scholarly journals NUT Carcinoma: A Clinical, Morphological and Immunohistochemical Mimicker—The Role of RNA Sequencing in the Diagnostic Procedure

2021 ◽  
pp. 106689692110479
Author(s):  
Gorana Gasljevic ◽  
Matthias S. Matter ◽  
Olga Blatnik ◽  
Mojca Unk ◽  
Stefan Dirnhofer
Keyword(s):  
Rna Sequencing ◽  
Wide Spectrum ◽  
Left Lung ◽  
Immunohistochemical Analysis ◽  
Excisional Biopsy ◽  
Interesting Case ◽  
Fusion Partner ◽  
Large Tumor ◽  
Serum Alpha Fetoprotein ◽  
Nut Carcinoma

Background: NUT carcinoma is a highly aggressive and rare subset of squamous cell carcinoma with grim prognosis. It is under-recognized by both pathologists and oncologists. Recognition is challenging due to its rareness and the fact that its clinical and laboratory features as well as morphological and immunohistochemical characteristics may mimic other malignancies. Case presentation: An interesting case of NUT carcinoma in a 47-year-old male with a large tumor mass in the inferior part of the mediastinum and left lung and increased levels of serum alpha fetoprotein (AFP) is described. Immunohistochemical analysis of both the primary tumor in a bronchoscopy specimen and an excisional biopsy of a subcutaneous metastasis showed positivity for AFP and leukocyte common antigen (LCA) that were misleading and resulted in diagnostic pitfalls of mediastinal germ cell tumor (clinically) and hematolymphoid neoplasm (pathologic report). Immunohistochemical demonstration of NUT protein expression revealed the proper diagnosis, which was further confirmed by RNA sequencing revealing a BRD4- NUTM1 gene fusion.Conclusions: Since NUT carcinoma can show a wide spectrum of histological and immunophenotypic features and can clinically mimic other tumors, use of RNA sequencing with identification of specific NUTM1 fusion partner could be crucial when there are discrepant clinical and histopathological findings. As well, since the category of so-called NUTM1-rearranged neoplasms is rapidly expanding, identification of NUTM1 fusion partner may be essential for the appropriate clinical management.

scholarly journals A Novel NFIX-STAT6 Gene Fusion in Solitary Fibrous Tumor: A Case Report

2021 ◽  
Vol 22 (14) ◽  
pp. 7514
Author(s):  
David S. Moura ◽  
Juan Díaz-Martín ◽  
Silvia Bagué ◽  
Ruth Orellana-Fernandez ◽  
Ana Sebio ◽  
...  
Keyword(s):  
Solitary Fibrous Tumor ◽  
Gene Fusion ◽  
Wide Spectrum ◽  
Bioinformatic Analysis ◽  
Fusion Partner ◽  
Rna Seq ◽  
Genomic Location ◽  
Nuclear Factor I ◽  
New Gene ◽  
Fibrous Tumor

Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2–STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2–STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8–STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity.

Expanding the molecular taxonomy of NUT midline carcinomas with multiomic analyses.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21008-e21008
Author(s):  
Henry G. Kaplan ◽  
Alex Barrett ◽  
Jiaxin Niu ◽  
Somasundaram Subramaniam ◽  
Maria Matsangou
Keyword(s):  
Dna Sequencing ◽  
Rna Sequencing ◽  
Molecular Taxonomy ◽  
Fusion Partner ◽  
Targeted Proteomics ◽  
Single Nucleotide Variants ◽  
Proteomic Data ◽  
Spatial Profiling ◽  
Tumor Mutational Burden ◽  
Custom Panel

