[Show abstract][Hide abstract] ABSTRACT: Nasal glomangiopericytoma is rare. The immunophenotype is heterogeneous, more frequently smooth-muscle-actin and CD34-positive. We report expression patterns for several vascular-related proteins such as CD99, CD146, Bcl2, and WT1 as well as for treatment-related proteins such as mTOR and EGFR in a nasal glomangiopericytoma. The patient (woman, 86 years) presented with a left nasal tumefaction. The resected specimen (1.5-cm) showed a glomangiopericytoma. Tumor cells expressed smooth-muscle-actin, CD31, CD34, and progesterone receptor. They also expressed the vascular-cell-related proteins Bcl2, CD99, CD146, and WT1, as well as mTOR and EGFR. Nasal glomangiopericytomas show immunohistochemical heterogeneity for vascular-related markers, suggesting a possible extensive pericytic differentiation. The expression of potential targets for drug treatments such as mTOR and EGFR may impact on the clinical follow-up of these tumors occurring at advanced ages, which may require complex surgery.
[Show abstract][Hide abstract] ABSTRACT: Secretory breast carcinoma (SBC) is a rare breast carcinoma with distinctive morphologic features and a recurrent specific chromosomal translocation t(12;15)(p13;q25), usually of low histologic grade and favorable prognosis. We describe the morphologic and genetic characteristics of 11 cases of SBC from 10 patients. Histologic and immunohistochemical analyses, fluorescence in situ hybridization using break-apart probes specific to ETV6 on 12p13, reverse transcription polymerase chain reaction with in-house probes specific to the ETV6-NTRK3 gene fusion, and DNA copy number variation by array comparative genomic hybridization analyses were performed on all cases. Seven cases were of low histologic grade, 3 were intermediate, and 1 had high-grade nuclear atypia, necrosis, and numerous mitoses. This patient had a fatal outcome. Five cases displayed low hormonal receptor expression, whereas the rest had basal-type immunoprofiles. All interpretable cases harbored an ETV6-NTRK3 gene fusion by reverse transcription polymerase chain reaction and/or an ETV6 rearrangement by fluorescence in situ hybridization, with duplication of the oncogenic derivative in 2 cases. Array comparative genomic hybridization analysis showed simplex genomic profiles. The 2 cases with ETV6-NTRK3 duplication included a gain of 12p starting from the ETV6 locus to the telomere, associated with a gain of the 15q from the centromere to NTRK3 in 1 case, and in the other a normal profile up to NTRK3 on 15q, and then a loss up to the telomere, suggesting loss of corresponding normal chromosome 15. These findings provide a novel insight into the morphologic and genetic spectrum of SBC, ranging from low-grade to high-grade histology, with occasional low hormonal receptor expression, simplex genomic profiles, and possible unfavorable course.
The American journal of surgical pathology 08/2015; 39(11). DOI:10.1097/PAS.0000000000000487 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
To the authors' knowledge, the incidence of late recurrence (> 5 years after initial management) is unknown and no prognostic factors for late events have been characterized in patients with soft tissue sarcomas.
Follow-up data from patients with localized soft tissue sarcoma who were included in the French Sarcoma Group database from January 1990 to June 2005 were reviewed. The outcomes of interest were the cumulative probabilities of late (> 5 years) local and metastatic disease recurrence with death as a competing event. Estimations and 95% confidence intervals (95% CIs) were computed with the cumulative incidence function.
A total of 719 patients who were alive and event free > 5 years after their initial diagnosis were included in the current study. Sixty-seven patients (9.3%) developed a late local recurrence and 42 patients (5.8%) developed a late metastatic recurrence, respectively. On multivariate analysis, internal trunk location (hazard ratio [HR], 3.9; 95% CI, 2.2-6.7 [P < .001]) and tumor size > 100 mm (HR, 2.1; 95% CI, 1.1-4 [P = .035]) were the 2 factors found to be independently associated with an increased risk of late local recurrence. Grade > 1 (graded according to the French Federation of Cancer Centers Sarcoma Group) (HR, 4.7; 95% CI 1.1-21 [P = .04]) was the sole factor found to be independently associated with an increased risk of late metastatic recurrence.
