37 results on '"Ptáková N"'
Search Results
2. 22P Next generation sequencing-based molecular profiling of lung carcinoma: A routine care experience
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Polivka, J., Pesek, M., Svaton, M., Vanecek, T., Mukensnabl, P., and Ptakova, N.
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- 2020
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3. 386P Oncogenic fusions in CNS gliomas assessed by next generation sequencing: The real-world experience
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Polivka, J., Svajdler, M., Priban, V., Martinek, P., Ptakova, N., and Kasik, P.
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- 2020
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4. 9 Milder pancreatic and pulmonary phenotype associated with nonsense mutations located within the legacy exon 24 of the CFTR gene
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Holubová, A., primary, Libile, M., additional, Dvořáková, L., additional, Skalická, V., additional, Bartošová, J., additional, Holčíková, A., additional, Vávrová, V., additional, Němečková, J., additional, Peldová, P., additional, Ptáková, N., additional, and Macek, M., additional
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- 2016
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5. Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring
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Paděrová, J., primary, Holubová, A., additional, Simandlová, M., additional, Puchmajerová, A., additional, Vlčková, M., additional, Malíková, M., additional, Pourová, R., additional, Vejvalková, S., additional, Havlovicová, M., additional, Šenkeříková, M., additional, Ptáková, N., additional, Drábová, J., additional, Geryk, J., additional, Maver, A., additional, Křepelová, A., additional, and Macek, M., additional
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- 2016
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6. WS17.4 Unexpected findings in the broadly used Elucigene CF-EU2 CFTR genotyping assay
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Holubová, A., Libik, M., Dvoľáková, L., Paděrová, J., Ptákova, N., and Macek, M., Jr.
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- 2015
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7. SMARCB1-deficient sinonasal adenocarcinoma: a rare variant of SWI/SNF-deficient malignancy often misclassified as high-grade non-intestinal-type sinonasal adenocarcinoma or myoepithelial carcinoma.
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Skálová A, Taheri T, Bradová M, Vaněček T, Franchi A, Slouka D, Kostlivý T, de Rezende G, Michálek J, Klubíčková N, Ptáková N, Nemcová A, Michal M, Agaimy A, and Leivo I
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- Humans, Middle Aged, Male, Female, Aged, Adult, Biomarkers, Tumor genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins deficiency, In Situ Hybridization, Fluorescence, Diagnosis, Differential, Aged, 80 and over, High-Throughput Nucleotide Sequencing, Neoplasm Grading, SMARCB1 Protein deficiency, SMARCB1 Protein genetics, Adenocarcinoma genetics, Adenocarcinoma pathology, Transcription Factors genetics, Transcription Factors deficiency, Myoepithelioma genetics, Myoepithelioma pathology, Paranasal Sinus Neoplasms genetics, Paranasal Sinus Neoplasms pathology, Mutation
- Abstract
SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival., (© 2023. The Author(s).)
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- 2024
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8. Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations.
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Klubíčková N, Dermawan JK, Mosaieby E, Martínek P, Vaněček T, Hájková V, Ptáková N, Grossmann P, Šteiner P, Švajdler M, Kinkor Z, Michalová K, Szepe P, Plank L, Hederová S, Kolenová A, Spasov NJ, Kosemehmetoglu K, Pažanin L, Špůrková Z, Baník M, Baumruk L, Meyer A, Kalmykova A, Koshyk O, Michal M, and Michal M
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- Adult, Humans, Child, Receptor, trkA genetics, Proto-Oncogene Proteins B-raf genetics, Neoplasm Recurrence, Local genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Oncogene Proteins, Fusion genetics, Neoplasms, Connective and Soft Tissue, Fibrosarcoma genetics, Fibrosarcoma pathology, Soft Tissue Neoplasms genetics
- Abstract
Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2024
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9. Poorly differentiated extra-axial extraskeletal chordoma diagnosed by methylation profiling: case report and analysis of brachyury expression in SWI/SNF-deficient tumors.
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Klubíčková N, Michal M, Kinkor Z, Soukup J, Ryška A, Brtková J, Lutonský M, Hájková V, Ptáková N, Michal M, Farkas M, and Švajdler M
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- Humans, Male, Aged, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms metabolism, Transcription Factors genetics, Cell Differentiation, Chordoma pathology, Chordoma genetics, Chordoma diagnosis, Chordoma metabolism, DNA Methylation, Fetal Proteins genetics, Fetal Proteins metabolism, SMARCB1 Protein genetics, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics
- Abstract
Chordoma is a rare malignant tumor with notochordal differentiation, usually affecting the axial skeleton of young patients. We report a case of a high-grade epithelioid tumor involving the synovium and soft tissues of the knee in a 74-year-old male patient. The preliminary biopsy was inconclusive, but a diagnosis of metastatic clear-cell carcinoma of unknown origin was suggested. However, imaging studies did not reveal any primary lesions. The resection specimen consisted of nests and sheets of oval to polygonal cells with discernible cell borders, clear or lightly amphophilic cytoplasm, and round to oval nuclei with occasional well-visible eosinophilic nucleoli. Rare atypical mitoses, necrotic areas, and bizarre nuclei were noted. The biopsy and resection specimens underwent a wide molecular genetic analysis which included methylation profiling. The DKFZ sarcoma classifier assigned the methylation class chordoma (dedifferentiated) with a calibrated score of 0.96, and additionally, a loss of SMARCB1 locus was noted in the copy number variation plot. To verify these findings, T-brachyury and SMARCB1 immunostaining was performed afterward, showing diffuse nuclear positivity and complete loss in the tumor cells, respectively. To assess the prevalence of T-brachyury immunopositivity among SWI/SNF-deficient tumors and to evaluate its specificity for poorly differentiated chordoma, we analyzed a series of 23 SMARCB1- or SMARCA4-deficient tumors, all of which were negative. After incorporating all the available data, including the absence of any morphological features of conventional chordoma, the case was diagnosed as poorly differentiated chordoma. As illustrated herein, the utilization of methylation profiling in the diagnostic process of some carefully selected unclassifiable soft tissue neoplasms may lead to an increased detection rate of such extremely rare soft tissue tumors and enable their better characterization., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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10. High-grade non-intestinal type sinonasal adenocarcinoma with ETV6::NTRK3 fusion, distinct from secretory carcinoma by immunoprofile and morphology.
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Klubíčková N, Mosaieby E, Ptáková N, Trinquet A, Laé M, Costes-Martineau V, and Skálová A
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- Humans, Biomarkers, Tumor genetics, Immunohistochemistry, Oncogene Proteins, Fusion genetics, ETS Translocation Variant 6 Protein, Adenocarcinoma genetics, Adenocarcinoma pathology, Carcinoma genetics, Carcinoma pathology, Salivary Gland Neoplasms genetics, Salivary Gland Neoplasms pathology
- Abstract
We report 2 cases of high-grade sinonasal adenocarcinoma with a distinct morphological and immunohistochemical phenotype. Albeit histologically different from secretory carcinoma of the salivary glands, both tumors presented here share an ETV6::NTRK3 fusion. The highly cellular tumors were composed of solid and dense cribriform nests, often with comedo-like necroses in the center, and minor areas with papillary, microcystic, and trabecular formations without secretions, mostly located at the periphery of the lesion. The cells displayed high-grade features, with enlarged, crowded, and often vesicular nuclei with conspicuous nucleoli and brisk mitotic activity. The tumor cells were immunonegative for mammaglobin while showing immunopositivity for p40/p63, S100, SOX10, and GATA3, as well as for cytokeratins 7, 18, and 19. For the first time, we describe 2 cases of primary high-grade non-intestinal type adenocarcinomas of the nasal cavity, distinct from secretory carcinoma by morphology and immunoprofile, harboring the ETV6::NTRK3 fusion., (© 2023. The Author(s).)
