diagnosis and management, like carcinoma or ovarian cancer 38 39 .

In this study, 50% of the tumors were spontaneously addressed for a second opinion by the non-expert pathologist, versus only 40% in a previous study 25 . All pathologists in the RA region took part in the study and full comprehensiveness was achieved. However, to achieve such a successful recruitment, many requirements must be met. In particular, there must be a key opinion leader and expert pathologist with recognized expertise in the field. Financial support to the pathologists participating in the study also seems essential. Finally, it is important, to keep the pathologists informed through regular meetings and newsletters. They must be involved and get feedback about the final diagnosis of their patient as well as about the advancement of the study. Cancer network participation can facilitate the involvement of pathologists and ensure exhaustiveness. It is well established in sarcoma pathology that "expert" opinion is not always absolutely convergent, though often different conceptualizations of a tumor do not necessarily generate different treatment implications. With the help of CONTICANET (CONnective TIssue CAncer NETwork), a similar prospective study has been initiated in the Aquitaine (France) and Venetia (Italy) regions to compare the rate of diagnostic discordance and confirm our conclusions. The correlation between concordance and free survival will be essentially evaluated on grade II/III tumors. The assessment of concordance is important for the patient for its impact on the diagnosis. The optimal diagnosis but also the optimum treatments (R0, radiotherapy decision) have an important role. Their prognostic value will be determinate in another article.

Conclusion

In conclusion, the inexperience of non-specialized pathologists with the multitude and complexity of sarcoma tumors, and the non availability of new molecular diagnostic tools are the most important factors accounting for diagnosis discrepancies. A centralized pathological review, a rapid and efficient help with access to molecular biology analysis seem of vital importance in these rare tumors. More efficient information and education of the pathologists also seems essential to ensure accurate diagnosis and grading 31 .

Competing interests

I declare that all authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. We would like just specify that Dr Dominic Cellier is the scientific relationship director of Merck-Serono. Merck-Serono is our financial support.

Authors' contributions

AL: Data collection, data analyse, interpretation data, statistical analyse, article writing; FD: Data collection, data analyse, interpretation data, written participation; DR-V: Data collection, histological review, interpretation data, final article review; A-VD: Data collection, histological review, interpretation data, final article review; DC: Study design, administrative participation, final article review; FG: Data collection, administrative participation, final article review; DS: Data collection, data analyse, final article review; PB: Data collection, administrative participation, final article review; GDL: Data collection, administrative participation, final article review; J-YB: Project conception, study design, data collection, final article review; IR-C: Project conception, study design, data collection, statistical analyse, final article review. All authors read and approved the final manuscript

Acknowledgements

The authors are grateful to Marie-Dominique Reynaud for editing assistance, to the data managers Muriel Rogasik and Philippe Cousin, and to all pathologists of the Rhone-Alpes region for their active collaboration in the study:

Dr Agard Catherine, Dr Allias-Montmayeur Fabienne, Dr Angonin Régis, Dr Augros Marylin, Dr Bailly Christiane, Dr Balme Brigitte, Dr Bancel Brigitte, Dr Barnoud Raphaelle, Dr BenLagha Nadia, Dr Benabidallah Samir, Dr Berger Gerard, Dr Beschet Isabelle, Dr Beurlet Jacques, Dr Billard Françoise, Dr Bland Vincent, Dr Bonin Anne-Marie, Dr Bottero Noelle, Dr Bourloux Jocelyne, Dr Bouvier Raymonde, Dr Bozon Catherine, Dr Brambilla Elisabeth, Dr Bringeon Béatrice, Dr Buenerd Annie, Dr Cantero Brigitte, Dr Cavaillés Catherine, Dr Chalabreysse Lara, Dr Chalabreysse Philippe, Dr Chambonniere Marie-Laure, Dr Chanoz Jacques, Dr Chanoz-Poulard Geneviève, Dr Chassagne-Clément Catherine, Dr Chevallier Michèle, Dr Chouvet Brigitte, Dr Ciapa Agnès, Dr Claret-Tournier Catherine, Dr Clemenson Alix, Dr Collardeau Frachon Sophie, Dr Corrand-Faure Anne, Dr Corsois Laurent, Dr Crozes Carole, Dr Cruel Thierry, Dr David Catherine, Dr De la Fouchardiere Arnaud, Dr Decaussin-Petrucci Myriam, Dr Decouvelaere Anne-Valérie, Dr Denier Jean-François, Dr Der Garabedian Philiberte, Dr Derolland Philippe, Dr Descombes-Thivolet Brigitte, Dr Dieny Anne-Florence, Dr Dijoud Frederique, Dr Donne Chantal, Dr Donsbeck Anne-Valérie, Dr Douchet Catherine, Dr Dumollard Jean, Dr Dusserre Isabelle, Dr Economides-Jarsaillon Ariane, Dr Elbaz Nadine, Dr Fabre Blandine, Dr Faisant Monique, Dr Faure Anne, Dr Faure Claire, Dr Faysse Michaelie, Dr Feutry Catherine, Dr Fontaniere Bernard, Dr Frachon-Collardeau Sophie, Dr Gasnier Plaweski F, Dr Gentil-Perret Anne, Dr Glehen Alexandra, Dr Godard William, Dr Godeneche Janique, Dr Gouarderes Catherine, Dr Gouzy-Grosjean Fabienne, Dr Griot Annick, Dr Guillaubey Colette, Dr Guillaud Catherine, Dr Herve-Nicollet Catherine, Dr Hervieu Valérie, Dr Isaac Sylvie, Dr Istier Luc, Dr Jouvet Anne, Dr Kanitakis Jean, Dr Kermanac'h Pascale, Dr Khaddage Abir, Dr Klein Laurence, Dr Knopf Jean-François, Dr Koeb Marie-Hélène, Dr Labadie Michel, Dr Lantuejoul Sylvie, Dr Laurent Isabelle, Dr Lauro Carole, Dr Le Breton Frédérique, Dr Lucht-Versini Pascale, Dr Mabrut Marianne, Dr Machayekhi Jean-Pierre, Dr Maisonneuve Martine, Dr Maisonneuve-Gilly Dominique, Dr Mege-Lechevallier Florence, Dr Meyronet David, Dr Morcillo J-L, Dr Muller Bernard, Dr Muller Christine, Dr Neyra Monique, Dr Pasquier Dominique, Dr Perrot Guy, Dr Pialat Jean, Dr Picchetti Nicole, Dr Pinel Nicole, Dr Pocachard, Dr Pugens Gilles, Dr Ranchère-Vince Dominique, Dr Reis Borges Ruth, Dr Richard Jacques, Dr Roux Jean-Jacques, Dr Roux-Gilly Marie-Georges, Dr Saint Genis Luc, Dr Saint-Pierre Ghislaine, Dr Salameire Dimitri, Dr Salle Monique, Dr Salon Caroline, Dr Serain Francois, Dr Soubeyrand Marie-Sophie, Dr Streichenberger Nathalie, Dr Sturm Nathalie, Dr Suignard Yves, Dr Terdjman Pierre, Dr Treilleux Isabelle, Dr Vancina Serge, Dr Vaunois Brigitte, Dr Vercherin Axelle, Dr Vitetta Franck, Dr Vock-Bonnet Marthe, Dr Youssef Nelly, Pr Devouassoux Mojgan, Pr Pasquier Basile, Pr Peoc'h Michel, Pr Scoazec Jean-Yves, Pr Thivolet Bejoui Francoise.

Financial support: Merck Serono, National League against Cancer (Ain and Rhône committees), CONTICANET network.

Presented in part at 2008 CTOS.

