Publications by authors named "Samuel Navarro"

117 Publications

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

Front Cell Dev Biol 2021 3;9:670185. Epub 2021 Jun 3.

Cancer CIBER (CIBERONC), Madrid, Spain.

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
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http://dx.doi.org/10.3389/fcell.2021.670185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209546PMC
June 2021

Neuroendocrine differentiation in a large series of genetically-confirmed Ewing's sarcoma family tumor: Does it provide any diagnostic or prognostic information?

Pathol Res Pract 2021 Mar 6;219:153362. Epub 2021 Feb 6.

Pathology Department, Valencia University, Spain. Electronic address:

Given the potential for neuroendocrine differentiation in Ewing's sarcoma family of tumors (ESFT), we aimed to determine neuroendocrine expression in a large series of genetically-confirmed ESFT and its prognostic significance in clinically-localised neoplasms (n = 176). Slides prepared from tissue microarrays were stained for Insulinoma-associated protein 1 (INSM1), CD56, chromogranin-A and synaptophysin. INSM1 expression was present in 59% of ESFT, while synaptophysin, chromogranin-A and CD56 were expressed in only 13%, 8% and 5% of ESFT, respectively. Histological subtypes were only significantly correlated with INSM1 (p = 0.032) or CD56 (p = 0.016) immunoexpression. Regarding prognosis, no significant association was found between INSM1, synaptophysin or chromogranin-A immunoexpression and progression-free survival (PFS) or overall survival (OS). Despite the low proportion of tumors with CD56 immunoreactivity, CD56 expression was shown to correlate with both poor PFS (p < 0.001) and poor OS (p < 0.001) in the present series. In conclusion, neuroendocrine differentiation is often present in ESFT, and in the present study INSM1 expression in particular was found to be higher than previously described in Ewing's tumors. Nevertheless, this finding does not distinguish these tumors from other round cell tumors that may show focal or diffuse neuroendocrine differentiation. CD56 expression could be used as a prognostic factor in ESFT, although given the results herein obtained, we recommend a prospective validation in independent series including localized and disseminated tumors in ESFT.
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http://dx.doi.org/10.1016/j.prp.2021.153362DOI Listing
March 2021

[Update of the recommendations for the determination of biomarkers in colorectal carcinoma. National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology].

Rev Esp Patol 2021 Jan-Mar;54(1):41-54. Epub 2020 Oct 16.

Departamento de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid, España.

This update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica - SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica - SEAP), reviews the advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the possible benefits of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From a pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide which, like the previous one, will be revised when necessary in the future.
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http://dx.doi.org/10.1016/j.patol.2020.07.004DOI Listing
October 2020

Digital Image Analysis Applied to Tumor Cell Proliferation, Aggressiveness, and Migration-Related Protein Synthesis in Neuroblastoma 3D Models.

Int J Mol Sci 2020 Nov 17;21(22). Epub 2020 Nov 17.

Department of Pathology, Medical School, University of Valencia-INCLIVA Biomedical Health Research Institute, 46010 Valencia, Spain.

Patient-derived cancer 3D models are a promising tool that will revolutionize personalized cancer therapy but that require previous knowledge of optimal cell growth conditions and the most advantageous parameters to evaluate biomimetic relevance and monitor therapy efficacy. This study aims to establish general guidelines on 3D model characterization phenomena, focusing on neuroblastoma. We generated gelatin-based scaffolds with different stiffness and performed SK-N-BE(2) and SH-SY5Y aggressive neuroblastoma cell cultures, also performing co-cultures with mouse stromal Schwann cell line (SW10). Model characterization by digital image analysis at different time points revealed that cell proliferation, vitronectin production, and migration-related gene expression depend on growing conditions and are specific to the tumor cell line. Morphometric data show that 3D in vitro models can help generate optimal patient-derived cancer models, by creating, identifying, and choosing patterns of clinically relevant artificial microenvironments to predict patient tumor cell behavior and therapeutic responses.
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http://dx.doi.org/10.3390/ijms21228676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698558PMC
November 2020

Imbalance between genomic gain and loss identifies high-risk neuroblastoma patients with worse outcomes.

Neoplasia 2021 01 13;23(1):12-20. Epub 2020 Nov 13.