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- 2023
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11. Corrigendum to "Immunohistochemical and genetic analysis of respiratory epithelial adenomatoid hamartomas and seromucinous hamartomas: are they precursor lesions to sinonasal low-grade tubulopapillary adenocarcinomas?" Human Pathology (2020) 97, 94-102.
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Baněčková M, Michal M, Laco J, Leivo I, Ptáková N, Horáková M, Michal M, and Skálová A
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- 2023
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12. TFG::MET-rearranged soft tissue tumor: A rare infantile neoplasm with a distinct low-grade triphasic morphology.
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Michal M, Ud Din N, Švajdler M, Klubíčková N, Ptáková N, Hájková V, Michal M, and Agaimy A
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- Female, Humans, Biomarkers, Tumor genetics, Gene Fusion, Proteins genetics, Fibrosarcoma genetics, Neoplasms, Connective and Soft Tissue, Neurofibrosarcoma, Skin Neoplasms, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms pathology
- Abstract
This article presents 2 cases of TFG::MET-rearranged mesenchymal tumor, an extremely rare molecular subset among an emerging group of mesenchymal neoplasms with kinase gene (NTRK, BRAF, RET and others) alterations. Both tumors were congenital, occurred in female patients and presented as huge masses on the trunk and thigh, measuring 18 and 20 cm in the largest dimension. Both cases showed identical areas with a distinctive triphasic morphology resembling fibrous hamartoma of infancy (FHI), consisting of haphazardly arranged ovoid to spindled cells traversed by variably cellular and hyalinized fascicles admixed with (most likely non-neoplastic) adipose tissue. In other areas, a high-grade infantile fibrosarcoma/malignant peripheral nerve sheath tumor-like (IFS/MPNST-like) morphology was present in both cases. While the first case co-expressed CD34 and S100 protein, the other case did not. When combined with the three previously reported MET-rearranged cases (of which two harbored TFG::MET fusion), 3/5 and 3/4 of MET-rearranged and TFG::MET fusion-associated tumors, respectively exhibited similar triphasic FHI-like low-grade morphology. This points toward the existence of a relatively distinct morphological subset among kinase-fusion-associated tumors which seems to be strongly associated with MET fusions. It seems some of these low-grade cases may transform into a high-grade variant with IFS/MPNST-like morphology as has been observed in other tumors with kinase gene fusions. While most cases seem to follow an indolent clinical course, the recognition of these tumors is clinically relevant as MET tyrosine kinase inhibitors might represent an effective treatment option for clinically aggressive or unresectable cases., (© 2022 Wiley Periodicals LLC.)
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- 2023
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13. Extraskeletal myxoid chondrosarcoma: A study of 17 cases focusing on the diagnostic utility of INSM1 expression and presenting rare morphological variants associated with non-EWSR1::NR4A3 fusions.
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Lenz J, Klubíčková N, Ptáková N, Hájková V, Grossmann P, Šteiner P, Kinkor Z, Švajdler M, Michal M, Konečná P, Macháčová D, Hurník P, Tichý M, Tichý F, Kyllar M, Fiala L, Kavka M, and Michal M
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- Humans, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Repressor Proteins genetics, DNA-Binding Proteins genetics, Receptors, Thyroid Hormone genetics, Chondrosarcoma diagnosis, Chondrosarcoma genetics, Sarcoma genetics, Neoplasms, Connective and Soft Tissue genetics, Receptors, Steroid genetics
- Abstract
Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain lineage. Insulinoma-associated protein 1 (INSM1) has recently been described as a highly specific and sensitive immunohistochemical marker for EMC. The goal of this study was to evaluate the diagnostic significance of INSM1 immunohistochemistry in EMC. Furthermore, correlations between molecular and morphological findings were performed. Sixteen of 17 EMC cases were stained with the INSM1 antibody. Tumors with at least 5% INSM1-positive cells and any staining intensity were considered positive. Molecular testing was successfully performed in 12/17 cases. The immunohistochemical analysis detected 13 INSM1-positive (81%) and 3 INSM1-negative tumors (19%). The extent of the staining was classified as 1+ in 7 cases (44%), 2+ in 2 cases (13%), 3+ in 2 cases (13%) and 4+ in 2 cases (13%). Intensity of immunostaining was weak in 5 cases (31%), moderate in 2 cases (13%) and strong in 6 cases (38%). Molecular assays revealed 8 EWSR1::NR4A3 positive tumors (67%), 2 TAF15::NR4A3 positive tumors (17%), 1 TCF12::NR4A3 positive tumor (8%) and 1 NR4A3 positive tumor (8%) in which no other gene alteration was identified. Two of them, namely TCF12 positive and one TAF15 positive tumors, were highly cellular and partially associated with pseudopapillary architecture. Our study found that moderate/strong expression of INSM1 in more than 25% of tumor cells was present in only 31% of cases. Thus, the diagnostic utility of INSM1 is rather low. Two morphologically unique cases of non-EWSR1 rearranged EMC with an extremely rare pseudopapillary growth pattern are also reported., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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14. Epithelioid fibrous histiocytoma: three diagnostically challenging cases with novel ALK gene fusions, unusual storiform growth pattern, and a prominent spindled morphology.
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Mansour B, Donati M, Michalová K, Michal M, Ptáková N, Hájková V, and Michal M
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- Humans, Gene Fusion, Receptor Protein-Tyrosine Kinases genetics, Middle Aged, Histiocytoma, Benign Fibrous diagnosis, Histiocytoma, Benign Fibrous genetics, Histiocytoma, Benign Fibrous pathology, Sarcoma pathology, Soft Tissue Neoplasms pathology
- Abstract
Epithelioid fibrous histiocytoma (EFH) is a distinctive cutaneous neoplasm with a relatively variable morphological appearance. Recently, it has been shown that this tumor is molecularly characterized by ALK gene fusions. We report three EFHs with unusual histological presentation represented by a prominent/predominant spindle cell proliferation arranged in a variably storiform/whirling architectural pattern with or without stromal sclerosis. One of the cases closely resembled cellular fibrous histiocytoma. All three cases were immunohistochemically ALK-positive and were analyzed for ALK gene rearrangements using a next-generation sequencing-based assay (FusionPlex Sarcoma Kit, ArcherDx). Three novel fusions, namely AP3D1::ALK, COL1A::ALK, and LRRFIP2::ALK, were detected and further confirmed by FISH in all 3 cases and RT-PCR in 1 case. All patients were elderly (62-63 years) and presented with a solitary polypoid lesion on the extremities. The awareness of these morphological variants is important since it entertains a wide and slightly different differential diagnosis than conventional EFH. We also presented evidence that a clear separation of EFH from BFH in all cases may not be as straightforward as previously thought. The consistent ALK immunoexpression and the continually expanding scale of ALK gene rearrangements provide a useful tool to distinguish EFH from its histologic mimics., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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15. TIMP3::ALK fusions characterize a distinctive myxoid fibroblastic tumor of the vocal cords: a report of 7 cases.
