Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

BACKGROUND: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. PATIENTS AND METHODS: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. RESULTS: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. CONCLUSION: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

Retroperitoneal sarcomas: patterns of care at diagnosis, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group.

BACKGROUND: Retroperitoneal sarcomas (RPS) are heterogeneous. No previous study has investigated the impact of specialized surgery, evaluated locoregional relapse (LRR), abdominal sarcomatosis and distant metastatic relapse as separate events, or considered histological subtypes separately. This study addresses these specific points in a homogeneous cohort of patients with completely resected primary RPS. PATIENTS AND METHODS: We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 and eventually referred to one of 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. RESULTS: Five hundred eighty-six patients were included. Median follow-up was 6.5 years [95% confidence interval (CI) 5.9-7.1]. Five hundred thirty-seven patients had localized disease and 389 patients (76%) had macroscopically complete resection of the tumor. In this latter group, the 5-year LRR-free survival rate was 46% [41-52] and the 5-year overall survival (OS) rate was 66% [61-71]. In multivariate analysis, gender, adjacent organ involvement, specialization of the surgeon, piecemeal resection and perioperative radiotherapy were independently associated with LRR. Specialization of the surgeon and piecemeal resection were independently associated with abdominal sarcomatosis whereas histology and adjacent organ involvement were independently associated with distant metastasis. Age, gender, grade, adjacent organ involvement and piecemeal resection were significantly associated with OS. Prognostic factors for LRR and OS were analyzed in well-differentiated and dedifferentiated liposarcomas and leiomyosarcomas. Grade 3 was an independent prognostic factor for OS of dedifferentiated liposarcomas. CONCLUSION: This study underlines the crucial role of pretherapeutic assessment and meticulous histological examination of RPS as well as the need to consider histological subtypes separately. Surgery in a specialized center and avoidance of piecemeal resection stand out as the two most important prognostic factors for RPS and highlight the importance of treating these patients in specialized centers.

Response to chemotherapy is not related to chromosome instability in synovial sarcoma.

BACKGROUND: Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic complexity and response to chemotherapy. PATIENTS AND METHODS: The study population included 65 SS patients diagnosed between 1991 and 2013 and with available tissue material. Genomic profiling was carried out by using array-CGH. Forty-five SS out of the 65 patients were treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy. Radiological response was assessed according to RECIST criteria. Histological response was defined by the percentage of recognizable tumor cells on the surgical specimen. RESULTS: Genomic complexity was significantly associated with MFS. However, there was no statistically significant association between radiological or histological response and genomic complexity. CONCLUSION: The absence of significant association between response to chemotherapy and genomic complexity suggests that the prognostic value of chromosome instability in SS is independent of response to chemotherapy; mechanisms leading to metastatic relapse of SS are intrinsic to the biology of the tumor and current cytotoxic drugs are only poorly efficient to prevent it.

Retroperitoneal sarcomas: patterns of care in advanced stages, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group.

BACKGROUND: Retroperitoneal sarcomas (RPS) are heterogeneous. Advanced stages include unresectable locoregional (LR) disease, abdominal sarcomatosis and distant metastasis. There is no available report assessing palliative chemotherapy in advanced RPS. This study analyzes management and outcome in a large cohort of patients with advanced RPS, considering main histological subtypes separately. PATIENTS AND METHODS: We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 across 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. RESULTS: Five-hundred eighty-six patients were included, 299 patients received palliative chemotherapy, with a median of two lines (range 0-8). Fifty patients underwent palliative surgery. Two hundred fifty-five patients (85%) were assessable for response after first line of chemotherapy. Among them, 69 patients (27%) had progressive disease, 145 (57%) had stable disease, 37 (14.5%) had partial response and 4 (1.5%) complete response. Median time from first line of palliative chemotherapy to progression was 5.9 months [4.9-7.3] and median overall survival (OS), 15.8 months [13-18]. In multivariate analysis, prognosis factors independently associated with poor OS were male gender, performance status (PS) >1 and grade >1. There was no difference according to stage of disease. Palliative surgery did not appear to add any survival benefit. CONCLUSION: These results emphasize the scarcity of available options for RPS in the advanced setting and the urgent need to develop new strategies. Patients with good PS should be included in clinical trials and best supportive care should be considered in those with poor PS.

