<i>NTRK</i>‐rearranged spindle cell neoplasms are ubiquitous tumours of myofibroblastic lineage with a distinct methylation class

Tauziède‐Espariat, Arnault; Duchesne, Mathilde; Baud, Jessica; Quang, Mégane Le; Bochaton, Dorian; Azmani, Rihab; Croce, Sabrina; Hostein, Isabelle; Kesrouani, Carole; Guillemot, Delphine; Bourdeaut, Franck; Cardoen, Liesbeth; Hasty, Lauren; Lechapt, Emmanuèle; Métais, Alice; Chrétien, Fabrice; Puget, Stéphanie; Varlet, Pascale; Loarer, François Le

doi:10.1111/his.14842

Cited by 17 publications

(15 citation statements)

References 54 publications

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“…Immunohistochemical positivity for S100 and CD34 is frequently found among all these tumors as well, and fusion partners seem to be shared by most 30,31 . Most importantly, a study, including soft tissue, viscera, and central nervous system NTRK -rearranged tumors of adults and children, demonstrated a similar methylation pattern by unsupervised t-distributed stochastic neighbor embedding analysis, ultrastructural features resembling a myofibroblastic lineage, and they grouped together by hierarchical clustering of RNA-sequencing data 32 . This strengthens their association as a single entity, or at least a family of closely related tumor types, rather than multiple entities with similar genetic drivers altering the tyrosine kinase signaling network.…”

Section: Discussionmentioning

confidence: 94%

Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions

de Castro,

dos Santos,

Mantoan

et al. 2023

International Journal of Gynecological Pathology

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NTRK gene fusions are part of a paradigm shift in oncology, arising as one of the main genomic alterations with actionability in the so-called “agnostic setting.” In gynecologic pathology, the recent description of uterine sarcoma resembling fibrosarcoma and with NTRK rearrangements (NTRK-rearranged uterine sarcoma) highlights the importance of recognizing clinicopathological cues that can lead to genomic profiling. Herein, we report the case of a 43-year-old woman presenting with vaginal bleeding and pelvic mass. Histopathology of the tumor showed moderately atypical spindle cells arranged in long fascicles reminiscent of fibrosarcoma, along with immunohistochemical positivity for S100, CD34, and pan-tropomyosin receptor kinase. This prompted RNA-sequencing and the finding of a rare EML4::NTRK3 fusion. Clinical, histologic, and molecular findings are described, in addition to discussions regarding differential diagnoses and possible implications of the findings in clinical practice.

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Section: Discussionmentioning

confidence: 94%

Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions

de Castro,

dos Santos,

Mantoan

et al. 2023

International Journal of Gynecological Pathology

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“…Total RNA was extracted from FFPE material and sequenced with the Truseq RNA exome Kit (Illumina, San Diego, USA) as previously described 4 . The sequencing reads were aligned and analyzed as previously described 5 …”

Section: Methodsmentioning

confidence: 99%

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

Lethongsavarn,

Vieille,

Kikweta Makhama

et al. 2023

Genes Chromosomes & Cancer

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DICER1‐mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1‐mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous‐like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer‐like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous‐like tubes were negative for SALL4 and Inhibin. Whole RNA‐ and targeted DNA‐sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1‐mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous‐like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1‐mutated sarcomas and devise specific therapeutic strategies.

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“…RNA sequencing was performed using the Archer FusionPlex Sarcoma panel and the Illumina TruSeq RNA Exome Library Prep Kit, as previously described. 15,16…”

Section: Methodsmentioning

confidence: 99%

“…All tumours exhibiting any immunohistochemical expression of pan‐TRK were subjected to molecular confirmation of NTRK fusion status by RNA sequencing and/ or FISH. RNA sequencing was performed using the Archer FusionPlex Sarcoma panel and the Illumina TruSeq RNA Exome Library Prep Kit, as previously described 15,16 …”

Section: Methodsmentioning

confidence: 99%

Pan‐TRK immunohistochemistry in gynaecological mesenchymal tumours: diagnostic implications and pitfalls

Moura,

Costa,

Velasco

et al. 2023

Histopathology

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AimsNTRK‐rearranged sarcomas of the female genital tract mainly occur in the uterus (more commonly cervix than corpus) and are characterized by a “fibrosarcoma‐like” morphology and NTRK gene rearrangements. These neoplasms may exhibit histological overlap with other entities and can present diagnostic difficulties without molecular confirmation. Pan‐TRK immunohistochemistry was developed to identify tumours harbouring NTRK rearrangements. The aim of this study was to characterize pan‐TRK immunohistochemical expression in a large cohort of gynaecological mesenchymal neoplasms and investigate the utility of pan‐TRK immunohistochemistry to distinguish NTRK‐rearranged sarcoma from its mimics.Methods and resultsA total of 473 gynaecological mesenchymal tumours (461 without known NTRK fusions and 12 NTRK‐rearranged sarcomas) were selected. Pan‐TRK immunohistochemistry (EPR17341, Abcam) was performed on whole tissue sections and tissue microarrays. Molecular interrogation of pan‐TRK positive tumours was performed by RNA sequencing or fluorescence in situ hybridization (FISH). Of the 12 NTRK‐rearranged sarcomas, 11 (92%) exhibited diffuse (≥70%) cytoplasmic pan‐TRK staining with moderate/marked intensity, while the other was negative. Eleven (2.4%) additional tumours also exhibited pan‐TRK immunohistochemical expression: three low‐grade endometrial stromal sarcomas, seven high‐grade endometrial stromal sarcomas, and an undifferentiated uterine sarcoma. Molecular confirmation of the absence of NTRK rearrangements was possible in nine of these tumours. Of these nine neoplasms, seven exhibited focal/multifocal (<70%) pan‐TRK cytoplasmic staining with weak/moderate intensity.ConclusionEven though pan‐TRK immunohistochemical expression is not entirely sensitive or specific for NTRK‐rearranged sarcomas, these neoplasms tend to exhibit diffuse staining of moderate/strong intensity, unlike its mimics. Pan‐TRK should be performed in monomorphic uterine (corpus and cervix) spindle cell neoplasms that are negative for smooth muscle markers and hormone receptors and positive for CD34 and/ or S100. Ultimately, the diagnosis requires molecular confirmation.

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NTRK‐rearranged spindle cell neoplasms are ubiquitous tumours of myofibroblastic lineage with a distinct methylation class

Abstract: all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.

Cited by 17 publications

References 54 publications

Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions

Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

Pan‐TRK immunohistochemistry in gynaecological mesenchymal tumours: diagnostic implications and pitfalls

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