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Klubíčková N, Michal M, Agaimy A, Zidar N, Pavlovský M, Yorita K, Grossmann P, Hájková V, Ptáková N, Šteiner P, and Michal M
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- Female, Humans, Male, Middle Aged, Immunohistochemistry, Gene Fusion, Proteoglycans genetics, Receptor Protein-Tyrosine Kinases genetics, Tissue Inhibitor of Metalloproteinase-3 genetics, Vocal Cords, Biomarkers, Tumor genetics
- Abstract
We report 7 cases of an indolent, variably myxoid tumor of the vocal cords, characterized by overt cellular atypia with large cells containing intranuclear and intracytoplasmic vacuoles, delicate curvilinear vessels, and sparse inflammatory infiltrate. Six patients were male, aged 15 to 65 years, and 1 patient was a 54-year-old female. All tumors were located in the superficial portion of the vocal cord. One patient suffered a recurrence that was completely resected; all patients with available follow-up data currently have no evidence of disease. The tumors contained alternating areas with myxoid stroma and more compacted regions with tumor cells organized in short fascicles, interwoven with delicate curvilinear vasculature. Overt cellular atypia with large cells containing intranuclear and intracytoplasmic vacuoles or resembling ganglion cells was present in all cases but mitoses and necrosis were absent. ALK immunostaining was positive in all cases, while most tumors were negative for smooth muscle actin. Targeted RNA-sequencing revealed an identical TIMP3::ALK fusion with exon 1 of TIMP3 gene being fused with exon 12 of ALK gene in all analyzable cases. For various reasons discussed, it remains unclear whether this tumor represents a mere subtype of IMT or a separate entity. Nevertheless, it is a morphologically distinct and diagnostically challenging lesion that needs to be recognized by surgical pathologists in order to prevent overdiagnosis in this clinically very delicate area., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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16. RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions.
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Klubíčková N, Agaimy A, Hájková V, Ptáková N, Grossmann P, Šteiner P, Michal M, and Michal M
- Subjects
- DNA-Binding Proteins genetics, Endonucleases genetics, Gene Fusion, Humans, Mitogen-Activated Protein Kinase Kinases, Nuclear Proteins genetics, Nuclear Proteins metabolism, Proto-Oncogene Proteins B-raf genetics, RNA, TEA Domain Transcription Factors, Transcription Factors genetics, Fibrosarcoma genetics, Skin Neoplasms
- Abstract
Myxoinflammatory fibroblastic sarcoma (MIFS) has been shown to harbor various recurrent molecular aberrations; most of which, however, seem to be present in only a minority of cases. In order to better characterize the molecular underpinnings of MIFS, fourteen cases were analyzed by targeted RNA-sequencing (RNA-seq), VGLL3 enumeration FISH probe, and BRAF break-apart and enumeration probes. Neither t(1;10)(p22;q24) nor BRAF gene amplifications were found. However, VGLL3 gene amplification was detected in 5 cases by FISH which corresponded with an increase in VGLL3 expression detected by RNA-seq. In 1 of these cases, RNA-seq additionally revealed a novel SND1::BRAF fusion. Two of the 9 cases lacking VGLL3 amplification harbored either a SEC23IP::VGLL3 or a TEAD1::MRTFB rearrangement by RNA-seq, both confirmed by RT-PCR and Sanger sequencing. The detected molecular aberrations have a potential to either activate the expression of genes regulated by the transcription factors of the TEAD family, which are involved in tumor initiation and progression, or switch on the MEK/ERK signaling cascade, which plays an important role in cell cycle progression. Our results broaden the molecular genetic spectrum of MIFS and point toward the importance of the VGLL3-TEAD interaction, as well as the deregulation of the MEK/ERK pathway in the pathogenesis of MIFS, and may represent a potential target for therapy of recurrent or advanced disease., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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17. Patients with neuregulin 1 (NRG1) rearranged cancer are suitable for the theranostic approach and targeted therapy.
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Ondič O, Ptáková N, Janovský V, Vančurová J, Hósová M, Michal M, and Pešek M
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- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung metabolism, Antineoplastic Agents therapeutic use, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Precision Medicine, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Neoplasms genetics, Neoplasms metabolism, Neuregulin-1 genetics, Neuregulin-1 metabolism
- Abstract
Introduction: Neuregulin 1 (NRG1) gene fusion was detected in a wide range of carcinomas. It is most frequently present in lung adenocarcinomas, especially in KRAS and BRAF wild-type cases., Purpose: We present a newly described diverse group of NRG1 rearranged carcinomas. The paper explains basic molecular principles associated with this oncogenic driver. It consists of ERBB3 (HER3) and ERBB2 (HER2) receptor activation with downstream activation of PIK and MAPK canonical pathways. The experience with new therapeutic modalities is summarized., Conclusions: So far, the global results of cytotoxic, immune and targeted therapies were dis-appointing. Further research (including two studies in Europe) is underway, developing new therapeutic strategies and examining this cancer bio-logy. In the meantime, it is possible to dia-gnose NRG1 rearranged carcinomas in the Czech Republic since mRNA next generation sequencing (NGS) analysis is readily available.
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- 2022
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18. Sclerosing Polycystic Adenoma of Salivary Glands: A Novel Neoplasm Characterized by PI3K-AKT Pathway Alterations-New Insights Into a Challenging Entity.