e21008 Background: NUT midline carcinoma (NMC) is an aggressive squamous cell carcinoma molecularly defined by a chromosomal rearrangement of nuclear protein in testis (NUTM1) with bromodomain-containing protein 3 or 4 (BRD3/4). While NMCs are characterized by this rare canonical gene rearrangement little is known about the transcriptome and proteosome of this rare disease. As such, we set out to comprehensively characterize five NMC cases in which we attained targeted DNA sequencing, full-transcriptome RNA sequencing, and targeted proteomics. We further examine and integrate these results in order to better understand the relationship between gene expression and protein abundance within the context of NMC. Methods: All cases were analyzed for genomic and transcriptomic alterations against a custom panel via the Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth and full-transcriptome RNA sequencing) for germline and/or somatic mutations. The xT assay detects single nucleotide variants, specific insertion/deletions, amplifications and gene fusions, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. Proteomic data were obtained utilizing digital spatial profiling through Nanostring immune, MAPK and PI3/AKT, and pan tumor nCounter GeoMix panels. Results: Clinical characteristics, histology, and genomic/proteomic alterations for 5 NMC cases are presented. Cases were defined by pathological assessment and the identification of the canonical NUTM1 fusion, further broken down by fusion partner with three patients having NUTM1-BRD4 fusions, one NUT-BRD3, and one NUT-ZMYND8. TMBs ranged for 0.8-.6 mutations/megabases (n=5). All patients were MSI stable (5/5). Of three patients with available PD-L1 IHC result, one had elevated PD-L1 tumor staining at 70%. Results will be presented from full-transcriptome RNA expression analysis indicating overexpression of BRAF, MYC, mTOR, and EGFR, among others. Targeted proteomics were performed to assess relative abundance at the protein level (results to be presented). Clinical follow up for the five patients revealed that two have survived beyond 7 months. A lung primary patient treated with surgical resection and post op radiation (XRT) is NED at 63 months. A sinus primary patient is NED at 16 months after a partial response (PR) to taxotere/5FU/Cisplatin followed by resection and XRT/cis platin. One patient had a brief PR from ifosphamide/etoposide/vorinostat. One patient's tumor grew through XRT/cisplatin. Conclusions: Multi-omic analysis has the potential to further elucidate the mechanisms of tumor growth in NMC and identify new targets for the treatment of this aggressive and poor prognosis disease.

scholarly journals An interesting case of melanoma with divergent differentiation aberrantly expressing calretinin stain

2020 ◽  
Vol 29 (2) ◽  
pp. 139-141
Author(s):  
Chien Sheng Tan ◽  
Suyin Ong
Keyword(s):  
Rare Variant ◽  
Wide Spectrum ◽  
Interesting Case ◽  
Malignant Cells ◽  
Aberrant Expression ◽  
Potential Pitfall ◽  
Divergent Differentiation

Metaplastic melanoma or melanoma with divergent differentiation is a rare variant of melanoma with a wide spectrum of mesodermal and ectodermal differentiation. This is a case of metaplastic melanoma with aberrant expression for calretinin stain in the chondroid component and malignant cells adjacent to it. The finding of calretinin positivity in melanoma could be useful in diagnosing metastatic metaplastic melanoma. The awareness of the possibility of aberrant calretinin positivity in metaplastic melanoma with chondroid differentiation is critical to avoid a potential pitfall in misdiagnosing metaplastic melanoma as sarcoma or mesothelioma.

scholarly journals Experimental and Meta-Analytic Validation of RNA Sequencing Signatures for Predicting Status of Microsatellite Instability

2021 ◽  
Vol 8 ◽  
Author(s):  
Maksim Sorokin ◽  
Elizaveta Rabushko ◽  
Victor Efimov ◽  
Elena Poddubskaya ◽  
Marina Sekacheva ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Esophageal Cancer ◽  
Microsatellite Instability ◽  
Endometrial Carcinoma ◽  
Rna Sequencing ◽  
Wide Spectrum ◽  
The Cancer Genome Atlas ◽  
Laboratory Diagnostics ◽  
Reaction Products ◽  
Uterine Carcinosarcoma