Late recurrence of soft tissue sarcoma is relatively uncommon. However, the results of the current study emphasize the critical role of long-term follow-up to detect late local disease recurrence in patients with retroperitoneal or very large soft tissue sarcomas, and late metastatic recurrence in patients with high-grade disease. Conversely, the prolonged follow-up of patients with grade 1 disease is not needed.
Cancer 10/2014; 120(19). DOI:10.1002/cncr.28836 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While absent from normal epithelia, an actin bundling protein, fascin, become expressed in invasive carcinoma of different origins. It is highly enriched at the tumors’ invasive fronts suggesting that it could play a role in cancer invasion. Multiple studies have shown that fascin, through its role in formation of cellular protrusions such as filopodia and invadopodia, enhances cancer cell migration and invasion in vitro. However, the role of fascin in vivo remains unknown. We have generated a compound transgenic mouse model that allows expression of fascin in the intestinal epithelium in the Apc-mutated background. Conditional expression of fascin led to decrease in mice survival and increase in tumor burden compared to control animals. Induction of fascin expression in adult tumor-bearing animals accelerated tumor progression and led to formation of invasive adenocarcinoma. Altogether, our study shows that fascin can promote tumor progression in vivo, but also unravels an unexpected role of fascin in tumor initiation.
European Journal of Cell Biology 09/2014; 93(10-12). DOI:10.1016/j.ejcb.2014.08.002 · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
The aim of this study was to determine the frequency of primary sinonasal adult sarcoma, identify histological subtypes, and analyze prognostic factors.Study DesignRetrospective review.Method
Forty-eight adult sinonasal sarcomas included in the French Sarcoma Group database (Conticabase) were reviewed.ResultsThe most frequent tumor types were alveolar rhabdomyosarcoma (33.3%), embryonal rhabdomyosarcoma (14,6%), unclassified sarcoma (14.6%), and leiomyosarcoma (12.5%). All round cell tumors were rhabdomyosarcomas. The 5-year overall survival (OS), metastasis-free survival (MFS), and local recurrence-free survival (LRFS) rates were 62.3%, 73%, and 88.8%, respectively. Histotype was a prognostic factor for OS, MFS, and LRFS, with the worst prognosis associated with rhabdomyosarcomas, regardless of the subtype. The tumor grade influenced the OS and MFS. Surgery was a predictive factor for a complete response.Conclusions
These results suggest that sinonasal tract should be considered as an unfavorable site for rhabdomyosarcoma. Moreover, surgery should always be considered in treatment.Level of EvidenceN/A. Laryngoscope, 2014
The Laryngoscope 09/2014; 125(3). DOI:10.1002/lary.24910 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rhabdomyosarcoma (RMS) is a soft tissue sarcoma categorized into two major subtypes: alveolar RMS (ARMS) and embryonal RMS (ERMS). Most ARMS express the PAX3-FOXO1 (P3F) fusion oncoprotein generated by the 2;13 chromosomal translocation. In the present study, the downstream target genes of P3F were identified by analyzing two independent sets of gene expression profiles: primary RMS tumors and RD ERMS cells transduced with inducible P3F constructs. We found 34 potential target genes (27 upregulated and 7 downregulated) that were significantly and differentially expressed between P3F-positive and P3F-negative categories, both in primary RMS tumors and in the inducible P3F cell culture system. Gene ontology analysis of microarray data of the inducible P3F cell culture system employed indicated apoptosis, cell death, development, and signal transduction as overrepresented significant functional categories found in both upregulated and downregulated genes. Therefore, among the 34 potential target genes, the expression of cell death‑related [Gremlin1, cysteine knot superfamily 1, BMP antagonist 1 (GREM1) and death-associated protein kinase 1 (DAPK1)] and development‑related [myogenic differentiation 1 (MYOD1) and hairy/enhancer-of-split related with YRPW motif 1 (HEY1)] genes were further investigated. The differential expression of GREM1, DAPK1, MYOD1 and HEY1 was confirmed in independent tumors and inducible cell culture systems. The expression of GREM1, DAPK1 and MYOD1 were significantly upregulated; HEY1 was significantly downregulated in independent P3F-positive ARMS tumors and transcriptionally active P3F cells, compared to those in ERMS tumors and transcriptionally inactive P3F cells. This study identified target genes of P3F and suggested that four downstream targets (GREM1, DAPK1, MYOD1 and HEY1) can contribute to the biological activities of P3F involved in growth suppression or cell death and myogenic differentiation.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.