Sarcoma: concordance between initial diagnosis and centralized expert review in a population-based study within three European regions.

BACKGROUND: Sarcomas represent a heterogeneous group of tumors. Accurate determination of histological diagnosis and prognostic factors is critical for the delineation of treatment strategies. The contribution of second opinion (SO) to improve diagnostic accuracy has been suggested for sarcoma but has never been established in population-based studies. METHODS: Histological data of patients diagnosed with sarcoma in Rhone-Alpes (France), Veneto (Italy) and Aquitaine (France) over a 2-year period were collected. Initial diagnoses were systematically compared with SO from regional and national experts. RESULTS: Of 2016 selected patients, 1463 (73%) matched the inclusion criteria and were analyzed. Full concordance between primary diagnosis and SO (the first pathologist and the expert reached identical conclusions) was observed in 824 (56%) cases, partial concordance (identical diagnosis of connective tumor but different grade or histological subtype) in 518 (35%) cases and complete discordance (benign versus malignant, different histological type or invalidation of the diagnosis of sarcoma) in 121 (8%) cases. The major discrepancies were related to histological grade (n = 274, 43%), histological type (n = 144, 24%), subtype (n = 18, 3%) and grade plus subtype or grade plus histological type (n = 178, 29%). CONCLUSION: More than 40% of first histological diagnoses were modified at second reading, possibly resulting in different treatment decisions.

A prospective epidemiological study of new incident GISTs during two consecutive years in Rhône Alpes region: incidence and molecular distribution of GIST in a European region.

BACKGROUND: Preliminary data indicate that the molecular epidemiology of localised gastrointestinal stromal tumour (GIST) may be different from that of advanced GIST. We sought to investigate the molecular epidemiology of sarcomas, including GIST, in the Rhone-Alpes region in France. PATIENTS AND METHODS: A prospective and exhaustive study in the Rhone-Alpes Region in France to assess the precise incidence of primary sarcomas with systematic centralised pathological review and molecular analysis was conducted for 2 consecutive years. RESULTS: Among 760 patients with a confirmed diagnosis of sarcoma, 131 (17%) had a GIST. The majority of patients had gastric primaries (61%). Mutational analysis could be performed in 106 tumour samples (74%), and 71 (67%) had exon 11 mutations. PDGFRA mutations were found in 16% of cases, which is twice as high as previously reported for advanced GIST. CONCLUSION: Data indicate that PDGFRA mutations in localised GIST may be twice as high as what was previously reported in patients with advanced disease. This finding may have important consequences for patients offered adjuvant imatinib, although most of these tumours are in the low-risk group.

Soft tissue sarcomas of the trunk wall (STS-TW): a study of 343 patients from the French Sarcoma Group (FSG) database.

BACKGROUND: Soft tissue sarcomas of the trunk wall (STS-TW) are usually studied together with soft tissue sarcomas of other locations. We report a study on STS-TW forming part of the French Sarcoma Group database. PATIENTS AND METHODS: Three hundred and forty-three adults were included. We carried out univariate and multivariate analysis for overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). RESULTS: Tumor locations were as follows: thoracic wall, 82.5%; abdominal wall, 12.3% and pelvic wall, 5.2%. Median tumor size was 6.0 cm. The most frequent tumor types were unclassified sarcoma (27.7%) and myogenic sarcoma (19.2%). A total of 44.6% of cases were grade 3. In all, 21.9% of patients had a previous medical history of radiotherapy (PHR). Median follow-up was 7.6 years. The 5-year OS, MFS and LRFS rates were 60.4%, 68.9% and 58.4%, respectively. Multivariate analysis retained PHR and grade for predicting LRFS and PHR, size and grade as prognostic factors of MFS. Factors influencing OS were age, size, PHR, depth, grade and surgical margins. The predictive factors of incomplete response were PHR, size and T3. CONCLUSIONS: Our results suggest similar classical prognostic factors as compared with sarcomas of other locations. However, a separate analysis of STS-TW revealed a significant poor prognosis subgroup of patients with PHR.