Pathology Department, Medical School, University of Valencia-INCLIVA, Valencia, Spain; CIBERONC, Madrid, Spain. Electronic address:

Survival in high-risk neuroblastoma (HR-NB) patients remains poor despite multimodal treatment. We aimed to identify HR-NB patients with worse outcomes by analyzing the genomic instability derived from segmental chromosomal aberrations. We calculated 3 genomic instability indexes for primary tumor SNP array profiles from 127 HR-NB patients: (1) Copy number aberration burden (%gains+%losses), (2) copy number load (CNL) (%gains-%losses) and (3) net genomic load (NGL) (%gains-%losses). Tumors were classified according to positive or negative CNL and NGL genomic subtypes. The impact of the genomic instability indexes on overall survival (OS) was assessed with Cox regression. We identified 38% of HR-NB patients with poor 5-year OS. A negative CNL genomic background was related to poor prognosis in patients ≥18 months showing tumors with homogeneous MYCN amplification (9.5% survival probability, P < 0.05) and patients with non-MYCN amplified NB (18.8% survival probability related to >2.4% CNL, P < 0.01). A positive CNL genomic background was associated with worse outcome in patients with heterogeneous MYCN amplification (22.5% survival probability, P < 0.05). We conclude that characterizing a tumor genomic background according to predominance of genome gained or lost contributes toward improved outcome prediction and brings greater insight into the tumor biology of HR-NB patients.
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http://dx.doi.org/10.1016/j.neo.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674617PMC
January 2021

Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN-amplified neuroblastoma cell line.

J Exp Clin Cancer Res 2020 Oct 28;39(1):226. Epub 2020 Oct 28.

Department of Pathology, Medical School, University of Valencia/INCLIVA, Valencia, Spain.

Background: Increased tissue stiffness is a common feature of malignant solid tumors, often associated with metastasis and poor patient outcomes. Vitronectin, as an extracellular matrix anchorage glycoprotein related to a stiff matrix, is present in a particularly increased quantity and specific distribution in high-risk neuroblastoma. Furthermore, as cells can sense and transform the proprieties of the extracellular matrix into chemical signals through mechanotransduction, genotypic changes related to stiffness are possible.

Methods: We applied high density SNPa and NGS techniques to in vivo and in vitro models (orthotropic xenograft vitronectin knock-out mice and 3D bioprinted hydrogels with different stiffness) using two representative neuroblastoma cell lines (the MYCN-amplified SK-N-BE(2) and the ALK-mutated SH-SY5Y), to discern how tumor genomics patterns and clonal heterogeneity of the two cell lines are affected.

Results: We describe a remarkable subclonal selection of genomic aberrations in SK-N-BE(2) cells grown in knock-out vitronectin xenograft mice that also emerged when cultured for long times in stiff hydrogels. In particular, we detected an enlarged subclonal cell population with chromosome 9 aberrations in both models. Similar abnormalities were found in human high-risk neuroblastoma with MYCN amplification. The genomics of the SH-SY5Y cell line remained stable when cultured in both models.

Conclusions: Focus on heterogeneous intratumor segmental chromosome aberrations and mutations, as a mirror image of tumor microenvironment, is a vital area of future research.
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http://dx.doi.org/10.1186/s13046-020-01729-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592549PMC
October 2020

A three-dimensional bioprinted model to evaluate the effect of stiffness on neuroblastoma cell cluster dynamics and behavior.

Sci Rep 2020 04 14;10(1):6370. Epub 2020 Apr 14.

Pathology Department, Medical School, University of Valencia-INCLIVA, Valencia, Spain.

Three-dimensional (3D) bioprinted culture systems allow to accurately control microenvironment components and analyze their effects at cellular and tissue levels. The main objective of this study was to identify, quantify and localize the effects of physical-chemical communication signals between tumor cells and the surrounding biomaterial stiffness over time, defining how aggressiveness increases in SK-N-BE(2) neuroblastoma (NB) cell line. Biomimetic hydrogels with SK-N-BE(2) cells, methacrylated gelatin and increasing concentrations of methacrylated alginate (AlgMA 0%, 1% and 2%) were used. Young's modulus was used to define the stiffness of bioprinted hydrogels and NB tumors. Stained sections of paraffin-embedded hydrogels were digitally quantified. Human NB and 1% AlgMA hydrogels presented similar Young´s modulus mean, and orthotopic NB mice tumors were equally similar to 0% and 1% AlgMA hydrogels. Porosity increased over time; cell cluster density decreased over time and with stiffness, and cell cluster occupancy generally increased with time and decreased with stiffness. In addition, cell proliferation, mRNA metabolism and antiapoptotic activity advanced over time and with stiffness. Together, this rheological, optical and digital data show the potential of the 3D in vitro cell model described herein to infer how intercellular space stiffness patterns drive the clinical behavior associated with NB patients.
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http://dx.doi.org/10.1038/s41598-020-62986-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156444PMC
April 2020

Controversial issues in soft tissue solitary fibrous tumors: A pathological and molecular review.

Pathol Int 2020 Mar 6;70(3):129-139. Epub 2020 Jan 6.

Pathology Department, University of Valencia, Valencia, Spain.

