Search

BackgroundSince 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France.MethodsThe nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed.ResultsOver 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (pConclusionsThis nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1

Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK) cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN). In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN). First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68), endothelial cells, NK cells, granzyme B positive (GrzB+) cells and CD8+ T cells in the SLN. Negative SLN (SLN-) were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+). High densities of macrophages and endothelial cells (CD34), prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells.

Abstract Background Separating benign from malignant soft-tissue masses often requires a biopsy. The objective of this study was to assess whether shear-wave elastography (SWE) helped to separate benign from malignant soft-tissue masses. Methods In 2015–2016, we prospectively included patients with soft-tissue masses deemed by our multidisciplinary sarcoma board to require a diagnostic biopsy. All patients underwent ultrasonography (US) followed by SWE to measure elasticity. We compared benign and malignant tumors, overall and after separating tumors with vs. without a fatty component. The biopsy findings, and surgical-specimen histology when available, served as the reference standard. Results We included 136 patients, 99 with non-fatty and 37 with fatty soft-tissue masses. Mean elasticity and tumor-to-fat elasticity ratio (T/F) values were significantly lower for the benign than the malignant soft-tissue masses in the overall cohort (30.9 vs. 50.0 kilopascals (kPa), P = 0.03; and 2.55 vs. 4.30, P = 0.046) and in the non-fatty subgroup (37.8 ± 31.9 vs. 58.9 ± 39.1 kPa, P = 0.049 and 2.89 ± 5.25 vs. 5.07 ± 5.41, P = 0.046). Data for fatty tumors were non relevant due to lack of conclusive results. By receiver operating characteristics curve analysis, a T/F cutoff of 3.5 had 46% sensitivity and 84% specificity for separating benign and malignant soft-tissue masses. Conclusions SWE had good specificity and poor sensitivity for separating benign from malignant soft-tissue masses.

Abstract The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.

Introduction: Malignant Peripheral Nerve Sheath Tumors (MPNST) are very rare and aggressive tumors, which can affect children, adolescents, and young adults. These tumors are frequently associated with type 1 neurofibromatosis (NF1). This study aims to determine prognostic factors in unselected pediatric MPNST to specify the risk stratification strategy. Methods: A national multicenter retrospective study encompassing all French pediatric patients (0–18 years) treated for MPNST, confirmed by a pathology review, from 1995 to 2017. Results: Overall, 66 patients (median age 13.0 years [range, 0.1–18.0]) developed a MPNST located in the limbs (36%), trunk (27%), head and neck (21%) and para-vertebral area (15%). Forty-eight percent of patients had NF1, 50% had a histologic grade III tumor and 77% a large tumor (>5 cm), including 30% very large (>10 cm). Most patients (94%) had localized tumors. After a median follow-up of 7.6 years [range, 0.4–18.7], the 5-year overall (OS) and event-free (EFS) survivals were 46.7% [95%CI, 35.8–60.8] and 40.8% [95%CI, 30.3–54.9], respectively. On multivariate analysis were found to be associated with a worse outcome (OS): metastatic disease (HR (Hazard-Ratio) 6.4 [1.8; 22.0]), grade 3 FNCLCC (HR 4.77 [1.4; 15.8]),> 10-cm size (HR 2.3 [1.1; 4.8]) and the presence of NF1 (HR 2.2 [1.1; 4.4]). Histologic subtypes of MPNST (classical, malignant Triton or epithelioid tumor) were not correlated with outcome. Conclusion: The overall outcome of MPNST was poor in patients with NF1 and in high grade, very large and metastatic tumors. The identification of these risk factors allows us to define adapted risk stratification to propose new therapeutic strategies for high-risk cases.

