Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC)

Chu, Ying-Hsia; Dias‐Santagata, Dora; Farahani, Alexander; Boyraz, Barış; Faquin, William C.; Nosé, Vânia; Sadow, Peter M.

doi:10.1038/s41379-020-0574-4

Cited by 85 publications

(105 citation statements)

References 30 publications

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“…In contrast, the phenotype of NTRK ‐rearranged PTC is only recently beginning to be appreciated. In a few published studies, including one from our own institution, 21 the most commonly reported PTC subtype was the follicular variant followed by the solid PTC, 17,21‐24 although the classic variant of PTC has been reported 19,30 . Our study is consistent with the literature in that most of our cases (92%) were classified as follicular or solid PTC.…”

Section: Discussionsupporting

confidence: 89%

“…In thyroid, NTRK1 and NTRK3 rearrangements have been reported in well‐ and poorly differentiated PTCs with a high positive predictive value 9,23 . NTRK3 is the most frequently rearranged gene, with ETV6 as the most common fusion partner, followed by the fusion of NTRK1 (1q23) with nuclear pore complex‐associated protein ( TPR ; 1q31) or tropomyosin 3 ( TPM3 ;1q21) 21‐25 . Both NTRK1 and NTRK3 fusions are of great interest in thyroid carcinomas; NTRK fusions are clinically targetable oncogenic drivers and usually mutually exclusive of other driver mutations 26 .…”

Section: Introductionmentioning

confidence: 99%

“…The advent of selective TRK inhibitors such as larotrectinib and entrectinib showing a significant efficacy in treating advanced tumors with NTRK fusions, regardless of tumor site of origin or NTRK fusion type, has sparked great interest in NTRK genetic testing in solid tumors 3,26,27 . In addition, NTRK fusion testing might have an added prognostication value, since some studies have suggested that NTRK ‐rearranged PTCs might have more aggressive pathological features such as large, infiltrative, multifocal tumors with gross extrathyroidal extension (ETE), extensive lymphovascular invasion (LVI), and frequent nodal metastasis 21,24,28,29 . Advanced stage at presentation is common, including distant metastasis 29,30 .…”

Section: Introductionmentioning

confidence: 99%

“…It is therefore of utmost importance to suspect this molecular alteration to suggest molecular testing. There are few reports describing the histopathologic features of NTRK ‐rearranged PTCs, 19,21,24,30 but cytomorphologic features in fine‐needle aspiration (FNA) specimens have not yet been described. Suspecting NTRK ‐rearranged PTCs in FNA specimens would be important to avoid misdiagnosis and appropriately guide ancillary testing to triage patients for appropriate clinical management.…”

Section: Introductionmentioning

confidence: 99%

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Fine‐needle aspiration cytomorphology of papillary thyroid carcinoma with NTRK gene rearrangement from a case series with predominantly indeterminate cytology

Abi‐Raad

Prasad

Adeniran

et al. 2020

Cancer Cytopathology

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Background Neurotrophic tyrosine kinase receptor (NTRK) rearrangement has been reported in a subset of papillary thyroid carcinoma (PTC) cases. Little is known about the cytomorphologic features of NTRK‐rearranged PTC. Methods We report an institutional series of 13 fine‐needle aspiration (FNA) specimens of NTRK‐rearranged PTC with a predominantly indeterminate cytology diagnosis. NTRK3 or NTRK1 rearrangements were detected on FNA or surgical specimens by next‐generation sequencing. Results The 13 patients had a median age of 18 years; 10 patients were female and 3 patients were male. In 10 (77%) cases, cytology was indeterminate, and histopathologic follow‐up was predominantly the follicular variant of PTC (n = 8 [62%]), mostly infiltrative subtype. Of 12 FNA specimens available for review, a predominant loosely cohesive group pattern was the most commonly encountered architectural pattern (n = 5 [41%]), followed by single cell (n = 3 [25%]), thick cord (n = 2 [17%]), and microfollicular pattern (n = 2 [17%]). Background lymphocytic thyroiditis was observed in 9 cases. At the cellular level, the cytoplasm was moderate and granular, occasionally vacuolated. Classic PTC nuclear features (eg, nuclear enlargement, elongation, grooves, and nuclear membrane irregularity) were present but were often focal and subtle. Chromatin was often granular. Intranuclear pseudoinclusions were absent or rare. Conclusion Our study demonstrates that most cases of NTRK rearrangement lack classic PTC cytomorphologic characteristics. Loosely cohesive groups and single cells with granular, sometimes vacuolated cytoplasm and subtle nuclear features are often seen on FNA specimens. Recognizing these characteristics may be helpful to preoperatively prompt molecular testing, including NTRK rearrangement analysis.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fine‐needle aspiration cytomorphology of papillary thyroid carcinoma with NTRK gene rearrangement from a case series with predominantly indeterminate cytology

Abi‐Raad

Prasad

Adeniran

et al. 2020

Cancer Cytopathology

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“…The presence of NTRK fusions in thyroid cancers in adults is variable. These tumors are characterized by multinodular growth, extensive lymphovascular invasion, and lymph node metastasis 25 …”

Section: Figurementioning

confidence: 99%

Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

Ruíz-Cordero¹,

Ng²

2020

Cancer Cytopathology

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Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas

et al. 2023

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ImportanceThyroid epithelial malignant neoplasms include differentiated thyroid carcinomas (papillary, follicular, and oncocytic), follicular-derived high-grade thyroid carcinomas, and anaplastic and medullary thyroid carcinomas, with additional rarer subtypes. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has fostered developments in precision oncology, with the approval of tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for patients with solid tumors, including advanced thyroid carcinomas, harboring NTRK gene fusions.ObservationsThe relative rarity and diagnostic complexity of NTRK gene fusion events in thyroid carcinoma present several challenges for clinicians, including variable access to robust methodologies for comprehensive NTRK fusion testing and poorly defined algorithms of when to test for such molecular alterations. To address these issues in thyroid carcinoma, 3 consensus meetings of expert oncologists and pathologists were convened to discuss diagnostic challenges and propose a rational diagnostic algorithm. Per the proposed diagnostic algorithm, NTRK gene fusion testing should be considered as part of the initial workup for patients with unresectable, advanced, or high-risk disease as well as following the development of radioiodine-refractory or metastatic disease; testing by DNA or RNA next-generation sequencing is recommended. Detecting the presence of NTRK gene fusions is important to identify patients eligible to receive tropomyosin receptor kinase inhibitor therapy.Conclusions and RelevanceThis review provides practical guidance for optimal integration of gene fusion testing, including NTRK gene fusion testing, to inform the clinical management in patients with thyroid carcinoma.

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Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC)

Cited by 85 publications

References 30 publications

Fine‐needle aspiration cytomorphology of papillary thyroid carcinoma with NTRK gene rearrangement from a case series with predominantly indeterminate cytology

Fine‐needle aspiration cytomorphology of papillary thyroid carcinoma with NTRK gene rearrangement from a case series with predominantly indeterminate cytology

Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas

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