The clinical evolution of solitary fibrous tumor (SFT) remains unclear. Although various clinical, morphological and molecular criteria may indicate increased risk of malignancy, some SFT can still progress despite having a clearly benign appearance. Various risk stratification systems have been proposed, but unfortunately they are not sufficient to precisely determine the malignant potential. In this review, we discuss current knowledge on SFT, focusing on the following controversial issues: (i) the diverse morphologic spectrum: 'the great simulator;' (ii) malignant transformation or dedifferentiation; (iii) current risk stratification systems; and (iv) molecular factors associated with clinical evolution. The morphological spectrum of SFT and the list of differential diagnoses continue to expand. Both have increased considerably since the first descriptions of specific molecular alterations. A classification of malignant SFT should not be based on histology alone. The correlation of all pathological and molecular factors is recommended; its inclusion in risk stratification systems may help to improve diagnosis and prognosis.
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http://dx.doi.org/10.1111/pin.12894DOI Listing
March 2020

Correction to: Solitary fibrous tumor: a case series identifying pathological adverse factors-implications for risk stratification and classification.

Virchows Arch 2020 Apr;476(4):625-626

Pathology Department, University of Valencia, Valencia, Spain.

In Tables 4 and 5, there were entries that were not properly aligned on its designated rows. The correct tables are presented in this article.].
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http://dx.doi.org/10.1007/s00428-019-02697-4DOI Listing
April 2020

Solitary fibrous tumor: a case series identifying pathological adverse factors-implications for risk stratification and classification.

Virchows Arch 2020 Apr 16;476(4):597-607. Epub 2019 Sep 16.

Pathology Department, University of Valencia, Valencia, Spain.

Solitary fibrous tumors (SFTs) are a rare type of mesenchymal lesion in which specific clinicopathologic factors have been related to patient outcome. We collected clinical, pathological, and molecular data of 28 patients with histologically confirmed SFT having at least one pathological factor associated with aggressive behavior. Molecular analysis to detect NAB2/STAT6 gene fusion, TP53, and/or TERT promoter mutation was performed. We analyzed the pathological factors predictive of recurrence/metastasis and compared with clinical outcome. The risk of metastasis was calculated using four previously described scoring systems. Histopathologically, all tumors revealed hypercellularity, 11 had ≥ 4 mitoses/10 HPF, and 12 showed necrosis. Dedifferentiation was observed in three tumors. STAT6 was positive in all cases. Desmin, p16, INSM1, and HTER immunoexpressions were detected in 14, 18, 21, and 46% of the SFT, respectively. The NAB2/STAT6 gene fusion was detected in 16 tumors. After a median follow-up of 34 months, 32.0% recurred, 32.1% metastasized, and 35.7% died of disease. TERT mutations were detected in almost half the tumors. Tumors with TP53 mutations or with TP53 and TERT promoter mutations were almost always classified as high risk, and the patients developed metastases and/or died of disease. Tumors with intermediate-risk and TERT mutation had a worse evolution. SFTs with adverse pathological parameters were not always related with a poor outcome, thus confirming the unpredictable clinical behavior of SFT. The inclusion of molecular factors (TP53 and TERT promoter status) may provide new prognostic indicators for future risk stratification systems, especially in the intermediate-risk group.
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http://dx.doi.org/10.1007/s00428-019-02660-3DOI Listing
April 2020

Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications.

ESMO Open 2019 27;4(3):e000470. Epub 2019 May 27.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain.

Background: The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors.

Material And Methods: We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation.

Results: Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04).

Conclusions: The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.
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http://dx.doi.org/10.1136/esmoopen-2018-000470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555614PMC
May 2019

The topology of vitronectin: A complementary feature for neuroblastoma risk classification based on computer-aided detection.

Int J Cancer 2020 01 8;146(2):553-565. Epub 2019 Jul 8.

Departamento de Biología Celular, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roció/CSIC/Universidad de Sevilla, Seville, Spain.

Tumors are complex networks of constantly interacting elements: tumor cells, stromal cells, immune and stem cells, blood/lympathic vessels, nerve fibers and extracellular matrix components. These elements can influence their microenvironment through mechanical and physical signals to promote tumor cell growth. To get a better understanding of tumor biology, cooperation between multidisciplinary fields is needed. Diverse mathematic computations and algorithms have been designed to find prognostic targets and enhance diagnostic assessment. In this work, we use computational digital tools to study the topology of vitronectin, a glycoprotein of the extracellular matrix. Vitronectin is linked to angiogenesis and migration, two processes closely related to tumor cell spread. Here, we investigate whether the distribution of this molecule in the tumor stroma may confer mechanical properties affecting neuroblastoma aggressiveness. Combining image analysis and graph theory, we analyze different topological features that capture the organizational cues of vitronectin in histopathological images taken from human samples. We find that the Euler number and the branching of territorial vitronectin, two topological features, could allow for a more precise pretreatment risk stratification to guide treatment strategies in neuroblastoma patients. A large amount of recently synthesized VN would create migration tracks, pinpointed by both topological features, for malignant neuroblasts, so that dramatic change in the extracellular matrix would increase tumor aggressiveness and worsen patient outcomes.
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http://dx.doi.org/10.1002/ijc.32495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899647PMC
January 2020

Vitronectin as a molecular player of the tumor microenvironment in neuroblastoma.

BMC Cancer 2019 May 22;19(1):479. Epub 2019 May 22.

Pathology Department, Medical School, University of Valencia-INCLIVA, Valencia, Spain.

Background: Vitronectin is a multifunctional glycoprotein known in several human tumors for its adhesive role in processes such as cell growth, angiogenesis and metastasis. In this study, we examined vitronectin expression in neuroblastoma to investigate whether this molecule takes part in cell-cell or cell-extracellular matrix interactions that may confer mechanical properties to promote tumor aggressiveness.

Methods: We used immunohistochemistry and image analysis tools to characterize vitronectin expression and to test its prognostic value in 91 neuroblastoma patients. To better understand the effect of vitronectin, we studied its in vitro expression using commercial neuroblastoma cell lines and in vivo using intra-adrenal gland xenograft models by immunohistochemistry.

Results: Digital image analysis allowed us to associate vitronectin staining intensity and location discriminating between territorial vitronectin and interterritorial vitronectin expression patterns. High territorial vitronectin expression (strong staining associated with pericellular and intracellular location) was present in tumors from patients with metastatic undifferentiating neuroblastoma, that were MYCN amplified, 11q deleted or with segmental chromosomal profiles, in the high-risk stratification group and with high genetic instability. In vitro studies confirmed that vitronectin is expressed in tumor cells as small cytoplasmic dot drops. In vivo experiments revealed tumor cells with high and dense cytoplasmic vitronectin expression.

Conclusions: These findings highlight the relevance of vitronectin in neuroblastoma tumor biology and suggest its potential as a future therapeutic target in neuroblastoma.
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http://dx.doi.org/10.1186/s12885-019-5693-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532218PMC
May 2019

Improving tumour budding evaluation in colon cancer by extending the assessment area in colectomy specimens.

Histopathology 2019 Oct 7;75(4):517-525. Epub 2019 Aug 7.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain.

Aims: It is recommended that tumour budding in colon cancer be counted on haematoxylin and eosin-stained sections in a hotspot area of 0.785 mm with a ×20 microscope objective. However, tumour buds may be difficult to visualise on haematoxylin and eosin-stained sections, and counting in such a limited area may result in overestimation in cases with focal budding. The aim of this study was to assess the contributions of various factors to improving tumour budding risk stratification: increasing the number of fields counted, using cytokeratin immunostaining, and recording proliferation, the apoptotic index and the emperipoletic index in tumour buds.

Methods And Results: We created an exploratory series composed of 172 cases of colon cancer in all stages, and we analysed the survival probability in a second cohort of 158 stage I-II patients. According to our results, counting of budding in 10 fields was the only factor that was significantly correlated with disease-free survival probability in stage I-II patients [hazard ratio (HR) for high versus low grade of 7.64, 95% confidence interval (CI) 5.54-27.92, P = 0.01; HR for intermediate versus low grade of 3.02, 95% CI 1.54-26.72, P = 0.04). Emperipolesis was frequently observed in tumour buds, whereas the mitotic index and the apoptotic index were extremely low. Although cytokeratin immunostaining increased interobserver concordance, it did not improve the accuracy of tumour budding grading.

Conclusions: According to our results, counting in 10 fields significantly enhanced the budding grade risk stratification in colon cancer patients, and cytokeratin immunostaining could be reserved as a complementary technique for challenging cases with an inflammatory infiltrate and/or striking fibrosis.
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http://dx.doi.org/10.1111/his.13900DOI Listing
October 2019

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy.

Cancer Med 2019 06 6;8(6):3120-3130. Epub 2019 May 6.

Department of Medical Oncology, CIBERONC, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.

Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions. Thirty-six patients diagnosed with advanced colorectal cancer from two referent public hospitals from Paraguay were recruited from May 2017 to February 2018. Sequenom Mass spectrometry, Oncocarta Panel V.1 was applied to analyze the mutational profile from formalin-fixed paraffin-embedded samples. The microsatellite status was tested by immunohistochemistry (IHC). The mean age of the patients was 52 years with a range from 20 to 74 years. Eighty-three percent of the patients included in the study have advanced-stage tumors at the moment of the diagnosis. Sixteen patients (44.4%) were wild-type for all the oncogene regions analyzed with the Oncocarta panel. Thirty-two hot-spot pathogenic variants on seven oncogenes, among 20 patients (55.6%), were identified, including KRAS, NRAS, BRAF, PI3KCA, FGFR, epidermal growth factor receptor, and PDGFRA. Moreover, 14 (38.8%) of these patients presented pathogenic variants in KRAS/NRAS or BRAF genes that have implications in the clinical practice decisions. Five patients (14%) presented MSI. The IHC study for microsatellite status and the molecular profile analysis through Sequenom mass spectrometry are feasible and useful methods, due to identify those patient candidates for targeted therapies and for the budgetary calculations of the National Health Plans.
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http://dx.doi.org/10.1002/cam4.2191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558499PMC
June 2019

Extra-Adrenal Adult Neuroblastoma With Aberrant Germ Cell Marker Expression: Maturation After Chemotherapy as an Important Clue to a Challenging Diagnosis.

Int J Surg Pathol 2019 Aug 24;27(5):568-573. Epub 2019 Mar 24.

1 Hospital Clinico Universitario, Valencia, Spain.

Adult neuroblastoma is an extremely infrequent neoplasm, usually occurring in the adrenal medulla or in the paraspinal sympathetic ganglia, as its childhood counterpart. We report a very unusual case of a Schwannian stroma-poor adult neuroblastoma of inguinal location, showing aberrant expression of germ cell markers: SALL4 and OCT4. This aberrant marker expression, the unusual positivity for NKX2.2 and the very scattered (instead of diffuse strong) PHOX2B expression, complicated the initial diagnosis. In this case, the posttreatment histological evaluation revealed the neuroblastic nature of the lesion. Neuroblastoma maturation after treatment is an unusual finding in adults, and in this case, added an important clue for the final diagnosis. Germs cells markers expression in neuroblastoma is an interesting feature to explore and may define a subset of neuroblastomas with a different biological nature.
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http://dx.doi.org/10.1177/1066896919835945DOI Listing
August 2019

High Oct4 expression: implications in the pathogenesis of neuroblastic tumours.

BMC Cancer 2019 Jan 3;19(1). Epub 2019 Jan 3.

Pathology Department, Medical School, University of Valencia-INCLIVA, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.

Background: Neuroblastic tumours (NBTs) are paediatric solid tumours derived from embryonic neural crest cells which harbour their own cancer stem cells (CSC). There is evidence indicating that CSC may be responsible for tumour progression, chemotherapy resistance and recurrence in NBTs. Oct4 is a transcription factor which plays a key role in mammal embryonic development and stem cell fate regulation. The aim of the study is to elucidate the clinical significance of Oct4 in NBTs.

Methods: We studied Oct4 expression in 563 primary NBTs using digital image quantification. Chi-square test was applied to analyse the correlation between histopathology and the Oct4 cell percentage. Survival analysis was carried out with Kaplan-Meier curves and log-rank test. Additionally, a multivariate Cox regression analysis with the stepwise backwards (Wald) method was undertaken to calculate the impact of Oct4 expression level on survival.

Results: We found that tumours with a high proportion of cells expressing Oct4 correlated statistically with undifferentiated and poorly differentiated neuroblastoma / nodular ganglioneuroblastoma, and that Oct4 expression was not present in ganglioneuroma (p < 0.05). Statistical analysis also indicated a relationship between high Oct4 expression levels, high-risk patients according to the International Neuroblastoma Risk Group pre-treatment classification parameters, larger blood vessels and low survival rates.

Conclusions: These results suggest that the Oct4 gene may regulate NBT pathogenic differentiation pathways, and should thus be considered as a target for knockdown when developing novel therapies for high-risk NBT patients.
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http://dx.doi.org/10.1186/s12885-018-5219-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318846PMC
January 2019

c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells.

Sci Rep 2018 10 23;8(1):15615. Epub 2018 Oct 23.

Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, E-28021, Spain.

Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.
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http://dx.doi.org/10.1038/s41598-018-33689-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199246PMC
October 2018

Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression.

Mod Pathol 2019 02 11;32(2):306-313. Epub 2018 Sep 11.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain.

At the histological level, tumor budding in colon cancer is the result of cells undergoing at least partial epithelial-to-mesenchymal transition. The microRNA 200 family is an important epigenetic driver of this process, mainly by downregulating zinc-finger E-box binding homeobox (ZEB) and transforming growth factor beta (TGF-β) expression. We retrospectively explored the expression of the miR200 family, and ZEB1 and ZEB2, and their relationship with immune resistance mediated through PD-L1 overexpression. For this purpose, we analyzed a series of 125 colon cancer cases and took samples from two different tumor sites: the area of tumor budding at the invasive front and from the tumor center. We found significant ZEB overexpression and a reduction in miR200 in budding areas, a profile compatible with epithelial-to-mesenchymal transition. In multivariate analysis of the cases with localized disease, low miR200c expression in budding areas, but not at the tumor center, was an adverse tumor-specific survival factor (hazard ratio: 0.12; 95% confidence interval: 0.03-0.81; p = 0.02) independent of the clinical stage of the disease. PD-L1 was significantly overexpressed in the budding areas and its levels correlated with a mesenchymal transition profile. These results highlight the importance of including budding areas among the samples used for biomarker evaluation and provides relevant data on the influence of mesenchymal transition in the immune resistance mediated by PD-L1 overexpression.
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http://dx.doi.org/10.1038/s41379-018-0124-5DOI Listing
February 2019

[Low-grade fibromyxoid sarcoma, an essential differential diagnosis in myxoid tumors with benign appearance].

