RET, NTRK, ALK, BRAF, and MET Fusions in a Large Cohort of Pediatric Papillary Thyroid Carcinomas

Pekova, Barbora; Sýkorová, Vlasta; Dvořáková, Šárka; Václavíková, Eliška; Moravcová, Jitka; Katra, Rami; Astl, Jaromı́r; Vlček, Petr; Kodetová, Daniela; Včelák, Josef; Bendlová, Běla

doi:10.1089/thy.2019.0802

Cited by 115 publications

(115 citation statements)

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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%

“…NTRK fusions are encountered in 2 categories of tumors; at a high frequency in some rare cancers such as secretory carcinoma of the salivary gland, secretory breast carcinoma, congenital mesoblastic nephroma, and infantile fibrosarcoma, 4‐8 and at a lower frequency in more common cancers, including thyroid cancer 9‐18 . However, NTRK fusions are found at a higher frequency in certain PTC populations, reaching as high as 26% in pediatric PTC patients and 10% to 15% in postradiation PTC patients 17,19‐22 …”

Section: Introductionmentioning

confidence: 99%

“…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%

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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%

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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 frequency of these fusions in our cohort was 2.3%, similar to that in previous reports [3,4]. Although higher frequency (18.3-25.9%) of NTRK1/3 rearrangements had been observed in the pediatric group [23,27], there was no significant difference in age at diagnosis between NTRK1/ 3-rearranged and BRAF V600E -negative non-NTRK1/3 PTC in our study cohort. This could be partly attributed to that the patient population at our hospital is mainly adult.…”

Section: Discussionsupporting

confidence: 88%

“…PTC was included in only two of studies with a limited number of cases [19,20]. On the other hand, although the histological features of PTC with NTRK gene fusions, especially with an ETV6-NTRK3 fusion, have been reported in previous studies [21][22][23][24][25][26][27], comprehensive morphologic comparison between NTRK-rearranged and non-NTRK PTC has not been systemically investigated. This study aimed to examine the frequency of NTRK1/3 rearrangements in a Taiwanese cohort of PTC, to further characterize the clinicopathological features of PTC with NTRK fusions, and to validate the sensitivity and specificity of pan-TRK immunohistochemistry as a screening tool.…”

Section: Introductionmentioning

confidence: 99%

Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing

et al. 2020

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NTRK1/3 rearrangements have been reported in 2.3-3.4% of papillary thyroid carcinoma (PTC) and are regarded as potential therapeutic targets. Recently, the application of immunohistochemistry (IHC) to detect NTRK rearrangements has been widely discussed. The current study aimed to characterize the clinicopathological features of PTC with NTRK1/3 fusions, to examine the utility of pan-TRK IHC, and to compare IHC with fluorescent in situ hybridization (FISH) and next-generation sequencing (NGS). In a cohort of 525 consecutive PTC cases, 60 BRAF V600E-negative cases underwent complete analyses of FISH, and 12 (2.3%) cases with NTRK1/3 break-apart were found. A novel ERC1-NTRK3 fusion was identified by NGS in one case. Pathological features of non-infiltrative tumor border, clear cell change, and reduced nuclear elongation and irregularity were significantly more common in NTRK1/3-rearranged PTC when compared with 48 BRAF V600E-negative non-NTRK1/3 PTC cases. In whole tissue sections, pan-TRK IHC was positive in 3/7 (42.9%) cases with an ETV6-NTRK3 rearrangement including 2 cases with low percentage of stained tumor cells, 2/3 (66.7%) with non-ETV6 NTRK3 rearrangements, and 2/2 (100%) with NTRK1 rearrangements. All FISH-negative cases were negative for pan-TRK in tissue microarray sections. As a result, pan-TRK IHC showed a sensitivity of 58.3% and specificity of 100% for NTRK1/3 rearrangements in BRAF V600E-negative PTC. In conclusion, NTRK1/3-rearranged PTC shared some unique morphologic features. Pan-TRK IHC showed high specificity and moderate sensitivity for NTRK1/3-rearranged PTC and should be interpreted with caution due to staining heterogeneity. Based on the above findings, we propose an algorithm integrating morphology, IHC, and molecular testing to detect NTRK1/3 rearrangements in PTC.

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Thyroid Cancer

Boucai,

Zafereo,

Cabanillas

2024

JAMA

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ImportanceApproximately 43 720 new cases of thyroid carcinoma are expected to be diagnosed in 2023 in the US. Five-year relative survival is approximately 98.5%. This review summarizes current evidence regarding pathophysiology, diagnosis, and management of early-stage and advanced thyroid cancer.ObservationsPapillary thyroid cancer accounts for approximately 84% of all thyroid cancers. Papillary, follicular (≈4%), and oncocytic (≈2%) forms arise from thyroid follicular cells and are termed well-differentiated thyroid cancer. Aggressive forms of follicular cell-derived thyroid cancer are poorly differentiated thyroid cancer (≈5%) and anaplastic thyroid cancer (≈1%). Medullary thyroid cancer (≈4%) arises from parafollicular C cells. Most cases of well-differentiated thyroid cancer are asymptomatic and detected during physical examination or incidentally found on diagnostic imaging studies. For microcarcinomas (≤1 cm), observation without surgical resection can be considered. For tumors larger than 1 cm with or without lymph node metastases, surgery with or without radioactive iodine is curative in most cases. Surgical resection is the preferred approach for patients with recurrent locoregional disease. For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma.ConclusionsApproximately 44 000 new cases of thyroid cancer are diagnosed each year in the US, with a 5-year relative survival of 98.5%. Surgery is curative in most cases of well-differentiated thyroid cancer. Radioactive iodine treatment after surgery improves overall survival in patients at high risk of recurrence. Antiangiogenic multikinase inhibitors and targeted therapies to genetic mutations that give rise to thyroid cancer are increasingly used in the treatment of metastatic disease.

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RET, NTRK, ALK, BRAF, and MET Fusions in a Large Cohort of Pediatric Papillary Thyroid Carcinomas

Cited by 115 publications

References 46 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

Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing

Thyroid Cancer

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