Microsatellite instability (MSI) is an important diagnostic and prognostic cancer biomarker. In colorectal, cervical, ovarian, and gastric cancers, it can guide the prescription of chemotherapy and immunotherapy. In laboratory diagnostics of susceptible tumors, MSI is routinely detected by the size of marker polymerase chain reaction products encompassing frequent microsatellite expansion regions. Alternatively, MSI status is screened indirectly by immunohistochemical interrogation of microsatellite binding proteins. RNA sequencing (RNAseq) profiling is an emerging source of data for a wide spectrum of cancer biomarkers. Recently, three RNAseq-based gene signatures were deduced for establishing MSI status in tumor samples. They had 25, 15, and 14 gene products with only one common gene. However, they were developed and tested on the incomplete literature of The Cancer Genome Atlas (TCGA) sampling and never validated experimentally on independent RNAseq samples. In this study, we, for the first time, systematically validated these three RNAseq MSI signatures on the literature colorectal cancer (CRC) (n = 619), endometrial carcinoma (n = 533), gastric cancer (n = 380), uterine carcinosarcoma (n = 55), and esophageal cancer (n = 83) samples and on the set of experimental CRC RNAseq samples (n = 23) for tumors with known MSI status. We found that all three signatures performed well with area under the curve (AUC) ranges of 0.94–1 for the experimental CRCs and 0.94–1 for the TCGA CRC, esophageal cancer, and uterine carcinosarcoma samples. However, for the TCGA endometrial carcinoma and gastric cancer samples, only two signatures were effective with AUC 0.91–0.97, whereas the third signature showed a significantly lower AUC of 0.69–0.88. Software for calculating these MSI signatures using RNAseq data is included.

scholarly journals Histochemical and Immunohistochemical Study of Peripolar Cells in Sheep

2013 ◽  
Vol 2013 ◽  
pp. 1-9
Author(s):  
Passos Joana ◽  
Prada Justina ◽  
Bento Lígia ◽  
Rodrigues Paula ◽  
Pires Isabel
Keyword(s):  
Immunohistochemical Study ◽  
Contractile Function ◽  
Wide Spectrum ◽  
Smooth Muscle Actin ◽  
S100 Protein ◽  
Immunohistochemical Analysis ◽  
Muscle Actin ◽  
Peripolar Cells ◽  
Negative Results ◽  
Immunohistochemical Analyses

Peripolar cells are granulated cells located in the vascular pole of the renal corpuscle. Even though these cells have already been described, there are still many unknown histological and physiological characteristics. We carried out histochemical and immunohistochemical analyses of peripolar cells in sheep and compared their number in both normal and injured kidneys, discriminating according to the age of the animal. We tested HE, Toluidine Blue, PAS, and Masson's Trichrome stains to select the best stain for identification and quantification. Masson Trichrome yielded the best results and was selected for this purpose. We identified the cells by the presence of cytoplasmatic granules and by their position in the vascular pole. We found no statistically significant association between the number of peripolar cells and the age of the animal or the occurrence of lesions. In the immunohistochemical analysis, we found that the cells were positive to α-smooth muscle actin and less consistently positive to NSE and S100 protein. Chromogranin A, cyclooxygenase-2, AE1/AE3, and Wide Spectrum Cytokeratin and desmin yielded negative results. We conclude that although there was evidence of a contractile function, there was no evidence to support that peripolar cells have either a neuroendocrine or an epithelial nature.

Heterotopic Pancreatic Tissue Presenting as a Solid and Cystic Lung Lesion: A Very Unusual Bronchopulmonary Foregut Malformation

2004 ◽  
Vol 7 (2) ◽  
pp. 204-209 ◽  
Author(s):  
Ronald R. De Krijger ◽  
Marcel J.I.J. Albers ◽  
Ad J.J.C. Bogers ◽  
Wolter J. Mooi
Keyword(s):  
Left Lung ◽  
Lower Lobe ◽  
Supportive Therapy ◽  
Microscopic Analysis ◽  
Immunohistochemical Analysis ◽  
Pancreatic Tissue ◽  
Congenital Cystic Adenomatoid Malformation ◽  
Lung Pathology ◽  
Heterotopic Pancreatic Tissue ◽  
First Case