Assessment of percutaneous fine needle aspiration cytology as a technique to provide diagnostic and prognostic information in neuroblastoma.

The International Neuroblastoma Staging System (INSS) criteria for diagnosis requires an unequivocal pathological diagnosis and favours the identification of prognostic markers in the samples. Surgical biopsies of the primary tumour and bone marrow (BM) sampling in metastatic disease constitute the major sources of tumour material for the laboratory. We analysed the possibility of percutaneous fine needle aspiration cytology (FNAC) constituting an alternative procedure to the conventional technique of sampling of the primary tumour in children with advanced neuroblastoma. From July 1987 through July 1998, 64 consecutive children suspected of having advanced neuroblastoma and referred to our institution underwent percutaneous FNAC of deeply located tumours. FNAC was performed using 22-gauge needles under ultrasound guidance, before any chemotherapy and within the first days following admission. No complication occurred after FNAC. The median number of the extracted tumour cells was 2.3x10(6) (range: 0-40.6x10(6)). Cytology analysis was possible in 59/64 cases (92%) and immunocytochemistry in 56/64 (88%) allowing confirmation of the diagnosis. N-Myc analysis was available in 46/64 (72%). In addition, the presence of a partial deletion of chromosome 1p (del 1p) was assessed, since 1992, in 24/47 cases (51%), where enough cells were available. FNAC of deeply located advanced neuroblastoma is safe and information is available in a few hours after admission. The provided material is reliable for confirmation of diagnosis and analysis of biological prognostic markers in the majority of cases. More invasive tumour sampling procedures are required only in selected cases.

Evaluation of core needle biopsy as a substitute to open biopsy in the diagnosis of soft-tissue masses.

Open biopsy is recommended for a soft-tissue sarcoma (s-t-S) diagnosis. Core needle biopsy (CNB) was recently associated with minimal morbidity, cost and time-consumption, but also potential inaccuracy. Its diagnostic utility was investigated retrospectively in 110 patients with soft-tissue masses (s-t-M) undergoing CNB between September 1994 and September 2000. Sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values were determined for malignancy (benign/malign), soft-tissue tumour (yes/no), and sarcoma diagnosis (yes/no), comparing CNB and the best standard test available; concordance was evaluated. 103/110 CNB were suitable for analysis. Final diagnosis was 23 benign tumours (19%), 65 s-t-S (59%), 9 lymphomas (8%), 6 fibromatoses (desmoid) (5%) and 7 carcinomas (6%). CNB Sp and PPV were 100%, Se was 95, 99 and 92%, and NPV 85, 95 and 88% for diagnosing malignancy, soft-tissue tumour and sarcoma. CNB Se and NPV were 100% for malignancy, connective tumour and sarcoma in lymphomas, high-grade sarcomas and desmoid tumours. In low grade sarcomas, Se was 94 and 85%, and NPV 84 and 77% for malignancy and sarcoma. Histological grade on CNB seems uneasy, except for grade-III tumours. CNB is accurate, not misleading for s-t-M diagnosis, avoids open biopsy complications, and allows one-surgery or neo-adjuvant chemotherapy planning when combined with appropriate imaging.

Does nephroblastomatosis influence the natural history and relapse rate in Wilms' tumour? A single centre experience over 11 years.