Abstract Background Crystal storing histiocytosis is a rare disorder associated with monoclonal gammopathy. In this disease, monoclonal heavy and light chains accumulate in the lysosome of macrophages, leading to histiocytic reaction in different organs. It is secondary to the presence of a small B-cell clone, responsible for monoclonal immunoglobulin production. Histological diagnosis is a challenge and differential diagnoses include fibroblastic and histiocytic neoplasm. Clinical manifestations depend on the involved organs, rarely including peritoneum or digestive tract. Case presentation We present a case of a 75-year-old with a medical history of colonic carcinoma. She presented with abdominal pain and inflammatory syndrome revealing a colonic mass. Hemicolectomy was performed. Initial diagnosis was fibroblastic tumour. The patient worsened, and diagnosis of a diffuse crystal storing histiocytosis was finally done. Haematological exploration found an indolent IgG-kappa multiple myeloma. The initial treatment with conventional chemotherapy did not permit an improvement of the patient condition. Immunotherapy with anti-CD38 monoclonal antibody (daratumumab) was proposed with a clinical and biological response. Conclusion This case report emphasizes the histopathological challenge of histiocytic tumours which may involve digestive track. It focuses on the concept of monoclonal gammopathy of clinical significance, which can have a large spectrum of manifestations.

Chondrosarcomas are heterogenous tumours of the bone cartilage and have highly variable prognoses. Here, the authors perform a multi-omics analysis, revealing molecular features that can stratify clinical outcomes.

IL-35 is an immunosuppressive cytokine of the IL-12 family consisting of two subunits, EBV-induced gene 3 (EBI3) and p35. It has been shown to play a pro-tumor role in murine tumor models, and in various types of human cancer such as colorectal, pancreatic, or liver carcinoma, its expression has been associated with a worse clinical outcome. Here, we show by analyzing gene expression data from public databases and by immunohistochemical studies that IL-35 is overexpressed by tumor cells in diffuse-large B-cell lymphoma (DLBCL) compared to another type of mature aggressive B-cell lymphoma, Burkitt lymphoma. However, while high IL-35 expression was significantly associated with a worse overall survival in DLBCL patients treated with chemotherapy only (cyclophosphamide, doxorubicin, vincristine, prednisone, CHOP), no significant correlation between IL-35 expression levels and the patient outcome was observed in DLBCL patients treated with CHOP combined to rituximab (R-CHOP), the current conventional treatment. In addition, we found that an anti-IL-35 antibody, clone 15k8D10, used to assess IL-35 expression by immunohistochemistry in various human tissues including tumors does not recognize IL-35 heterodimer, nor its individual subunits EBI3 and p35, but cross-reacts with human IgG1, indicating that IL-35 expression in human cancers needs to be re-evaluated.

The French phase 3 trial (OS 2006) testing zoledronic acid, an osteoclast inhibitor, with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma (OS). To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 pre-therapeutic biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages (TAMs), CD8+ lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint were assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with better overall survival (p = 0.0025) and longer metastasis progression-free survival (MPFS, p = 0.0315) independently of metastatic status (p = 0.002). Only a trend was observed for patients with high CD68-positive cells (p = 0.0582). CD8+ staining was positive in >50% of cases with a median staining of 1%. Lower CD8+ levels were associated with metastatic disease at diagnosis and the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients (p = 0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated with outcome. Finally, CD163-positive TAMs and CD8 positive cells are crucial prognostic biomarkers in OS, whereas PD1/PDL-1 checkpoint plays a minor role. For the first time, we described a correlation between CD8 positive cells and survival in zoledronate-treated patients. The immunohistochemical analysis of the microenvironment in biopsies may represent a novel tool for therapeutic stratification.

Interleukin (IL)-27 is a cytokine of the IL-12 family that displays either immunostimulatory or immunosuppressive functions depending on the context. In various murine tumor models including melanoma models, ectopic expression of IL-27 has been shown to play an anti-tumoral role and to favor tumor regression. In this study, we investigated whether IL-27 might play a role in the development of melanoma in humans. We analyzed the in situ expression of IL-27 in melanocytic lesions (n = 82) representative of different stages of tumor progression. IL-27 expression was not observed in nevus (n = 8) nor in in situ melanoma (n = 9), but was detected in 28/46 (61%) cases of invasive cutaneous melanoma, notably in advanced stages (19/23 cases of stages 3 and 4). In most cases, the main source of IL-27 was tumor cells. Of note, when IL-27 was detected in primary cutaneous melanomas, its expression was maintained in metastatic lesions. These in situ data suggested that the immunosuppressive functions of IL-27 may dominate in human melanoma. Consistent with this hypothesis, we found that IL-27 could induce suppressive molecules such as PD-L1, and to a lesser extent IL-10, in melanoma cells, and that the in situ expression of IL-27 in melanoma correlated with those of PD-L1 and IL-10.

The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations.