Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Church, Alanna J.; Calicchio, Monica L.; Nardi, Valentina; Skálová, Alena; Pinto, André; Dillon, Deborah; Gomez‐Fernandez, Carmen; Manoj, Namitha; Haimes, Josh; Stahl, Joshua A; Cruz, Filemon S. Dela; Tannenbaum-Dvir, Sarah; Bender, Julia Glade; Kung, Andrew L.; DuBois, Steven G.; Kozakewich, Harry P.; Janeway, Katherine A.; Perez‐Atayde, Antonio R.; Harris, Marian H.

doi:10.1038/modpathol.2017.127

Cited by 133 publications

(131 citation statements)

References 38 publications

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“…Although pan‐TRK immunohistochemistry may serve as a useful adjunct in the screening and confirmation of NTRK alterations, one should be aware of its strengths and limitations: pan‐TRK immunohistochemistry may represent an alternative strategy to and complementary strategy for detecting NTRK1 / 2 / 3 rearrangements. In infantile fibrosarcoma and cellular mesoblastic nephroma, fluorescence in‐situ hybridisation for ETV6 rearrangement is not entirely sensitive, as a small subset of tumours (those with EML4 – NTRK3 fusion) would be missed with the ETV6 ‐targeted method . It is of note that all secretory carcinomas described to date are expected to be positive for ETV6 rearrangement; however, in addition to NTRK3 , RET has been described as an alternative fusion partner for ETV6 .…”

Section: Discussionmentioning

confidence: 99%

“…In infantile fibrosarcoma and cellular mesoblastic nephroma, fluorescence in-situ hybridisation for ETV6 rearrangement is not entirely sensitive, as a small subset of tumours (those with EML4-NTRK3 fusion) would be missed with the ETV6-targeted method. 39 It is of note that all secretory carcinomas described to date are expected to be positive for ETV6 rearrangement; however, in addition to NTRK3, RET has been described as an alternative fusion partner for ETV6. 12 As expected, the metastatic secretory carcinoma with confirmed ETV6-RET fusion in our study was negative for pan-TRK.…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Hung

Jo²,

Hornick³

2019

Histopathology

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Aims Secretory carcinoma (previously known as mammary analogue secretory carcinoma) is characterised by ETV6 rearrangements, most often ETV6–NTRK3 fusion. Given its histological overlap with other salivary gland tumours, secretory carcinoma can be difficult to diagnose without genetic confirmation. A recently developed pan‐TRK antibody shows promise for identifying tumours with NTRK fusions. The aim of this study was to evaluate the utility of pan‐TRK immunohistochemistry in distinguishing secretory carcinoma from mimics. Methods and results We examined whole‐tissue sections from 86 tumours, including 14 secretory carcinomas (12 parotid primaries and one buccal primary, and one metastasis; five with ETV6 rearrangement confirmed by fluorescence in‐situ hybridisation, and one with ETV6–NTRK3 fusion and one with ETV6–RET fusion detected by targeted sequencing), 14 acinic cell carcinomas, 18 polymorphous adenocarcinomas, 20 low‐grade mucoepidermoid carcinomas, and 20 pleomorphic adenomas. Immunohistochemistry was performed with a pan‐TRK rabbit monoclonal antibody. Pan‐TRK staining was detected in nine (64%) secretory carcinomas, all with a nuclear pattern and four with diffuse staining (>50% of cells). Among other tumour types, pan‐TRK immunoreactivity was observed in all (100%) pleomorphic adenomas (particularly myoepithelial cell‐rich, myxoid areas), 15 (83%) polymorphous adenocarcinomas, and four (20%) low‐grade mucoepidermoid carcinomas, all with predominantly membranous/cytoplasmic immunoreactivity; only six cases showed focal (<10%) nuclear staining. All acinic cell carcinomas were entirely negative. Conclusions Although pan‐TRK expression is not entirely sensitive or specific for secretory carcinoma, nuclear staining distinguishes secretory carcinoma from mimics. Acinic cell carcinomas are negative for pan‐TRK, though membranous expression of TRK is common in other salivary gland neoplasms. The lack of pan‐TRK immunoreactivity in a subset of secretory carcinomas may suggest non‐NTRK fusion partners.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Hung

Jo²,

Hornick³

2019

Histopathology

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“…Compared to translocation‐negative variants of congenital mesoblastic nephroma with classic or mixed histology, the cellular variant with ETV6–NTRK3 fusion carries a far better prognosis in terms of relapse free and overall survival . Some of the genetic alterations found in pediatric IFS‐like sarcomas have also been described in subsets of CMN, including EML4–NTRK3 , LMNA–NTRK1 , and BRAF intragenic deletions, providing further evidence that IFS and CMN are histogenetically related entities.…”

Section: Pediatric Mesenchymal Tumors Driven By Recurrent Kinase Fusionsmentioning

confidence: 90%

New advances in the molecular classification of pediatric mesenchymal tumors

Suurmeijer

Kao

Antonescu

2018

Genes Chromosomes & Cancer

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Pediatric soft tissue tumors are relatively rare and show significant overlap in morphology and immunoprofile, often posing diagnostic and management challenges. Thus, their classification remains often subjective or lumped under "unclassified categories," as a number of lesions lack objective and reproducible criteria in diagnosis. Although in a subset of cases immunohistochemistry has been proved useful to identify a specific line of differentiation, most tumors lack a readily defined histogenesis, being characterized by a rather non-specific immunoprofile. Furthermore, tumors with an ambiguous diagnosis are difficult to grade and their risk of malignancy or clinical management remains uncertain. Advances in molecular genetics, including the more wide application of next generation sequencing in routine clinical practice, have improved diagnosis and refined classification based on objective molecular markers. Importantly, some soft tissue tumors in children are characterized by recurrent gene fusions involving either growth factors (eg, PDGFB) or protein kinases (eg, ALK, ROS, NTRK, BRAF), which have paved the way for new targeted treatments that block the respective upregulated downstream pathways. However, the majority of gene fusions or mutations detected in soft tissue tumors result in an abnormal function of transcription factors or chromatin remodeling. The present review focuses on the latest genetic discoveries in the spectrum of both benign and malignant pediatric soft tissue neoplasia. These genetic abnormalities promise to provide relevant insight for their proper classification, prognosis, and treatment. The entities discussed herein are grouped either based on their shared genetic mechanism or based on their presumed line of differentiation.

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“…The cellular variant has similarities with congenital infantile fibrosarcoma and both are characterized by a t (12;15) (p13;q25) translocation resulting in a fusion of ETV6 and NTRK3 . However, variant TRK fusions have been identified and reported . This has important implications for testing strategies in these tumors, as negative result for ETV6 – NTRK3 fusion does not rule out other TRK fusions.…”

Section: Discussionmentioning

confidence: 99%

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

Halalsheh

McCarville

Neel

et al. 2018

Pediatric Blood & Cancer

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Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib.

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Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Cited by 133 publications

References 38 publications

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

New advances in the molecular classification of pediatric mesenchymal tumors

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

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