From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.
Median age was 59 years (range, 21-98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59-67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.
Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients.
Clinical Cancer Research 01/2013; 19(5). DOI:10.1158/1078-0432.CCR-12-2970 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Angiosarcomas represent less than 2% of all adult soft tissue sarcomas. Prognostic factors and the role of (neo-) adjuvant treatments in the management of localised angiosarcomas require further investigation.
We have conducted a retrospective multicenter study (June 1980 to October 2009) of 107 patients with localised angiosarcomas. All of the cases were centrally reviewed by a certified pathologist. Univariate and multivariate analyses were conducted to identify independent poor prognostic factors (PF). Overall survival (OS) and Local Recurrence-Free Survival (LRFS) were estimated using the Kaplan-Meier method. The effect of treatments was explored using the Cox model after adjusting for the PF.
The median age was 71 years. 22.4% and 62.6% developed an angiosarcoma in pre-existing lymphoedema and within irradiated tissue respectively. The median OS, LRFS and Disease Recurrence-Free Survival (DRFS) were 38.8, 27 and 36.1 months, respectively. In multivariate analysis, the following parameters influenced the OS: lymphoedema (Hazard ratio (HR)=2.0) and size >5cm (HR=1.5). After adjustment to these PF, R0 margins was the only treatment parameter that improving the OS (HR=0.2). In the multivariate analysis, the LRFS was influenced by an age >70 (HR=1.8) and pre-existing lymphoedema (HR=2.0). After adjustment for these PF, R0 margins (HR=0.5) and adjuvant radiotherapy (HR=0.3) improved the LRFS.
Our results suggest the following points: (i) pre-existing lymphoedema, tumour size and age >70 are probably the major prognostic factors in patients with localised angiosarcomas; (ii) the achievement of R0 margins is probably of major importance for improving the patient outcome and (iii) adjuvant radiotherapy probably decreased the risk of local recurrence.
European journal of cancer (Oxford, England: 1990) 09/2012; 49(2). DOI:10.1016/j.ejca.2012.08.016 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Akt activation by the IGF-1 receptor (IGF-1R) has been posited to be a mechanism of intrinsic resistance to mTORC1 inhibitors (rapalogues) for sarcomas. Here we show that rapamycin-induced phosphorylation of Akt can occur in an IGF-1R-independent manner. Analysis of synovial sarcoma cell lines showed that either IGF-1R or the PDGF receptor alpha (PDGFRA) can mediate intrinsic resistance to rapamycin. Repressing expression of PDGFRA or inhibiting its kinase activity in synovial sarcoma cells blocked rapamycin-induced phosphorylation of Akt and decreased tumor cell viability. Expression profiling of clinical tumor samples revealed that PDGFRA was the most highly expressed kinase gene among several sarcoma disease subtypes, suggesting that PDGFRA may be uniquely significant for synovial sarcomas. Tumor biopsy analyses from a synovial sarcoma patient treated with the mTORC1 inhibitor everolimus and PDGFRA inhibitor imatinib mesylate confirmed that this drug combination can impact both mTORC1 and Akt signals in vivo. Together, our findings define mechanistic variations in the intrinsic resistance of synovial sarcomas to rapamycin and suggest therapeutic strategies to address them.
