Ewing sarcomas are an uncommon group of malignant neoplasms. A multidisciplinary approach is highly recommended to reach a correct diagnosis, considering the clinical, radiological, and histopathological aspects. Since in up to 90% of cases, the translocation t (11; 22) (q24; q12) occurs resulting in a chimeric fusion transcript EWSR1-FLI-1. The pathologist has several tools in addition to conventional techniques (hematoxylin and eosin), such as immunohistochemistry, which plays a very important role in the differential diagnosis. We present a series of 15 cases of molecularly confirmed ES, in which we found a sensitivity of 100% for CD99 and 80% for PAX8 by immunohistochemistry. This indicates a high sensitivity; however, it is known that both CD99 and PAX8 are also expressed in other tumours. Therefore, molecular confirmation should be performed in all cases.
Sarcomas constitute a heterogeneous group of rare and difficult-to-treat tumors that can affect people of all ages, representing one of the most common forms of cancer in childhood and adolescence. Little is known about the molecular entities involved in sarcomagenesis. Therefore, the identification of processes that lead to the development of the disease may uncover novel therapeutic opportunities. Here, we show that the MEK5/ERK5 signaling pathway plays a critical role in the pathogenesis of sarcomas. By developing a mouse model engineered to express a constitutively active form of MEK5, we demonstrate that the exclusive activation of the MEK5/ERK5 pathway can promote sarcomagenesis. Histopathological analyses identified these tumors as undifferentiated pleomorphic sarcomas. Bioinformatic studies revealed that sarcomas are the tumors in which ERK5 is most frequently amplified and overexpressed. Moreover, analysis of the impact of ERK5 protein expression on overall survival in patients diagnosed with different sarcoma types in our local hospital showed a 5-fold decrease in median survival in patients with elevated ERK5 expression compared with those with low expression. Pharmacological and genetic studies revealed that targeting the MEK5/ERK5 pathway drastically affects the proliferation of human sarcoma cells and tumor growth. Interestingly, sarcoma cells with knockout of ERK5 or MEK5 were unable to form tumors when engrafted into mice. Taken together, our results reveal a role of the MEK5/ERK5 pathway in sarcomagenesis and open a new scenario to be considered in the treatment of patients with sarcoma in which the ERK5 pathway is pathophysiologically involved.
Over the last few decades, an increasing amount of information has been accumulated on biomarkers in non-small cell lung cancer (NSCLC). Despite these advances, most biomarkers have been identified in the adenocarcinoma histological subtype (AC). However, the application of molecular-targeted therapies in the prognosis and treatment of SCC in the clinical setting is very limited, becoming one of the main focus areas in research. Here, we prospectively analyzed the frequency of numerical/structural abnormalities of chromosomes 5, 7, 8, 9, 13 and 22 with FISH in 48 pulmonary SCC patients. From a total of 12 probes, only abnormalities of the 7p12 and 22q12 chromosomal regions were identified as unique genetic variables associated with the prognosis of the disease. The study for these two chromosomal regions was extended to 108 patients with SCC. Overall, chromosome losses were observed more frequently than chromosome gains, i.e., 61% versus 19% of all the chromosome abnormalities detected. The highest levels of genetic amplification were detected for the 5p15.2, 7p12, 8q24 and 22q11 chromosome bands, of which several genes are potentially involved in the pathogenesis of SCC, among others, include the EGFR gene at chromosome 7p12. Patients who displayed EGFR amplification (n = 13; 12%) were mostly older than 65 years (p = 0.07) and exclusively patients in early T-primary tumor stage (pT1–pT2; p = 0.03) with a significantly shortened overall survival (OS) (p ≤ 0.001). Regarding prognosis, the clinical, biological, and histopathologic characteristics of the disease that displayed a significant adverse influence on OS in the univariate analysis included patients older than 65 years (p = 0.02), the presence of lymph node involvement (p = 0.005), metastasis (p = 0.01) and, visceral pleural invasion (VPI) at diagnosis (p = 0.04). EGFR amplification also conferred an adverse impact on patient OS in the whole series (p = 0.02) and especially in patients in early stages (pT1–pT2; p = 0.01). A multivariate analysis of the prognostic factors for OS showed that the most informative combination of independent variables to predict an adverse outcome was the presence of VPI and/or EGFR amplification (p < 0.001). Based on these two variables, a scoring system was built to stratify patients into low- (no adverse features: score 0; n = 69), intermediate- (one adverse feature: score 1; n = 29) and high-risk (two adverse features: score 2; n = 5) groups, with significantly different (p = 0.001) OS rates at 50 months, which were as following: 32%, 28% and 0%, respectively. In the present study, we show that the presence of a high level of 7p12 (EGFR) amplification, exclusively detected in early stage SCC (pT1–pT2), is an independent adverse prognostic factor for OS. The identification of the EGFR gene copy number using FISH techniques may provide a more accurate diagnosis of high-risk populations after the complete resection of the primary tumor. When combined with VPI, three groups of pulmonary SCC were clearly identified that show the extent of the disease. This is of such importance that further prospective studies are necessary in larger series of SCC patients to be classified at the time of diagnosis. This could be achieved with the combined assessment of 7p12 amplification and VPI in primary tumor samples.
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