Rev Esp Patol 2018 Jul - Sep;51(3):178-182. Epub 2017 Jul 4.

Servicio de Anatomía Patológica, Hospital Clínico Universitario de Valencia, Valencia, España.

Low-grade fibromyxoid sarcoma is a rare neoplasm, primarily affecting young adults. It is a fibroblastic tumor with a deceptively benign appearance, which may produce local recurrences and late distant metastases. We present a case of an 11-year-old girl with a lesion on her thigh that was completely excised. Histopathology revealed a well-delimited neoplasm with myxoid stroma and fusiform cellularity without atypia or mitosis. Immunohistochemical expression of MUC4, together with molecular biology, which detected FUS-CREB3L2 fusion gene expression, confirmed the diagnosis of low-grade fibromyxoid sarcoma. We review the differential diagnosis of soft-tissue myxoid tumors, especially those with a benign appearance, highlighting the importance of immunohistochemical and molecular studies to rule out low-grade fibromyxoid sarcoma.
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http://dx.doi.org/10.1016/j.patol.2017.05.004DOI Listing
February 2019

Role of Activator Protein-1 Complex on the Phenotype of Human Osteosarcomas Generated from Mesenchymal Stem Cells.

Stem Cells 2018 10 11;36(10):1487-1500. Epub 2018 Aug 11.

Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.

Osteosarcoma (OS) is a highly aggressive bone tumor that usually arises intramedullary at the extremities of long bones. Due to the fact that the peak of incidence is in the growth spurt of adolescence, the specific anatomical location, and the heterogeneity of cells, it is believed that osteosarcomagenesis is a process associated with bone development. Different studies in murine models showed that the tumor-initiating cell in OS could be an uncommitted mesenchymal stem cell (MSC) developing in a specific bone microenvironment. However, only a few studies have reported transgene-induced human MSCs transformation and mostly obtained undifferentiated sarcomas. In our study, we demonstrate that activator protein 1 family members induce osteosarcomagenesis in immortalized hMSC. c-JUN or c-JUN/c-FOS overexpression act as tumorigenic factors generating OS with fibroblastic or pleomorphic osteoblastic phenotypes, respectively. Stem Cells 2018;36:1487-1500.
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http://dx.doi.org/10.1002/stem.2869DOI Listing
October 2018

Lymph microvascularization as a prognostic indicator in neuroblastoma.

Oncotarget 2018 May 25;9(40):26157-26170. Epub 2018 May 25.

Pathology Department, Medical School, University of Valencia-INCLIVA, Valencia, Spain.

Neuroblastoma is the most common extra-cranial solid pediatric cancer and causes approximately 15% of all childhood deaths from cancer. Although lymphatic vasculature is a prerequisite for the maintenance of tissue fluid balance and immunity in the body, little is known about the relationship between lymphatic vascularization and prognosis in neuroblastoma. We used our previously-published custom-designed tool to close open-outline vessels and measure the density, size and shape of all lymphatic vessels and microvascular segments in 332 primary neuroblastoma contained in tissue microarrays. The results were correlated with clinical and biological features of known prognostic value and with risk of progression to establish histological lymphatic vascular patterns associated with unfavorable histology. A high proportion of irregular intermediate lymphatic capillaries and irregular small collector vessels were present in tumors from patients with metastatic stage, undifferentiating neuroblasts and/or classified in the high risk. In addition, a higher lymphatic microvascularization density was found to be predictive of overall survival. Our findings show the crucial role of lymphatic vascularization in metastatic development and maintenance of tumor tissue homeostasis. These patterns may therefore help to indicate more accurate pre-treatment risk stratification and could provide candidate targets for novel therapies.
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http://dx.doi.org/10.18632/oncotarget.25457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995242PMC
May 2018

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma.

Anticancer Drugs 2018 09;29(8):717-724

Department of Pharmacology, Feinberg School of Medicine, Northwestern University.

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3β inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.
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http://dx.doi.org/10.1097/CAD.0000000000000652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092218PMC
September 2018

Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study.

Br J Cancer 2018 05 14;118(11):1502-1512. Epub 2018 May 14.

Department of Tumour Biology CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria.

Background: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues.

Methods: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH.

Results: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse.

Conclusions: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.
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http://dx.doi.org/10.1038/s41416-018-0098-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988829PMC
May 2018

Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis.

Ann Diagn Pathol 2018 Jun 29;34:1-12. Epub 2017 Nov 29.

Pathology Department, University of Valencia, Valencia, Spain.

Background: Despite extensive immunohistochemical (IHC) and molecular studies combined with morphologic findings, a group of round/ovoid cell tumors histologically similar to Ewing sarcomas (ES) but lacking EWSR1-rearrangements may remain unclassifiable.