We describe the history and lung pathology of a premature female infant, who presented with respiratory distress immediately after birth. A thoracic computerized tomography scan showed abnormalities suggestive of congenital cystic adenomatoid malformation of the left lung. In addition, echocardiography revealed a tetralogy of Fallot. A left thoracotomy was performed and the lower lobe of the left lung was removed. Despite intensive supportive therapy, pulmonary hypoperfusion resulted in severe hypoxemia and death. Gross and microscopic analysis of the resected lobe revealed a partly cystic and solid lesion with multiple bronchus-derived cysts and an exuberant multifocal proliferation of glandular tissue, resembling bronchial glands, mixed with heterotopic cartilage surrounding ducts. Immunohistochemical analysis showed the presence of chromogranin A-reactive islet-like structures amidst exocrine tissue showing trypsin and chymotrypsin immunoreactivity, establishing the diagnosis of pulmonary pancreatic heterotopy. In the remaining pulmonary parenchyma, there were secondary changes consistent with partial obstruction and lymphangiectasis which was attributed to the presence of the cardiac malformation. To our knowledge, this is only the fourth reported case of heterotopic pancreatic tissue in the lung, and the first case where this bronchopulmonary foregut anomaly is not associated with a enteric duplication.

scholarly journals The oldest reported mirror hand? The curse of the coal-house frog!

2012 ◽  
Vol 94 (4) ◽  
pp. e149-e151
Author(s):  
NJ Marsden ◽  
IS Whitaker ◽  
DE Boyce
Keyword(s):  
Upper Limb ◽  
Reconstructive Surgery ◽  
Wide Spectrum ◽  
Interesting Case ◽  
Age At Diagnosis ◽  
Anatomical Features ◽  
New Variant

Despite being one of the rarest congenital upper limb abnormalities, a wide spectrum of the typical mirror hand has been described in the literature. We report a very interesting case of a new variant of mirror hand presenting in a 78-year-old man. The unique features of the case include the age at diagnosis, the anatomical features present and the acquired function despite no form of reconstructive surgery.

scholarly journals Immunohistochemical analysis of angiogenesis in invasive ductal breast carcinoma with correlations to clinic pathological factor

2006 ◽  
Vol 63 (7) ◽  
pp. 635-642 ◽  
Author(s):  
Tatjana Ivkovic-Kapicl ◽  
Slavica Knezevic-Usaj ◽  
Milana Panjkovic ◽  
Katarina Mastilovic
Keyword(s):  
Hormone Receptors ◽  
Ductal Carcinoma ◽  
Histological Grade ◽  
P53 Protein ◽  
Immunohistochemical Analysis ◽  
Metastatic Potential ◽  
Biological Indicators ◽  
Invasive Ductal Breast Carcinoma ◽  
Large Tumor ◽  
Tumor Phenotype

Background/aim: Angiogenesis is the formation of new vessels from preexisting ones. The aim of our study was to determine the relevance of tumor-induced angiogenesis, its correlation with some of the commonly used clinical, pathological factors and the recent biological indicators, and metastatic potential of the tumor in a series of 120 patients with invasive ductal carcinoma of the breast. Methods. The identification of microvessels was performed immunohistochemically with factor VIII-related antigen. The microvessel count (MVC) was assessed at the invasive front of each carcinoma. The cases were divided into high-and low-microvessel density groups according to an average number of microvessels found in the multiple fields of the most vessel-dense part of each tumor. The nuclear immunohistochemical staining for hormone receptors, and the p53, and the membranous staining for cerbB-2 were evaluated. Results. There were significant correlations between a high MVC and a large tumor size, high histological grade, and c-erbB-2 protein over expression. There was no association between tumor angiogenesis, as assessed by the MVC, and the hormone receptors status, and the p53 protein expression. In the cases with a high MVC, there was a significant number of tumors with lymph node metastases. Conclusion. Our findings showed that a high MVC might point out an aggressive tumor phenotype. This might help to stratify patients for an appropriate therapy on an individual basis and, thus, offer the possibility of a more effectively tailored treatment program.