The presence of multifocal or diffuse nephrogenic rests (NRs) in one or both kidneys is termed nephroblastomatosis (Nbm). Nbm may be a predisposing factor for Wilms' tumour (WT). The aim of this retrospective study was to evaluate the impact of Nbm on the outcome of WT in children. We assessed the outcome of 81 children with Wilms tumours and practical implications of Nbm in the treatment and follow-up. All the pathology slides have been reviewed in 1997. 63 had WT without Nbm (group A) and 18 had WT associated with Nbm (group B). There was no statistical difference between the two groups according to the age at diagnosis and histology. Clinical abnormalities were more frequent in group B (33 versus 8%). There was no statistical difference between the percentage of stage IV in both groups, but bilaterality (stage V) was present only in the group B. Relapse was observed in 20/81 patients (25%): 11 (17%) in group A and 9 (50%) in group B. Mean delay of relapse was longer (25 months) in group B than in group A (10 months). For the whole population, with a median follow-up of 9 years, the event-free survival (EFS) and the overall survival (OS) probabilities were respectively 74%+/-10 and 83%+/-9 at 120 months. The difference in EFS between groups A (82+/-9%) and B (38%+/-29) was significant (P=0.004). The discovery of Nbm in the non-tumoral part of the kidney with WT can be an adverse factor and in particular favours the subsequent development of a new Wilms tumour. It justifies separate follow-up guidelines.

[Standards, options and recommendations (SOR) for clinical care of rhabdomyosarcoma (RMS) and other soft tissue sarcoma in children. Federation of the French Cancer Centers. French Society of Pediatric Oncology]. / Standards, options et recommandations pour la prise en charge des patients atteints de rhabdomyosarcome et autres tumeurs mésenchymateuses malignes de l'enfant.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. For pediatric issues, this project is a collaboration between the FNCLCC and the French Society of Pediatric Oncology (SFOP). The main objective is the development of clinical practice guidelines to improve the quality of health care and outcomes for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop a clinical practice guideline according to the definitions of Standards, Options and Recommendations for the clinical care of rhabdomyosarcoma and other soft tissue sarcoma in children and adolescents. METHODS: Data have been identified by literature search using Medline (1985-may 1997) and experts group personal references lists. The main criteria considered were incidence, risk factors, prognostic factors and efficacy of cancer treatment. Once the guideline was defined, the document was submitted for review to 14 national and international independent reviewers, and to the medical committees of the 20 French Cancer Centres and, in particular the 4 which have expertise in pediatric cancer management, for agreement. RESULTS: The main recommendations for rhabdomyosarcoma management are: 1/ diagnosis is based on appropriate clinical and radiological findings; 2/ pathological and immunohistochemical studies are essential to confirm the diagnosis; 3/ surgery must be performed by an experienced surgeon. Surgery and radiotherapy must be as conservative as possible; 4/ therapeutic strategies for rhabdomyosarcoma depend on location and extends and are based on chemotherapy, surgery and radiotherapy. Inclusion of patients in SFOP, SIOP and IRS clinical trials is recommended; 5/ treatment of metastatic rhabdomyosarcoma is based on intensive chemotherapy, and surgery with or without radiotherapy; 6/ the management of non-rhabdomyosarcoma is based on the likelihood of sensitivity to chemotherapy; 7/ at the present time, there are no clear data on which to base guidelines for timing and duration of follow-up studies in these conditions.

[Solid pseudopapillary tumors of the pancreas. Pathology report of 13 cases]. / Tumeurs pseudo-papillaires et solides du pancréas. Etude anatomoclinique de 13 cas.

OBJECTIVES: Solid pseudopapillary tumors of the pancreas are exceptional. The aims of our study were to reevaluate the mode of presentation of these tumors and to analyze the role of pathological examination in diagnostic assessment and prognostic evaluation. PATIENTS: We report the clinical, radiological and pathological findings in a retrospective series of 13 patients in whom a diagnosis of solid pseudopapillary tumor of the pancreas was made between 1983 and 1997. There were 12 females (median age: 22.5 years) and one male, aged 73. RESULTS: The tumor was discovered incidentally (3 cases) or because of nonspecific digestive symptoms (10 cases). Biological data were uninformative. The tumor was pancreatic in 12 cases and duodenal in 1. In all cases, imaging techniques showed an heterogeneous lesion with no or poor vascularization. A cystic component was identified in 4 cases. Surgical resection was performed in all cases. Pathological examination showed an encapsulated tumor in 8 cases, a non-encapsulated but well-limited lesion in 3 cases and an infiltrative tumor in 2 cases. At the time of diagnosis, multiple liver metastases were present in 1 case. Mean duration of follow-up was 24 months (range: 3-168). At last follow-up, all patients, including the patient with synchronous metastatic disease, were alive, without local recurrence. CONCLUSION: Our study confirms that most cases of solid pseudopapillary tumors of the pancreas present with a suggestive clinical picture, including their occurrence in young women and their good prognosis after surgical resection. However, our results also underline the occurrence of cases presenting with unusual features, including old age, male sex, extra-pancreatic localization and malignant evolution. Histopathological examination is essential for the establishment of the diagnosis but morphological data are of little prognostic value.