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Skálová A, Baněčková M, Laco J, Di Palma S, Agaimy A, Ptáková N, Costes-Martineau V, Petersson BF, van den Hout MFCM, de Rezende G, Klubíčková N, Koblížek M, Koshyk O, Vaneček T, and Leivo I
- Subjects
- Adenoma genetics, Adenoma pathology, Adolescent, Adult, Aged, Biomarkers, Tumor analysis, Child, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Neoplasms, Cystic, Mucinous, and Serous genetics, Neoplasms, Cystic, Mucinous, and Serous pathology, PTEN Phosphohydrolase genetics, Parotid Neoplasms genetics, Parotid Neoplasms pathology, Phenotype, Proto-Oncogene Proteins p21(ras) genetics, Sclerosis, Young Adult, Adenoma enzymology, Biomarkers, Tumor genetics, Class I Phosphatidylinositol 3-Kinases genetics, Mutation, Neoplasms, Cystic, Mucinous, and Serous enzymology, Parotid Neoplasms enzymology, Proto-Oncogene Proteins c-akt genetics
- Abstract
Sclerosing polycystic adenoma (SPA) is a rare salivary gland neoplasm originally thought to represent a non-neoplastic lesion. Recently we have encountered an index case of apocrine intraductal carcinoma of parotid gland of 62-year-old man with invasive salivary duct carcinoma component arising from SPA, a combination of tumor entities that has never been published so far. Here, we further explore the nature of SPA by evaluating 36 cases that were identified from the authors' consultation files. The patients were 25 females and 11 males aged 11 to 79 years (mean, 47.8 y). All tumors originated from the parotid gland. Their size ranged from 11 to 70 mm (mean, 28 mm). Histologically, all cases revealed characteristic features of SPA, such as lobulated well-circumscribed growth, focal hyalinized sclerosis, presence of large acinar cells with abundant brightly eosinophilic intracytoplasmic granules, and ductal components with variable cytomorphologic characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. In all cases, there were foci of intraluminal solid and cribriform intercalated duct-like epithelial proliferations with variable dysplasia which were positive for S100 protein and SOX10, and fully enveloped by an intact layer of myoepithelial cells. In addition, 14/36 cases (39%) had focal intraductal cribriform and micropapillary apocrine-type dysplastic epithelial structures composed of cells positive for androgen receptors and negative for S100/SOX10. The intraductal proliferations of both types showed focal mild to severe dysplasia in 17 cases (17/36; 47%). Two cases showed overt malignant morphology ranging from high-grade intraductal carcinoma to invasive carcinoma with an apocrine ductal phenotype. Next generation sequencing using ArcherDX panel targeting RNA of 36 pan-cancer-related genes and/or a TruSight Oncology 170/500 Kit targeting a selection of DNA from 523 genes and RNA from 55 genes was performed. Tumor tissue was available for molecular analysis in 11 cases, and 9 (9/11; 82%) of them harbored genetic alterations in the PI3K pathway. Targeted sequencing revealed HRAS mutations c.37G>C, p.(Gly13Arg) (2 cases) and c.182A>G, p.(Gln61Arg) (2 cases), and PIK3CA mutations c.3140A>G, p.(His1047Arg) (3 cases), c.1633G>A, p.(Glu545Lys) (1 case), and c.1624G>A, p.(Glu542Lys) (1 case). Moreover, mutations in AKT1 c.49G>A, p.(Glu17Lys) and c.51dup, p.(Tyr18ValfsTer15); c.49_50delinsAG, p.(Glu17Arg) (as a double hit) were found (2 cases). In addition, germinal and somatic mutation of PTEN c.1003C>T, p.(Arg335Ter); c.445C>T, p.(Gln149Ter), respectively, were detected. Gene fusions were absent in all cases. These prevalent molecular alterations converging on one major cancer-related pathway support the notion that SPA is a true neoplasm with a significant potential to develop intraluminal epithelial proliferation with apocrine and/or intercalated duct-like phenotype. The name SPA more correctly reflects the true neoplastic nature of this enigmatic lesion., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by study grant SVV 22639 from the Ministry of Education, Czech Republic and the Finnish Cancer Society, Helsinki. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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19. Renal cell tumor with sex-cord/gonadoblastoma-like features: analysis of 6 cases.
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Wang G, Amin MB, Grossmann P, Ptáková N, Hayes M, Hartmann A, Agaimy A, Lopez JI, Michal M, and Hes O
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- Adult, Aged, Aged, 80 and over, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Biomarkers, Tumor analysis, Female, Humans, Immunohistochemistry, Male, Middle Aged, Carcinoma, Renal Cell pathology, Gonadoblastoma, Kidney Neoplasms pathology, Ovarian Neoplasms
- Abstract
Renal tumors are one of the most diverse groups of tumors in pathology. Many emerging and important entities have been described recently. Here, we describe a series of renal tumors occurring in adult patients, with distinct histologic features, and with a striking resemblance to gonadal sex cord-stromal tumors. Patients were three males and three females aged 39-82 years; tumor size ranged from 0.9 to 3.6 cm. Five tumors were organ-confined, while one case had a focal perinephric invasion. No aggressive behavior was noted. Microscopically, all the tumors were composed of loose or compact tubular structures with elongated or angulated shapes. The tumor cells were cylindrical or cuboidal, with pale eosinophilic cytoplasm, irregular nuclear membranes, and ISUP/WHO grade 2-3 nuclei. The stroma showed focal or prominent collagen deposition with prominent basement membrane-like material. In all cases, the tumor cells were positive for PAX8, CD10, and vimentin and retained positivity for FH and SDHB. Cathepsin K and AMACR were variably positive. Tumors were negative for HMB45, Melan A, TFE3, SF1, inhibin, calretinin, ER, PR, CD117, OCT3/4, SALL4, ALK, and WT1. Molecular studies showed no abnormalities in TFEB, TFE3, or FH genes. In 3/4 tested cases, mutation of the NF2 gene was present. In all the tested male cases, loss of the Y chromosome was found. In the relatively short follow-up, these tumors appear to have indolent behavior. This study expands the clinicopathologic diversity of renal cell tumors by describing a series of potentially novel tumors morphologically resembling gonadal sex-stromal tumors, with negativity for sex cord-stromal markers. Potential relationship to recently described biphasic hyalinizing psammomatous renal cell carcinoma is discussed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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20. Correction to: EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers.
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Michal M, Rubin BP, Agaimy A, Kosemehmetoglu K, Rudzinski ER, Linos K, John I, Gatalica Z, Davis JL, Liu YJ, McKenney JK, Billings SD, Švajdler M, Koshyk O, Kinkor Z, Michalová K, Kalmykova AV, Yusifli Z, Ptáková N, Hájková V, Grossman P, Šteiner P, and Michal M
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- 2021
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21. Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database.
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Ptáková N, Martínek P, Holubec L, Janovský V, Vančurová J, Grossmann P, Navarro PA, Rodriguez Moreno JF, Alaghehbandan R, Hes O, Májek O, Pešek M, Michal M, and Ondič O
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Antigens, Differentiation, B-Lymphocyte genetics, Female, Histocompatibility Antigens Class II genetics, Humans, Lung Neoplasms pathology, Male, Middle Aged, Prostatic Neoplasms pathology, Syndecan-4 genetics, Tenascin genetics, Vesicle-Associated Membrane Protein 2 genetics, Adenocarcinoma genetics, Lung Neoplasms genetics, Neuregulin-1 genetics, Oncogene Proteins, Fusion genetics, Prostatic Neoplasms genetics, Receptors, Cell Surface genetics
- Abstract
The fusion genes containing neuregulin-1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost-effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data-drilling approach by performing a retrospective assessment of a de-identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA-based targeted next-generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom-designed RT-PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co-occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D-NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed., (© 2021 Wiley Periodicals LLC.)
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- 2021
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22. EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers.
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Michal M, Rubin BP, Agaimy A, Kosemehmetoglu K, Rudzinski ER, Linos K, John I, Gatalica Z, Davis JL, Liu YJ, McKenney JK, Billings SD, Švajdler M, Koshyk O, Kinkor Z, Michalová K, Kalmykova AV, Yusifli Z, Ptáková N, Hájková V, Grossman P, Šteiner P, and Michal M
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Child, Europe, Female, Gene Fusion, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Phenotype, Sarcoma chemistry, Sarcoma pathology, Sarcoma surgery, Soft Tissue Neoplasms chemistry, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms surgery, Treatment Outcome, United States, Biomarkers, Tumor genetics, Kruppel-Like Transcription Factors genetics, RNA-Binding Protein EWS genetics, Repressor Proteins genetics, Sarcoma genetics, Soft Tissue Neoplasms genetics
- Abstract
The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.
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- 2021
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23. Molecular Profiling of Clear Cell Myoepithelial Carcinoma of Salivary Glands With EWSR1 Rearrangement Identifies Frequent PLAG1 Gene Fusions But No EWSR1 Fusion Transcripts.
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Skálová A, Agaimy A, Vanecek T, Baněčková M, Laco J, Ptáková N, Šteiner P, Majewska H, Biernat W, Corcione L, Eis V, Koshyk O, Vondrák J Jr, Michal M, and Leivo I
- Subjects
- Adult, Aged, Female, Gene Expression Profiling, Gene Rearrangement, Humans, Male, Middle Aged, Oncogene Fusion, DNA-Binding Proteins genetics, Myoepithelioma genetics, RNA-Binding Protein EWS genetics, Salivary Gland Neoplasms genetics
- Abstract
Myoepithelial carcinoma of salivary glands is an underrecognized and challenging entity with a broad morphologic spectrum, including an EWSR1-rearranged clear cell variant. Myoepithelial carcinoma is generally aggressive with largely unknown genetic features. A retrospective review of Salivary Gland Tumor Registry in Pilsen searching for the key words "clear cell myoepithelial carcinoma," "hyalinizing clear cell," and "clear cell malignant myoepithelioma" yielded 94 clear cell myoepithelial carcinomas (CCMCs) for molecular analysis of EWSR1 rearrangement using fluorescence in situ hybridization (FISH). Tumors positive for EWSR1 gene rearrangement were tested by next-generation sequencing (NGS) using fusion-detecting panels. NGS results were confirmed by reverse-transcription polymerase chain reaction or by FISH. Twenty-six tumors originally diagnosed as CCMC (26/94, 27.6%) revealed split signals for EWSR1 by FISH. Six of these tumors (6/26, 23%) displayed amplification of the EWSR1 locus. Fifteen cases were analyzable by NGS, whereas 9 were not, and tissue was not available in 2 cases. None of the CCMCs with EWSR1 rearrangements detected by FISH had an EWSR1 fusion transcript. Fusion transcripts were detected in 6 cases (6/15, 40%), including LIFR-PLAG1 and CTNNB1-PLAG1, in 2 cases each, and CHCHD7-PLAG1 and EWSR1-ATF1 fusions were identified in 1 case each. Seven cases, including those with PLAG1 fusion, were positive for PLAG1 rearrangement by FISH, with notable exception of CHCHD7-PLAG1, which is an inversion not detectable by FISH. One single case with EWSR1-ATF1 fusion in NGS showed ATF1 gene rearrangement by FISH and was reclassified as clear cell carcinoma (CCC). In addition, another 4 cases revealed ATF1 rearrangement by FISH and were reclassified as CCC as well. Moreover, 12/68 (17%) CCMCs with intact EWSR1 gene were selected randomly and analyzed by NGS. PLAG1 fusions were found in 5 cases (5/12, 41.6%) with LIFR (2 cases), FGFR1 (2 cases), and CTNNB1 (1 case) as partner genes. Overall, PLAG1 gene rearrangements were detected in 10/38 (26%) tested cases. None of the tumors had SMARCB1 loss by immunohistochemistry as a possible explanation for the EWSR1 abnormalities in FISH. Novel findings in our NGS study suggest that EWSR1-FISH positive CCMC is a gene fusion-driven disease with frequent oncogenic PLAG1 fusions, including LIFR-PLAG1 and CTNNB1-PLAG1 in most cases. Productive EWSR1 fusions are found only in a minority of EWSR1-ATF1-rearranged cases, which were in part reclassifiable as CCCs. Detectable EWSR1-FISH abnormality in CCMCs without gene fusion perhaps represents a passenger mutation with minor or no oncologic effect.
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- 2021
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24. Molecular Profiling of Salivary Oncocytic Mucoepidermoid Carcinomas Helps to Resolve Differential Diagnostic Dilemma With Low-grade Oncocytic Lesions.
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Skálová A, Agaimy A, Stanowska O, Baneckova M, Ptáková N, Ardighieri L, Nicolai P, Lombardi D, Durzynska M, Corcione L, Laco J, Koshyk O, Žalud R, Michal M, Vanecek T, and Leivo I
- Subjects
- Adenoma, Oxyphilic chemistry, Adenoma, Oxyphilic pathology, Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Carcinoma, Mucoepidermoid chemistry, Carcinoma, Mucoepidermoid pathology, Diagnosis, Differential, Female, Gene Fusion, Gene Rearrangement, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Grading, Predictive Value of Tests, Retrospective Studies, Salivary Gland Neoplasms chemistry, Salivary Gland Neoplasms pathology, Transcription Factors genetics, Young Adult, Adenoma, Oxyphilic genetics, Biomarkers, Tumor genetics, Carcinoma, Mucoepidermoid genetics, Molecular Diagnostic Techniques, Salivary Gland Neoplasms genetics, Trans-Activators genetics
- Abstract
Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor," "oncocytoma," and "oncocytic carcinoma" in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.
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- 2020
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25. Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions.
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Vaňková B, Vaněček T, Ptáková N, Hájková V, Dušek M, Michal M, Švajdler P, Daum O, Daumová M, Michal M, Mezencev R, and Švajdler M
- Subjects
- Adenocarcinoma diagnosis, Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase genetics, Colorectal Neoplasms diagnosis, DNA Methylation, Female, Genetic Testing standards, High-Throughput Nucleotide Sequencing standards, Humans, Male, Middle Aged, MutL Protein Homolog 1 genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, Receptor Protein-Tyrosine Kinases genetics, Adenocarcinoma genetics, Colorectal Neoplasms genetics, Genetic Testing methods, High-Throughput Nucleotide Sequencing methods, MutL Protein Homolog 1 deficiency, Oncogene Proteins, Fusion genetics
- Abstract
Oncogenic gene fusions represent attractive targets for therapy of cancer. However, the frequency of actionable genomic rearrangements in colorectal cancer (CRC) is very low, and universal screening for these alterations seems to be impractical and costly. To address this problem, several large scale studies retrospectivelly showed that CRC with gene fusions are highly enriched in groups of tumors defined by MLH1 DNA mismatch repair protein deficiency (MLH1d), and hypermethylation of MLH1 promoter (MLH1ph), and/or the presence of microsatellite instability, and BRAF/KRAS wild-type status (BRAFwt/KRASwt). In this study, we used targeted next generation sequencing (NGS) to explore the occurence of potentially therapeutically targetable gene fusions in an unselected series of BRAFwt/KRASwt CRC cases that displayed MLH1d/MLH1ph. From the initially identified group of 173 MLH1d CRC cases, 141 cases (81.5%) displayed MLH1ph. BRAFwt/RASwt genotype was confirmed in 23 of 141 (~16%) of MLH1d/MLH1ph cases. Targeted NGS of these 23 cases identified oncogenic gene fusions in nine patients (39.1%; CI95: 20.5%-61.2%). Detected fusions involved NTRK (four cases), ALK (two cases), and BRAF genes (three cases). As a secondary outcome of NGS testing, we identified PIK3K-AKT-mTOR pathway alterations in two CRC cases, which displayed PIK3CA mutation. Altogether, 11 of 23 (~48%) MLH1d/MLH1ph/BRAFwt/RASwt tumors showed genetic alterations that could induce resistance to anti-EGFR therapy. Our study confirms that targeted NGS of MLH1d/MLH1ph and BRAFwt/RASwt CRCs could be a cost-effective strategy in detecting patients with potentially druggable oncogenic kinase fusions., (© 2020 Wiley Periodicals, Inc.)
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- 2020
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26. Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion.
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Skálová A, Banečkova M, Thompson LDR, Ptáková N, Stevens TM, Brcic L, Hyrcza M, Michal M Jr, Simpson RHW, Santana T, Michal M, Vaněček T, and Leivo I
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins c-myb genetics, Salivary Proteins and Peptides genetics, Young Adult, Mammary Analogue Secretory Carcinoma genetics, Oncogene Fusion genetics, Proto-Oncogene Proteins c-ret genetics, Salivary Gland Neoplasms genetics, Vimentin genetics
- Abstract
Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements., Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction., Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts., Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
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- 2020
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27. What is hiding behind S100 protein and SOX10 positive oncocytomas? Oncocytic pleomorphic adenoma and myoepithelioma with novel gene fusions in a subset of cases.
