Tetraploidization of Immortalized Myoblasts Induced by Cell Fusion Drives Myogenic Sarcoma Development with DMD Deletion.

Whole-genome doubling is the second most frequent genomic event, after TP53 alterations, in advanced solid tumors and is associated with poor prognosis. Tetraploidization step will lead to aneuploidy and chromosomic rearrangements. The mechanism leading to tetraploid cells is important since endoreplication, abortive cytokinesis and cell fusion could have distinct consequences. Unlike processes based on duplication, cell fusion involves the merging of two different genomes, epigenomes and cellular states. Since it is involved in muscle differentiation, we hypothesized that it could play a role in the oncogenesis of myogenic cancers. Spontaneous hybrids, but not their non-fused immortalized myoblast counterparts they are generated from, induced tumors in mice. Unstable upon fusion, the hybrid genome evolved from initial mitosis to tumors with a highly rearranged genome. This genome remodeling finally produced targeted DMD deletions associated with replicative stress, isoform relocalization and metastatic spreading, exactly as observed in human myogenic sarcomas. In conclusion, these results draw a model of myogenic oncogenesis in which cell fusion and oncogene activation combine to produce pleomorphic aggressive sarcomas.

Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.

Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis.

CIC-rearranged sarcomas rarely occur in visceral organs including the kidney. The most common fusion partner with CIC is the DUX4 gene, but variant fusion partners have also been reported. Herein, we describe the clinicopathologic features and comprehensive molecular profiling of 4 cases of primary renal CIC-rearranged sarcomas. All cases occurred in females, age range 13 to 82 years and included 3 resections and 1 needle biopsy specimen. There was a tendency for development of metastatic disease predominantly to the lungs and poor disease outcome despite different treatment strategies. Histologically, variable round cell (20% to 100%), spindle cell (0% to 80%), and rhabdoid morphologies (0% to 20%) were seen. By immunohistochemistry diffuse WT1 nuclear (2 to 3+, ∼90%) labeling was present in 1 case, with cytoplasmic staining in the others (3+, 40% to 75%). CD99 was focally positive in all 4 cases (≤10%); 1 case each was diffusely positive for c-myc (2 to 3+, ∼90%) and ETV4 (3+, ∼90%); 1 case was focally positive for c-myc (2+, ∼5%) and calretinin (2+, ∼5%); and all cases were negative for cytokeratin and NKX2.2. CIC rearrangement by fluorescence in situ hybridization was present in the 3 cases tested. Comprehensive genomic profiling (CGP) of 3 cases revealed a CIC-DUX4 fusion in 2 cases, and 1 CIC-NUTM1 fusion. All 4 CIC-rearranged renal sarcomas had low mutation burden, and except HLA-A and MLL mutations lacked genomic alterations in other oncogenic drivers. Material from the needle biopsy was insufficient for CGP but that case was positive with the DUX4 immunohistochemical stain as were the 2 CIC-DUX4 tumors. In conclusion, CIC-rearranged sarcomas rarely occur in the kidney with a tendency for poor outcome and in this series we illustrate an example with CIC-NUTM1 fusion, an emerging variant, at a visceral site. Testing by fluorescence in situ hybridization or CGP is optimal to avoid missing cases that harbor variant fusion partners.

Cutaneous inflammatory myofibroblastic tumours can be anaplastic lymphoma kinase-positive: report of the first four cases.

AIMS: Inflammatory myofibroblastic tumours (IMTs) usually have a soft tissue and visceral localization, but have been rarely reported in skin. The aim of this study was to characterize the histological and immunohistochemical features of a series of cutaneous IMTs. METHODS AND RESULTS: We retrieved from our archives over 10 years four cutaneous IMTs; one was diagnosed in a child, and three in young adults. Tumours were centred on the dermis, and also involved the subcutis in two cases. Two of them corresponded to the 'myxoid-vascular' pattern of IMT, whereas the others were characterized by compact fascicles of spindle-shaped cells. They stained positively for smooth muscle actin. All samples stained positively for anaplastic lymphoma kinase (ALK). ALK expression was limited to the cytoplasm of myofibroblasts and, in the three investigated cases, correlated with ALK rearrangement as shown by fluorescence in-situ hybridization analysis. CONCLUSIONS: This is the first report of ALK-positive IMTs with a cutaneous localization. Because of their morphological heterogeneity and low incidence in skin, the diagnosis of cutaneous IMTs is often challenging. A cutaneous spindled cell tumour associated with an inflammatory infiltrate should prompt pathologists to perform ALK staining, which, if positive, might be decisive for diagnosis.

The prognostic significance of lymphovascular invasion on biopsy specimens in lung cancer treated with definitive chemoradiotherapy.

PURPOSE: This study aims to determine prognostic factors for patients who have non-small-cell lung cancer (NSCLC) that is treated with definitive chemoradiation therapy. MATERIALS AND METHODS: Seventy-eight patients has been treated with radiation therapy and concomitant or sequential chemotherapy between 2000 and 2005. Paraffin-embedded biopsy specimens were obtained before treatment from 73 patients and reviewed by two independent pathologists. Complete follow-up data were collected. The impact of clinical and pathological factors and treatment modality on survival was studied using the χ(2) and Fisher exact tests. A multivariate analysis was performed using the Cox proportional hazard model. RESULTS: Seventy-three patients were evaluated, 58 men and 15 women. Median age was 62 years. Most had locally advanced disease (42 stage IIIB and 24 stage IIIA), whereas 7 were medically inoperable stage I-II patients. Lymphovascular invasion (LVI) was identified in 20 biopsy specimens (27.4 %). Radiotherapy delivered a median dose of 66 Gy (range, 60 to 70 Gy). The median overall survival was 20.5 months. Relapse-free and overall survival were significantly higher in the concomitant arm than in the sequential arm (P = .025 and P = .031, respectively). We found an independent association between the presence of LVI and both the risk of death with an adjusted hazard ratio (HR) of 2.69 (95% confidence interval [CI] 1.50-4.83) and the risk of metastatic progression (adjusted HR = 3.01; 95% CI 1.58-5.72). CONCLUSION: The presence of LVI on stage III NSCLC biopsy specimens was the only independent prognostic factor for poor outcome and may, therefore, be helpful in identifying patients at high risk of metastatic disease.