 <p>Cancer incidence and mortality in France in 1975-95</p>MenegozFBlackRJArveuxPMagneVFerlayJBuemiAEur J Cancer Prev1997654426610.1097/00008469-199710000-000059466116<p>Soft-tissue sarcomas in adults</p>ClarkMAFisherCJudsonIThomasJMN Engl J Med200535377011110.1056/NEJMra04186616107623<p>Conformity to clinical practice guidelines, multidisciplinary management and outcome of treatment for soft tissue sarcomas</p>Ray-CoquardIThiessePRanchere-VinceDChauvinFBobinJYSunyachMPAnn Oncol20041523071510.1093/annonc/mdh05814760127<p>WHO classification of tumors. Pathology and genetics</p>FletcherCDUnniKKMertensFTumors of Soft Tissue and BoneIARC press2002<p>Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow-up</p>CasaliPGJostLSleijferSVerweijJBlayJYAnn Oncol200819Suppl 2ii89ii9310.1093/annonc/mdn10118456783<p>Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations</p>ArbiserZKFolpeALWeissSWAm J Clin Pathol20011164473610.1309/425H-NW4W-XC9A-005H11601130<p>[Histological changes after chemotherapy of soft tissue sarcomas in the adult]</p>CoindreJMNguyenBBGoussotJFDeMIMareeDDe MascarelAAnn Pathol1985529593840024<p>Reproducibility of a histopathologic grading system for adult soft tissue sarcoma</p>CoindreJMTrojaniMContessoGDavidMRouesseJBuiNBCancer1986582306910.1002/1097-0142(19860715)58:2<306::AID-CNCR2820580216>3.0.CO;2-73719523<p>Sarcomas in north west England: I. Histopathological peer review</p>HarrisMHartleyALBlairVBirchJMBanerjeeSSFreemontAJBr J Cancer19916423152019775011892759<p>Cellular heterogeneity. Explanation for changing of tumor phenotype and biologic behavior in soft tissue sarcomas</p>KatenkampDPathol Res Pract198818366987052851775<p>Consensus conference on second opinions in diagnostic anatomic pathology. Who, What, and When</p>TomaszewskiJEBearHDConnallyJAEpsteinJIFeldmanMFoucarKAm J Clin Pathol200011433293510989631<p>Prospective peer review in surgical pathology</p>LindACBewtraCHealyJCSimsKLAm J Clin Pathol1995104556067572817<p>Mandatory second opinion surgical pathology at a large referral hospital</p>KronzJDWestraWHEpsteinJICancer1999861124263510.1002/(SICI)1097-0142(19991201)86:11<2426::AID-CNCR34>3.0.CO;2-310590387<p>Exhaustive prospective collection of new sarcomas: Report of an unexpectedly high incidence</p>DucimetiereALurkinDRanchere-VincePBironMPeochLIstierDSalameirePChalabreysseJBlayYRay-CoquardIJournal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition)200725No 18S (June 20 Supplement)20513<p>[Childhood cancer incidence and survival rates in the Rhone-Alpes regional paediatric registry 1987-1999]</p>BergerCTrombert-PaviotBMittonNFrappazDGalambrunCPlantazDArch Pediatr2006132121910.1016/j.arcped.2005.10.02216376530<p>Trends in treatment-related deaths (TRDs) in childhood cancer and leukemia over time: a follow-up of patients included in the childhood cancer registry of the Rhone-Alpes region in France (ARCERRA)</p>FreyconFTrombert-PaviotBCasagrandaLBertrandYPlantazDMarec-BerardPPediatr Blood Cancer200850612132010.1002/pbc.2150618300318<p>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</p>GuillouLCoindreJMBonichonFNguyenBBTerrierPCollinFJ Clin Oncol1997151350628996162<p>A coefficient of agreement for nominal scales</p>CohenJEduc Psychol Meas196020274610.1177/001316446002000104<p>Large sample standard errors of kappa and weighted kappa</p>FleissJLCohenJEverittBSPsychol Bull19697232332710.1037/h0028106<p>Prognostic factors predictive of survival for truncal and retroperitoneal soft-tissue sarcoma</p>SingerSCorsonJMDemetriGDHealeyEAMarcusKEberleinTJAnn Surg199522121859510.1097/00000658-199502000-0000912349527857146<p>Synovial