Design: We retrospectively analyzed 41 Ewing-like tumors (formalin-fixed, paraffin-embedded) previously determined as negative or non-informative for EWSR1-rearrangements by FISH and/or RT-PCR. A new histopathology revision and additional IHC and molecular analyses were carried out in order to investigate whether additional IHC and/or molecular testing in combination with the morphological findings may help in reaching a definitive diagnosis.

Results: Almost all the tumors (n=40) involved soft tissue and/or bone and half the patients died of disease. In the archival cases all diagnoses were Ewing sarcoma (ES), Ewing-like sarcoma (ELS), myoepithelial tumor and undifferentiated sarcoma (US). In the new review all the tumors were re-classified as, ES (n=16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n=1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n=7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n=3), neuroblastoma (n=2), unclassifiable neoplasm with neuroblastic differentiation (n=1), malignant rhabdoid tumor (n=2), lymphoblastic lymphoma (n=1), clear cell sarcoma of the gastrointestinal tract (n=1), small cell carcinoma (n=1), sclerosing rhabdomyosarcoma (n=1), desmoplastic small round cell tumor (n=1), malignant peripheral sheath nerve tumor (n=1), poorly-differentiated synovial sarcoma (n=1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n=1) and possible SMARCA4-deficient-sarcoma (n=1). NKX2.2, ETV4 and BCOR immunoreactivity was observed in all ES, CIC-rearranged sarcomas and sarcomas with BCOR alteration, respectively. CIC-rearrangement by FISH was observed in many of the CIC-rearranged sarcomas.

Conclusion: Our analysis of 41 Ewing-like tumors confirms that there may be a significant pathological and IHC overlap among Ewing-like tumors, with prognostic and therapeutic impacts. Additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies including FUS, CIC or BCOR analysis may support the final diagnosis when FISH or RT-PCR fail to detect EWSR1-rearrangements. Any molecular findings should always be interpreted in relation to the specific clinical and pathological context.
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http://dx.doi.org/10.1016/j.anndiagpath.2017.11.011DOI Listing
June 2018

HLA-DQ: Celiac disease inflammatory bowel disease.

World J Gastroenterol 2018 Jan;24(1):96-103

Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain.

Aim: To determine the genetic predisposition to celiac disease (CeD) in inflammatory bowel disease (IBD) patients by quantifying the frequency of CeD-related human leucocyte antigen (HLA) (HLA-CeD: HLA-DQ2 and -DQ8) in IBD patients globally, by type of IBD and gender, and by calculating the protective/risk contribution of these haplotypes in the development of the IBD disease.

Methods: We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors.

Results: 1034 subjects were analyzed: 457 IBD [207 ulcerative coliti (UC) and 250 Crohn's disease (CD)] patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-CeD ( = 0.0852). HLA-DQ2 was less frequent in UC patients ( = 0.0287), and HLA-DQ8 in CD ( = 0.0217). In women with UC, the frequency of DQ2.5cis (DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [ = 0.0344; preventive fraction (PF) = 13%]. PFs (7%-14%) were obtained with all HLA-CeD haplotypes. HLA DQB1*02:02-DQA1*02:01 (HLA-DQ2.2) was more frequent in CD patients with respect to controls ( = 0.001) and UC patients (etiological fraction = 15%).

Conclusion: HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and -DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLA-DQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CD patients and may constitute a genetic risk factor for CD development.
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http://dx.doi.org/10.3748/wjg.v24.i1.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757130PMC
January 2018

1p36 deletion results in a decrease in glycosaminoglycans which is associated with aggressiveness in neuroblastic tumors.

Histol Histopathol 2018 May 23;33(5):487-495. Epub 2017 Nov 23.

Cancer CIBER (CIBERONC), Madrid, Spain.

Despite our deep understanding of neuroblastic tumors, some patients still suffer treatment failure, so pre-treatment risk stratification still requires improvement and the search for new therapeutic targets must continue. Here we correlated prognostic clinical and biological features of neuroblastic tumors with the density of extracellular matrix glycosaminoglycans (the main components of the extracellular matrix 'ground substance'), in nearly 400 primary samples. We also studied the relationship between the density of extracellular matrix glycosaminoglycans and the expression of B3GALT6, an enzyme required for their synthesis. We associated a decrease in glycosaminoglycans with neuroblastomas that were histopathologically poorly-differentiated or undifferentiated, as well as with metastatic disease, and 1p36 deleted tumors. This decrease in glycosaminoglycans was also related to abnormal nuclear B3GALT6 expression in neuroblastic cells. These findings point towards the importance of the ground substance in the aggressiveness of neuroblastic tumors, which should therefore be considered when developing novel therapies for treating neuroblastomas.
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http://dx.doi.org/10.14670/HH-11-947DOI Listing
May 2018

Integrating Downstaging in the Risk Assessment of Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy: Validation of Valentini's Nomograms and the Neoadjuvant Rectal Score.