Detection of FGFR fusions in intrahepatic cholangiocarcinoma using targeted RNA sequencing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16185-e16185
Author(s):  
Maria Farooq ◽  
Havell Markus ◽  
Bradon McDonald ◽  
Jan B. Egan ◽  
Tania Contente-Cuomo ◽  
...  
Keyword(s):  
Prior Knowledge ◽  
Rna Sequencing ◽  
Intrahepatic Cholangiocarcinoma ◽  
Growth Factor Receptor ◽  
Digital Pcr ◽  
High Yield ◽  
Fusion Partner ◽  
Rna Molecules ◽  
Quantitative Performance ◽  
Highly Correlated

e16185 Background: Comprehensive sequencing efforts have identified fibroblast growth factor receptor (FGFR) translocations in numerous cancers. FGFR2 fusions were recently identified as an actionable therapeutic target in ̃17% of cholangiocarcinoma patients, predominantly found in patients with intrahepatic cholangiocarcinoma. Genomic partners for FGFR fusions are variable. In addition, obtaining high yield tissue biopsies for CCA remains challenging and tumor tissue available for molecular analyses is scarce. When combined, these two factors make detection of FGFR fusions in CCA challenging. An accurate molecular assay to detect FGFR fusions in CCA could improve utilization of FGFR-targeted therapies. Methods: The objective of our study was to develop an approach for targeted RNA analysis to improve sensitivity for FGFR fusion detection from limited tumor material. We adapted the sensitive targeted digital sequencing (TARDIS) approach recently developed in our lab for analysis of RNA. This approach utilizes a combination of open-ended targeted amplification followed by ligation, enabling detection of tyrosine kinase fusions without prior knowledge of the precise sequence of the fusion breakpoint or identity of the fusion partner. For evaluation of analytical performance, we analyzed RNA from a CCA organoid model with a known FGFR2 fusion, and Seraseq Fusion RNA Mix v3 Reference Material with two known FGFR3 fusions. Results: Without prior knowledge the partner or coordinates of the fusion breakpoint, we detected an FGFR2-KIF5C fusion in RNA from a CCA organoid model. The fusion breakpoint coordinates predicted by TARDIS-RNA were validated by comparison with RNA-Seq. To assess sensitivity and quantitative performance of the assay, we analyzed a serial dilution of the reference RNA sample from Seraseq with concentration of RNA molecules representing candidate fusions verified by digital PCR. Using TARDIS-RNA to analyze replicates with 5 ng RNA input, we were able to detect candidate fusions represented by as few as 2.7 fusion molecules on average. Concentrations of fusion molecules measured using the two methods were highly correlated (R = 0.96). Conclusions: These results demonstrate sensitivity and quantitative performance of a targeted RNA sequencing assay to detect and quantify FGFR fusions in tumor specimen from intrahepatic cholangiocarcinoma. On-going work is focused on further evaluating assay performance and characterizing FGFR fusions using additional tissue specimen.

scholarly journals A Histologically Diagnosed Case with Infantile Osteopetrosis Complicated by Hypopituitarism

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Gulden Diniz ◽  
Ozgur Olukman ◽  
Sebnem Calkavur ◽  
Muammer Buyukinan ◽  
Canan Altay
Keyword(s):  
Wide Spectrum ◽  
Sella Turcica ◽  
Clinical Manifestations ◽  
Endocrine System ◽  
Pituitary Hormones ◽  
Interesting Case ◽  
Biopsy Specimens ◽  
First Case ◽  
Endocrinological Symptoms ◽  
Severe Disorder

Malignant infantile osteopetrosis is a rarely seen severe disorder which appears early in life with general sclerosis of the skeleton. It is caused by functionally defective osteoclasts which fail to resorb bone. Affected infants can exhibit a wide spectrum of clinical manifestations including impaired hematopoiesis, hepatosplenomegaly, visual impairment, and hypocalcemia. With the exception of secondary hyperparathyroidism, involvement of the endocrine system seems to be quite rare. Hypopituitarism is defined as underproduction of the growth hormone in combination with deficiencies of other pituitary hormones. Any lesion that damages hypothalamus, pituitary stalk, or anterior pituitary can cause secondary hypopituitarism. In this report, we presented a rare combination of malignant infantile osteopetrosis and secondary hypopituitarism in a newborn who presented predominantly with endocrinological symptoms. This is the first case report of malignant infantile osteopetrosis accompanied by hypopituitarism secondary to sclerosis of the sella turcica. On the other hand, this is a very interesting case which was diagnosed based on histological examination of bone marrow biopsy specimens despite lack of any clinical suspicion.

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