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Baněčková M, Uro-Coste E, Ptáková N, Šteiner P, Stanowska O, Benincasa G, Colella G, Vondrák J Jr, Michal M, Leivo I, and Skálová A
- Subjects
- Adenoma, Oxyphilic genetics, Adenoma, Pleomorphic genetics, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Myoepithelioma genetics, Oncogene Fusion, Retrospective Studies, S100 Proteins analysis, S100 Proteins biosynthesis, SOXE Transcription Factors analysis, SOXE Transcription Factors biosynthesis, Salivary Gland Neoplasms genetics, Adenoma, Oxyphilic diagnosis, Adenoma, Pleomorphic diagnosis, Biomarkers, Tumor analysis, Myoepithelioma diagnosis, Salivary Gland Neoplasms diagnosis
- Abstract
Oncocytomas (OCs) in salivary glands are rare benign tumors composed of mitochondria-rich epithelial cells (oncocytes), mostly localized in the parotid gland. The treatment of choice is simple excision. Extensive oncocytic metaplasia of pleomorphic adenoma (PA) and myoepithelioma (ME) can be diagnostically challenging and may camouflage the correct diagnosis. These tumors should be treated more carefully compared with OC, given the risk of frequent recurrences and the possibility of malignant transformation. We have investigated 89 oncocytic lesions from our files, including OC (n = 74) and metaplastic oncocytic variant of PA/ME (n = 15). All OCs were stained for S100 protein and SOX10. The tumors with immunohistochemical expression of one or both markers were tested by next-generation sequencing (NGS). The NGS results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH). Ten cases originally diagnosed as OC, and 1 low-grade uncertain oncocytic tumor (11/74) revealed nuclear-cytoplasmic and/or nuclear positivity for S100 protein and/or SOX10, respectively. Fusion transcripts CHCHD7-PLAG1 and GEM-PLAG1 were found in 2 cases (1 fusion in each), and these were confirmed by RT-PCR and PLAG1 break-apart FISH probe, respectively. Another 5 cases were positive for PLAG1 rearrangement by FISH. In the control group of 15 oncocytic PA/ME, 4/15 tested tumors harbored gene fusions including NFT3-PLAG1, CHCHD7-PLAG1, FBXO32-PLAG1, and C1orf116-PLAG1 (1 fusion in each case) as detected by NGS. Two fusions were confirmed by RT-PCR, 1 case by FISH, and 1 case was not analyzable by FISH. We additionally tested 24 OCs negative for S100 protein and SOX10 by immunohistochemistry (IHC) and by FISH for rearrangement of PLAG1 gene, but none of them were positive. SOX10 and/or S100 protein immunopositivity in conjunction with rearrangement of the PLAG1 gene assisted in reclassification of a subset of oncocytomas as oncocytic variants of PA and ME. Therefore, we recommend to include S100 protein and SOX10 IHC when diagnosing tumors with predominantly oncocytoma-like differentiation. In addition, by NGS, 3 new gene fusions were detected in oncocytic ME, including NTF3-PLAG1, FBXO32-PLAG1, and GEM-PLAG1, and a new fusion C1orf116-PLAG1 was detected in oncocytic PA., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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28. Papillary thyroid carcinoma with prominent myofibroblastic stromal component: clinicopathologic, immunohistochemical and next-generation sequencing study of seven cases.
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Suster D, Michal M, Nishino M, Piana S, Bongiovanni M, Blatnik O, Hájková V, Ptáková N, Michal M, and Suster S
- Subjects
- Adult, Aged, Biomarkers, Tumor metabolism, Female, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Myofibroblasts metabolism, Myofibroblasts pathology, PAX8 Transcription Factor genetics, PAX8 Transcription Factor metabolism, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Stromal Cells metabolism, Stromal Cells pathology, Thyroid Cancer, Papillary genetics, Thyroid Cancer, Papillary metabolism, Thyroid Gland metabolism, Thyroid Neoplasms genetics, Thyroid Neoplasms metabolism, Young Adult, beta Catenin genetics, beta Catenin metabolism, Thyroid Cancer, Papillary pathology, Thyroid Gland pathology, Thyroid Neoplasms pathology
- Abstract
Papillary thyroid carcinoma with desmoid-type fibromatosis or nodular fasciitis-like stroma is an extremely unusual and poorly understood subtype of papillary thyroid cancer. Although prior studies have demonstrated alterations in the Wnt/β-catenin signaling pathway in some of these tumors, controversy still exists regarding the nature of the stromal spindle component. We have studied seven cases of papillary thyroid carcinoma with prominent myofibroblastic stroma, including six men and one woman aged 20-65 years (mean age = 44). All cases displayed areas consistent with conventional papillary thyroid carcinoma embedded in abundant myofibroblastic-like stroma. The myofibroblastic stroma in six cases resembled desmoid-type fibromatosis and in one case it more closely resembled nodular fasciitis. By immunohistochemical staining, the stromal spindle component showed positivity for SMA and low MIB1 proliferation index in all cases, and there was at least patchy strong nuclear positivity for beta-catenin in six/seven cases. Stains for cytokeratin AE1/AE3 and PAX8 were positive in the epithelial elements but negative in the stromal component. Next-generation sequencing was performed on six of seven cases. CTNNB1 gene mutations were identified in six/seven cases. The epithelial component showed BRAF mutations in two cases and an NRAS mutation in one case. The case with fasciitis-like stroma was negative for beta-catenin by sequencing and immunostaining as well as negative for USP6 gene rearrangement. Our findings indicate that papillary thyroid carcinoma with prominent myofibroblastic stroma may represent more than one category of lesions.
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- 2020
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29. Salivary Gland Mucinous Adenocarcinoma With Minor (Mammary Analogue) Secretory and Low-Grade In Situ Carcinoma Components Sharing the Same ETV6-RET Translocation and With No Other Molecular Genetic Aberrations Detected on NGS Analysis.
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Petersson F, Michal M, Ptáková N, Skalova A, and Michal M
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- Adenocarcinoma, Mucinous metabolism, Adenocarcinoma, Mucinous pathology, Female, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Mammary Analogue Secretory Carcinoma metabolism, Mammary Analogue Secretory Carcinoma pathology, Salivary Gland Neoplasms metabolism, Salivary Gland Neoplasms pathology, Translocation, Genetic, ETS Translocation Variant 6 Protein, Adenocarcinoma, Mucinous genetics, Mammary Analogue Secretory Carcinoma genetics, Proto-Oncogene Proteins c-ets genetics, Proto-Oncogene Proteins c-ret genetics, Repressor Proteins genetics, Salivary Gland Neoplasms genetics
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- 2020
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30. ZC3H7B-BCOR high-grade endometrial stromal sarcoma may present as myoma nascens with cytoplasmic signet ring cell change.