sarcoma: prognostic significance of tumor size, margin of resection, and mitotic activity for survival</p>SingerSBaldiniEHDemetriGDFletcherJACorsonJMJ Clin Oncol1996144120188648375<p>Soft tissue tumours</p>EnzingerFMWeiss SW. St Louis: Mosby42001<p>High-dose chemotherapy in adult soft tissue sarcoma</p>ReichardtPCrit Rev Oncol Hematol20024121576710.1016/S1040-8428(01)00153-611856592<p>[Recommendations for anatamo-pathologic management of soft tissue sarcomas in the adult. Pathologists of the FNCLCC Sarcoma Group (Federation Nationale des Centres de Lutte Contre le Cancer)]</p>CoindreJMAnn Pathol19981865051110051921<p>Histologic grading of adult soft tissue sarcomas</p>CoindreJMVerh Dtsch Ges Pathol199882596310095417<p>Validity and reproducibility of histologic diagnosis and grading for adult soft-tissue sarcomas</p>HasegawaTYamamotoSNojimaTHiroseTNikaidoTYamashiroKHum Pathol2002331111510.1053/hupa.2002.3018411823981<p>The value of expert second opinion in diagnosis of soft tissue sarcomas</p>LehnhardtMDaigelerAHauserJPulsASoimaruCKuhnenCJ Surg Oncol200897140310.1002/jso.2089717918224<p>Cytogenetic and molecular genetic techniques as adjunctive approaches in the diagnosis of bone and soft tissue tumors</p>BridgeJASandbergAASkeletal Radiol20002952495810.1007/s00256005060310883443<p>Immunohistochemistry in the diagnosis of soft tissue tumours</p>CoindreJMHistopathology200343111610.1046/j.1365-2559.2003.01639.x12823707<p>Contribution of molecular genetic data to the classification of sarcomas</p>LadanyiMBridgeJAHum Pathol2000315532810.1053/hp.2000.670610836292<p>Application of immunocytochemistry in the diagnosis of soft tissue sarcomas: a review and update</p>OrdóñezNGAdv Anat Pathol19985678510.1097/00125480-199801000-000519868514<p>[Pathological evaluation of soft tissue sarcoma for diagnosis, prognosis and treatment]</p>YamaguchiUHasegawaTGan To Kagaku Ryoho20043191340515446553<p>Morphologic review of 1000 soft tissue sarcomas from the Scandinavian Sarcoma Group (SSG) Register. The peer-review committee experience</p>Meis-KindblomJMBjerkehageBBohlingTDomanskiHHalvorsenTBLarssonOActa Orthop Scand Suppl1999285182610429617<p>Soft-tissue and bone sarcoma histopathology peer review: the frequency of disagreement in diagnosis and the need for second pathology opinions. The Southeastern Cancer Study Group experience</p>PresantCARussellWOAlexanderRWFuYSJ Clin Oncol19864111658613772418<p>Errors in diagnosis and margin determination of soft-tissue sarcomas initially treated at non-tertiary centers</p>RandallRLBrucknerJDPapenhausenMDThurmanTConradEUIIIOrthopedics20042722091214992389<p>Pathologic analysis of advanced adult soft tissue sarcomas, bone sarcomas, and mesotheliomas. The Eastern Cooperative Oncology Group (ECOG) experience</p>ShirakiMEnterlineHTBrooksJJCooperNSHirschlSRothJACancer19896424849010.1002/1097-0142(19890715)64:2<484::AID-CNCR2820640223>3.0.CO;2-T2736494<p>The impact of second opinion surgical pathology on the practice of head and neck surgery: a decade experience at a large referral hospital</p>WestraWHKronzJDEiseleDWHead Neck20022476849310.1002/hed.1010512112543<p>Expert second opinion pathology review of lymphoma in the Era of the world health organization classification</p>MatasarMJShiWSilberstienJBlood2007<p>Comparative study of ovarian cancer histopathology by registry pathologists and referral pathologists: a study by the Gilda Radner Familial Ovarian Cancer Registry</p>PiverMSTsukadaYWernessBADicioccioRAWhittemoreASPonderBAGynecol Oncol20007821667010.1006/gyno.2000.584010926797

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2407/10/150/prepub