Clin Colorectal Cancer 2018 06 28;17(2):104-112.e2. Epub 2017 Oct 28.

Department of Medical Oncology, Biomedical Research Institute INCLIVA. CIBERONC, Hospital Clínico Universitario of Valencia, Valencia, Spain. Electronic address:

Background: Adjuvant chemotherapy is controversial in patients with locally advanced rectal cancer after preoperative chemoradiation. Valentini et al developed 3 nomograms (VN) to predict outcomes in these patients. The neoadjuvant rectal score (NAR) was developed after VN to predict survival. We aimed to validate these tools in a retrospective cohort at an academic institution.

Patients And Methods: VN and the NAR were applied to 158 consecutive patients with locally advanced rectal cancer treated with chemoradiation followed by surgery. According to the score, they were divided into low, intermediate, or high risk of relapse or death. For statistical analysis, we performed Kaplan-Meier curves, log-rank tests, and Cox regression analysis.

Results: Five-year overall survival was 83%, 77%, and 67% for low-, intermediate-, and high-risk groups, respectively (P = .023), according to VN, and 84%, 71%, and 59% for low-, intermediate-, and high-risk groups, respectively (P = .004), according to NAR. When the score was considered as a continuous variable, a significant association with the risk of death was observed (NAR: hazard ratio, 1.04; P < .001; VN: hazard ratio, 1.10; P < .001).

Conclusion: We confirmed the value of these scores to stratify patients according to their individual risk when designing new trials.
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http://dx.doi.org/10.1016/j.clcc.2017.10.014DOI Listing
June 2018

Immunohistochemical analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family of tumors.

Pathol Res Pract 2017 Sep 25;213(9):1048-1053. Epub 2017 Aug 25.

Pathology Department, University of Valencia, Valencia, Spain.

Ewing sarcoma is an aggressive neoplasm of pediatric and adolescent patients. Immunohistochemistry (IHC) can be used to support the morphologic diagnosis of Ewing sarcoma family of tumors (ESFT) in a convincing clinical/radiological context. Although neither NKX2.2 nor CD99 alone are entirely specific, when combined, the diagnostic specificity is high. The aim of the present study was to investigate the IHC expression of NKX2.2, ETV4 and BCOR in a large series of genetically confirmed ESFT. The results for CD99 and CAV-1 immunoreactivity, and the histological and fusion gene subtypes were retrieved from our previous study. NKX2.2 demonstrated moderate or strong nuclear positivity in 91.2% of the tumors. The staining intensity was heterogeneous. Many of the ESFT with negative NKX2.2 immunoreactivity were in bone. Strong/moderate ETV4 nuclear expression was detected in two small round cell tumors, both were negative for NKX2.2. No relationships could be found between expression of NKX2.2 and the histological subgroups or ESFT gene fusion subtypes. BCOR was negative in all ESFT. In conclusion, NKX2.2, ETV4 and BCOR IHC may be helpful in daily practice for distinguishing ESFT from CIC or BCOR-associated sarcomas, especially in hospitals without access to molecular assays. In addition, the combination of strong CD99 membranous positivity and nuclear NKX2.2 positivity seems to be very reliable for ESFT diagnosis in an appropriate clinicoradiological setting. So far no antibody is entirely specific for ESFT diagnosis, and the IHC or molecular results in round cell tumors of bone may be strongly influenced by decalcification processes.
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http://dx.doi.org/10.1016/j.prp.2017.08.002DOI Listing
September 2017

Congenital undifferentiated sarcoma associated to BCOR-CCNB3 gene fusion.

Pathol Res Pract 2017 Nov 14;213(11):1435-1439. Epub 2017 Jul 14.

Department of Pathology, University Clinic Hospital of Valencia, Spain; Department of Pathology, Medical School of Valencia, University of Valencia - INCLIVA, Spain; Ciberonc, Madrid, Spain.

Small round cell sarcomas are aggressive bone and soft tissue tumors that predominantly affect children and young adults. A new group of sarcomas with a recurrent BCOR-CCNB3 gene fusion has been recently identified in previously unclassifiable small round cell sarcomas. BCOR-CCNB3 sarcomas share clinical and pathologic similarities with Ewing sarcoma, but show a stronger male predilection and less aggressiveness, as well as distinct gene expression profiling and pangenomic SNP array analyses. We report the unusual case of a congenital BCOR-CCNB3 retroperitoneal sarcoma in a female born at 34th gestational week, which was diagnosed in necropsy after 21hours of life. Immunohistochemical analysis showed diffuse expression of CD99 and CCNB3. SNPa showed two focal segmentary deletions at 5q34 and 22q11.23, the latter harboring among others the SMARCB1/INI1 tumor suppressor gene. Immunohistochemistry confirmed loss of INI1 in tumor cells, which has not been previously reported in this type of undifferentiated sarcomas.
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http://dx.doi.org/10.1016/j.prp.2017.07.012DOI Listing
November 2017
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