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Ondič O, Bednářová B, Ptáková N, Hájková V, Šteiner P, Šidlová H, Presl J, Bouda J, Alaghehbandan R, and Michal M
- Subjects
- Biomarkers, Tumor genetics, Carcinoma, Signet Ring Cell diagnosis, Endometrial Neoplasms genetics, Female, Humans, Middle Aged, Proto-Oncogene Mas, Proto-Oncogene Proteins genetics, Sarcoma, Endometrial Stromal genetics, Uterine Neoplasms pathology, Carcinoma, Signet Ring Cell pathology, Endometrial Neoplasms pathology, Proto-Oncogene Proteins metabolism, RNA-Binding Proteins metabolism, Repressor Proteins metabolism, Sarcoma, Endometrial Stromal pathology
- Abstract
We report on 51-year-old woman who presented with brown discharge and postcoital bleeding due to myoma nascens-like polypoid mass distending cervical canal. Histologically, the tumor consisted of high-grade spindle cell component with up to 15 mitotic figures per 10 HPF and also low-grade leiomyoma-like areas with focal myxoid change and so far undescribed cytoplasmic signet ring cell change. Immunohistochemically Desmin, actin, and h-caldesmon were negative. Conversely, BCOR positive expression was coupled with Cyclin D1 positivity and was antibody clone dependent. The molecular NGS and FISH study identified reciprocal fusion gene ZC3H7B-BCOR. In conclusion, these findings further support the idea of routine reflex molecular testing of uterine mesenchymal tumors with unusual clinical presentation or in case malignancy is suspected. Lastly, we suggest ZC3H7B-BCOR rearranged high-grade endometrial stromal sarcoma might be considered as a tumor suitable for BCL6-targeted treatment.
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- 2020
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31. Immunohistochemical and genetic analysis of respiratory epithelial adenomatoid hamartomas and seromucinous hamartomas: are they precursor lesions to sinonasal low-grade tubulopapillary adenocarcinomas?
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Baněčková M, Michal M, Laco J, Leivo I, Ptáková N, Horáková M, Michal M, and Skálová A
- Subjects
- Adenocarcinoma chemistry, Adenocarcinoma genetics, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Child, Diagnosis, Differential, Female, Hamartoma chemistry, Hamartoma genetics, Hamartoma pathology, Humans, Male, Middle Aged, Nasal Mucosa pathology, Nasopharyngeal Diseases genetics, Nasopharyngeal Diseases metabolism, Nasopharyngeal Diseases pathology, Neoplasm Grading, Nose Diseases genetics, Nose Diseases metabolism, Nose Diseases pathology, Nose Neoplasms chemistry, Nose Neoplasms genetics, Nose Neoplasms pathology, Precancerous Conditions genetics, Precancerous Conditions metabolism, Precancerous Conditions pathology, Predictive Value of Tests, Young Adult, Adenocarcinoma diagnosis, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Hamartoma diagnosis, Immunohistochemistry, Molecular Diagnostic Techniques, Nasal Mucosa chemistry, Nasopharyngeal Diseases diagnosis, Nose Diseases diagnosis, Nose Neoplasms diagnosis, Precancerous Conditions diagnosis
- Abstract
Respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH) are rare tumor-like lesions of the nasal cavity, paranasal sinuses, and nasopharynx. The pathogenesis of REAH/SH is still unclear. Neoplastic proliferation, chronic mechanical irritation, inflammation, or possible embryological tissue misplacement are speculated as possible mechanisms of their development. Low-grade tubulopapillary adenocarcinoma (LGTA) is a rare variant of nonsalivary, nonintestinal type sinonasal adenocarcinoma. The aim of this study was to evaluate the immunohistochemical and genetic profiles of 10 cases of REAH/SH, with serous, mucinous, and respiratory components evaluated separately and to compare these findings with the features of 9 cases of LGTA. All cases of REAH/SH and LGTA were analyzed immunohistochemically with a cocktail of mucin antigens (MUC1, MUC2, MUC4, MUC5AC, MUC6) and with epithelial (CK7, CK20, CDX2, SATB2) and myoepithelial markers (S100 protein, p63, SOX10). The next-generation sequencing assay was performed using FusionPlex Solid Tumor Kit (ArcherDx) in 10 cases of REAH/SH, and the EGFR-ZNF267 gene fusion was detected in 1 of them. Two female REAH/SH cases were assessed for the presence of clonality. Using the human androgen receptor assay, 1 case was proved to be clonal. The serous component of REAH/SH was positive for CK7/MUC1 and SOX10 similarly to LGTA. Although REAH/SH and LGTA are histopathologically and clinically separate entities, the overlap in their morphological and immunohistochemical profiles suggests that REAH/SH might be a precursor lesion of LGTA., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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32. NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct?
- Author
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Skálová A, Ptáková N, Santana T, Agaimy A, Ihrler S, Uro-Coste E, Thompson LDR, Bishop JA, Baněčkova M, Rupp NJ, Morbini P, de Sanctis S, Schiavo-Lena M, Vanecek T, Michal M, and Leivo I
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Intraductal, Noninfiltrating classification, Carcinoma, Intraductal, Noninfiltrating secondary, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Invasiveness, Reverse Transcriptase Polymerase Chain Reaction, Salivary Gland Neoplasms classification, Salivary Gland Neoplasms pathology, Biomarkers, Tumor genetics, Carcinoma, Intraductal, Noninfiltrating genetics, DNA-Binding Proteins genetics, Gene Fusion, Nuclear Proteins genetics, Nuclear Receptor Coactivators genetics, Proto-Oncogene Proteins c-ret genetics, Salivary Gland Neoplasms genetics, Terminology as Topic
- Abstract
Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.
- Published
- 2019
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33. S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4-RET fusion.
- Author
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Michal M, Ptáková N, Martínek P, Gatalica Z, Kazakov DV, Michalová K, Stoláriková L, Švajdler M, and Michal M
- Subjects
- Adult, Antigens, CD34 metabolism, Dermis metabolism, Dermis pathology, Humans, Hyalin metabolism, Male, Mutation, Neurofibromin 1 genetics, Nuclear Receptor Coactivators metabolism, Proto-Oncogene Proteins c-ret metabolism, S100 Proteins metabolism, Soft Tissue Neoplasms pathology, Antigens, CD34 genetics, Nuclear Receptor Coactivators genetics, Oncogene Fusion, Proto-Oncogene Proteins c-ret genetics, S100 Proteins genetics, Soft Tissue Neoplasms genetics
- Abstract
We report a case of a 35-year old male patient with a tumor located in the deep dermis on his forearm. The lesion was completely excised but recurred 4 years later. The patient showed no signs of neurofibromatosis type 1. The morphology and immunophenotype of the tumor corresponded to the recently characterized group of soft tissue spindle cell lesions defined by a relatively uniform cytomorphology, patternless architecture, conspicuous stromal and perivascular hyalinization, S100 and CD34 coexpression and recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Using a 592-gene panel and massively parallel next-generation sequencing platform, we initially detected only NF1 gene mutation in our case. However, further molecular testing with Archer fusion assay revealed a novel NCOA4-RET gene fusion, adding it to the list of multiple kinase fusions originally reported in these tumors. Although break-apart FISH showed false negative result due to the presence of intrachromosomal rearrangement, RT-PCR confirmed the fusion transcript. Knowing the exact fusion is of great clinical importance especially for patients within the aggressive subset of these neoplasms that could be treated with selective kinase inhibitors. The presented case underscores the benefits of massively parallel sequencing as the types and number of gene fusions these tumors can potentially harbor render single-gene assays such as FISH impractical, and in this particular case, also insensitive., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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34. Inflammatory myofibroblastic tumor of the uterus - case report.