Cancer Research 07/2012; 72(17):4515-25. DOI:10.1158/0008-5472.CAN-12-1319 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Radiation-induced breast angiosarcomas are rare but recognized complication of breast cancer radiotherapy and are of poor prognosis. Little is known about the genetic abnormalities present in these secondary tumors. Herein, we investigated the differences in the genome and in the transcriptome that discriminate these tumors as a function of their etiology. Seven primary breast angiosarcomas and 18 secondary breast angiosarcomas arising in the irradiation field of a radiotherapy were analyzed. Copy number alterations and gene expression were analyzed using Affymetrix SNP 6.0 Array and Affymetrix Exon Arrays, respectively. We showed that two transcriptome signatures of the radiation tumorigenesis coexisted in these tumors. One was histology specific and correctly discriminated 100% of the primary tumors from the radiation-induced tumors. The deregulation of marker genes, including podoplanin (PDPN), prospero homeobox 1 (PROX-1), vascular endothelial growth factor 3 (VEGFR3) and endothelin receptor A (EDNRA), suggests that the radiation-induced breast angiosarcomas developed from radiation-stimulated lymphatic endothelial cells. None of the genes of the histology-specific signature were present in our previously published signature of the radiation tumorigenesis which shows the presence of a chronic oxidative stress in radiation-induced sarcomas of various histologies. Nevertheless, this oxidative stress signature classified correctly 88% of the breast angiosarcomas as a function of the etiology. In contrast, MYC amplification, which is observed in all radiation-induced tumors but also at a low rate in primary tumors, was not a marker of the radiation tumorigenesis.
[Show abstract][Hide abstract] ABSTRACT: Leiomyosarcoma is rare in ileal location. We report the case of a 61years old female patient presenting with ileal leiomyosarcoma occurring at 14years after a uterine carcinoma treated by radiotherapy. The ileal tumor was treated by surgical resection. This tumor was peculiar by the macroscopic polypoid appearance and by expression of PDGFRA protein together with muscle differentiation proteins: smooth muscle actin, desmin and h-caldesmon. Lymph node necrotizing granuloma diagnosis on the surgical resection specimen lead to the diagnosis of tuberculosis and the patient was treated accordingly. At 3years after the diagnosis, the patient was well, without recurrence or metastases. In conclusion, we report the case of a patient diagnosed with ileal leiomyosarcoma occurring 14years after adjuvant radiotherapy for uterine carcinoma. Analysis of the intestinal resection specimen lead to the diagnosis of associated tuberculosis. Moreover, the leiomyosarcoma was peculiar by PDGFRA expression, feature which might be of clinical relevance since the treatment options in radioinduced tumors associated with other conditions are limited.
[Show abstract][Hide abstract] ABSTRACT: Digestive metastasis of breast cancer are rare but when they do occur the stomach is one of the commoner sites.
To describe the clinical, endoscopic, pathological features and treatment.
35 cases of gastric metastasis were identified retrospectively between 1980 and 2008.
The location of the gastric metastasis was fundus (n=15, 43%), antrum (n=15, 43%) or both (n=5, 14%). The histological subtype of primary breast cancer was invasive lobular carcinoma in 34 patients (97%). Hormonal receptors were positive in 19 out of 24 cases (79%), two out of 22 analysed were HER2 positive (9%). There were 16 (46%) patients with peritoneal carcinosis. The treatment was chemotherapy (n=13, 37%), hormonotherapy (n=2, 6%) or both (n=13, 37%). The 2-year survival rate after gastric metastasis diagnosis was 53% with a median follow up of 31 months [7-84 months].
Ninety-seven percent of gastric metastasis from breast cancers are derived from invasive lobular carcinoma. Seventy-nine percent of these are HER+ and comparison with the original histopathological slides of primary breast carcinoma should be performed to differentiate gastric metastasis from primary gastric carcinoma. Peritoneal carcinomatosis accompanied gastric metastasis in almost half the cases in this series and treatment was generally chemotherapy.