[Spindle cell lipoma and 13q deletion: diagnostic utility of cytogenetic analysis]. / Lipomes à cellules fusiformes et délétion 13q: apport de la cytogénétique dans l'aide au diagnostic.

AIM: Spindle cell lipomas are rare adipose tissues tumors. Histologically, these lesions are composed of mature adipocytes and spindle cells associated with collagen bundles. Spindle cell lipomas are benign tumors that can be difficult to distinguish from malignant tumors such as spindle cell liposarcomas, myxoid liposarcomas or well-differentiated liposarcomas. RESULTS: We report herein the description of two new cases. The first case was a deeply situated and infiltrating tumor located in the retromastoidian area. The karyotype showed the presence of two chromosomal abnormalities, a partial deletion of the long arm of chromosome 13, del(13)(q12) and a balanced reciprocal translocation t(2;6)(p16~21;p21). The second case was a subcutaneous tumor of posterior cervical localization. The karyotype showed a 13q deletion associated with a complex rearrangement of chromosomes 5, 6 and 10. The presence of the 13q deletion allowed us to confirm the diagnosis of spindle cell lipoma in both cases. This deletion has been previously described in six out the eleven published karyotype reports. The 13q deletion is usually associated with partial monosomy 16. The present case confirms that it can occur independently. The 6p21 rearrangement may also play a role in the pathobiology of this tumor, as suggested by the positive HMGIY expression detected by immunohistochemistry. CONCLUSION: Our study further illustrates that spindle cell lipomas can infiltrate the surrounding muscle and emphasizes the usefulness of cytogenetic analysis in the differential diagnosis of soft tissue tumors.

[Incidence rate, epidemiology of sarcoma and molecular biology. Preliminary results from EMS study in the Rhône-Alpes region]. / Incidence, épidémiologie des sarcomes et biologie moléculaire. Résultats préliminaires de l'étude EMS en Rhône-Alpes.

Sarcomas comprise a heterogeneous group of mesenchymal neoplasms. They can be grouped into 3 general categories, soft tissue sarcoma, visceral and primary bone sarcoma, which have different staging and treatment approaches. Soft tissue sarcomas are typically classified on the basis of genetic alterations and light-microscopic examination of hematoxylin-eosin-stained tissue, in which recognizable morphological characteristics of normal tissues are identified. Sarcomas are further characterized by histologic grade. The 3 most important prognostic variables are grade, size, and location of the primary tumor. This review includes a discussion of both soft tissue sarcomas (unclassified sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberans, angiosarcoma, Kaposi sarcoma, gastrointestinal stromal tumor, rhabdomyosarcoma, ...) and primary bone sarcomas (osteosarcoma, Ewing sarcoma and chondrosarcoma). The approach to a patient with a sarcoma begins with a biopsy that obtains adequate tissue for diagnosis without interfering with subsequent optimal definitive surgery. Subsequent treatment depends on the specific type of sarcoma. Due to the absence of clear knowledge for incidence rate, we conducted in 2005 and 2006 an exhaustive analysis of all diagnosed cases in the Rhône-Alpes region. Because sarcomas are relatively uncommon yet comprise a wide variety of different entities, second opinion was systematically performed for all included cases.