- Author
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Štiková Z, Ptáková N, Horáková M, Kosťun J, and Ondič O
- Subjects
- Aged, Biomarkers, Tumor, Female, Humans, Immunohistochemistry, Neoplasm Recurrence, Local, Protein Phosphatase 1, Leiomyosarcoma, Uterine Neoplasms
- Abstract
Inflammatory myofibroblastic tumor (IMT) of the uterus is rare but probably underdiagnosed tumor. It is usually benign but small fraction of cases may locally recur or rarely metastasize. Herein, we present a case report of 66-year-old patient with uterine IMT originally diagnosed as leiomyosarcoma of the uterus. The patient died within few months due to local tumor progression with skeletal metastases. Macroscopically, this was a voluminous locally aggressive yellowish-grey tumor of soft consistency limited to myometrium. Microscopically, the tumor was characterized by polymorphic spindle cell proliferation with marked nuclear atypia and numerous mitoses. Small geographic necroses was noticed. Typical histologic features of IMT were represented by lymphocytic infiltrate which was only very small and focal. Myxoid stroma was absent. Immunohistochemically, there was strong and diffuse cytoplasmic positivity of ALK (anaplastic lymphoma kinase). The presence of PPP1CB-ALK fusion transcript was confirmed by molecular-genetic methods. Proper diagnosis of uterine IMT is of importance as there is an option of targeted ALK inhibitor therapy in cases of aggressive tumor behaviour. Currently it is thought that histomorphology of uterine IMT may overlap with that of leiomyosarcoma and STUMP (smooth muscle tumor of uncertain malignant potential). The presence of ALK rearrangement is probably the only reliable diagnostic marker. Thus, ALK immunohistochemistry followed by molecular-genetic testing seems to represent suitable screening tool for the detection of uterine IMT.
- Published
- 2019
35. Fibro-osseous pseudotumor of digits and myositis ossificans show consistent COL1A1-USP6 rearrangement: a clinicopathological and genetic study of 27 cases.
- Author
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Švajdler M, Michal M, Martínek P, Ptáková N, Kinkor Z, Szépe P, Švajdler P, Mezencev R, and Michal M
- Subjects
- Adult, Bone Diseases genetics, Child, Child, Preschool, Collagen Type I, alpha 1 Chain, Diagnosis, Differential, Extremities, Fasciitis genetics, Fasciitis pathology, Female, Fibroblasts pathology, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Musculoskeletal Diseases pathology, Myositis Ossificans pathology, Collagen Type I genetics, Gene Rearrangement genetics, Musculoskeletal Diseases genetics, Myositis Ossificans genetics, Ubiquitin Thiolesterase genetics
- Abstract
Myositis ossificans (MO) and fibro-osseous pseudotumor of digits (FOPD) are localized, self-limiting bone-producing pseudosarcomatous lesions characterized by nodular fasciitis-like proliferation and osteoid and immature woven bone production, which may eventually develop into more mature lamellar bone. Traditionally, MO and FOPD were thought to be of reactive, non-neoplastic nature. USP6 gene rearrangement was recently reported as a consistent finding in MO and FOPD, thus expanding the spectrum of transient, USP6-rearranged neoplasms. COL1A1 was described as the fusion partner of USP6 in a subset of MO cases, but the fusion partners of USP6-rearranged FOPD have not been uncovered so far. Initially, we carefully reviewed all 27 cases of MO/FOPD from our archives, documenting the remarkable morphological overlap between both lesions. Sixteen cases were seen in consultation, and our review was requested to rule in or rule out tentative diagnoses by referring pathologists. Malignant diagnosis (osteosarcoma) was suggested by the submitting pathologists in 3 cases, whereas 7 cases were sent by the referring pathologists to "rule out sarcoma." In the following step, using next-generation sequencing, we confirmed the COL1A1-USP6 rearrangement in 5/7 cases of MO and found the same abnormality in 4/5 of FOPD. Overall, 9 of the 12 analyzable cases (75%) of MO and FOPD harbored this gene fusion. The presence of COL1A1-USP6 gene rearrangement in MO/FOPD links these lesions to other USP6-driven tumors and represents a very useful supportive marker, which may help to avoid overdiagnosis of MO/FOPD as a sarcoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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36. Immunohistochemical and selected genetic reflex testing of all uterine leiomyosarcomas and STUMPs for ALK gene rearrangement may provide an effective screening tool in identifying uterine ALK-rearranged mesenchymal tumors.
- Author
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Ptáková N, Miesbauerová M, Kosťun J, Grossmann P, Šidlová H, Pavelka J, Presl J, Alaghehbandan R, Bouda J, and Ondič O
- Subjects
- Anaplastic Lymphoma Kinase, Biomarkers, Tumor metabolism, Female, Humans, Immunohistochemistry, Leiomyosarcoma diagnosis, Leiomyosarcoma metabolism, Receptor Protein-Tyrosine Kinases metabolism, Retrospective Studies, Smooth Muscle Tumor diagnosis, Smooth Muscle Tumor metabolism, Uterine Neoplasms diagnosis, Uterine Neoplasms metabolism, Biomarkers, Tumor genetics, Gene Rearrangement, Genetic Testing methods, Leiomyosarcoma genetics, Receptor Protein-Tyrosine Kinases genetics, Smooth Muscle Tumor genetics, Uterine Neoplasms genetics
- Abstract
We examined the value of targeted molecular screening for the identification of uterine anaplastic lymphoma kinase (ALK)-rearranged mesenchymal tumors, including ALK immunohistochemistry followed by molecular genetic testing, in all uterine leiomyosarcomas and STUMPs (smooth muscle tumors of uncertain malignant potential). All leiomyosarcoma and STUMP cases diagnosed in a 10-year period (2006-2016) at Charles University Faculty of Medicine in Pilsen were retrieved and reviewed. Of 23 cases, one case (LMS [leiomyosarcoma]) was positive for ALK rearrangement, namely, PPP1CB-ALK fusion gene. No specific histologic features (i.e., lymphocytic infiltrate and stromal edema) were observed in this case. This suggests that inflammatory myofibroblastic tumor (IMT)-like histologic features may not be an initial reliable screening tool in identifying uterine IMT cases. Thus, we proposed a two-step IHC and molecular genetic testing (as a reflex test) for IMT in all uterine LMS and STUMP cases. This will enhance the proper detection of such tumors at the population level and ultimately offer patients available targeted therapies.
- Published
- 2018
- Full Text
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37. Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions: A Report of 17 cases.
- Author
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Skálová A, Vanecek T, Uro-Coste E, Bishop JA, Weinreb I, Thompson LDR, de Sanctis S, Schiavo-Lena M, Laco J, Badoual C, Santana Conceiçao T, Ptáková N, Baněčkova M, Miesbauerová M, and Michal M
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Carcinoma, Intraductal, Noninfiltrating chemistry, Carcinoma, Intraductal, Noninfiltrating pathology, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Middle Aged, Phenotype, Registries, Reverse Transcriptase Polymerase Chain Reaction, Salivary Gland Neoplasms chemistry, Salivary Gland Neoplasms pathology, Transcriptome, Biomarkers, Tumor genetics, Carcinoma, Intraductal, Noninfiltrating genetics, DNA-Binding Proteins genetics, Gene Expression Profiling instrumentation, Gene Fusion, Nuclear Proteins genetics, Nuclear Receptor Coactivators genetics, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-ret genetics, Salivary Gland Neoplasms genetics
- Abstract
Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.
- Published
- 2018
- Full Text
- View/download PDF
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