Pan-tropomyosin receptor kinase immunoreactivity, ETV6-NTRK3 fusion subtypes, and RET rearrangement in salivary secretory carcinoma

Yamamoto, Hidetaka; Sugii, Azusa; Taguchi, Kenichi; Hongo, Takahiro; Jiromaru, Rina; Sato, Masanobu; Nakano, Tomoko; Hashimoto, Kazuki; Fujiwara, Minako

doi:10.1016/j.humpath.2020.11.017

Cited by 10 publications

(23 citation statements)

References 30 publications

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“…In this phase, 2 case reports 23,24 were excluded and finally, 13 articles were included for quantitative synthesis (Figure 1). 7,8,[12][13][14][15][16][17][18][19][20][21][22] 3.1 | Methodological characteristics of the studies Data extracted from all 13 studies including details on the country of origin, authors, total number, and histopathological type of SGTs and pattern of pan-TRK IHC manifestation are provided in Tables S1 & 1.…”

Section: Resultsmentioning

confidence: 99%

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Diagnostic accuracy of pan‐TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland—A systematic review

Sharma

Sivakumar

Pandiar

2022

J Oral Pathology Medicine

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Background Secretory carcinoma (SC) is a well‐established salivary gland malignancy that has earned its popularity for its unique clinicopathological behavior. Although it is an indolent malignancy, few of them have been reported with high grade transformation making it mandatory to differentiate it from its prime histological mimicker, acinic cell carcinoma (AciCC). Recently, many studies have been directed toward validating the sensitivity and specificity of pan‐TRK IHC for confirming ETV6::NTRK3 gene fusion in SCs involving salivary gland. Aim The aim of the present systematic review was to establish the diagnostic utility of pan‐TRK immunostaining in histological differentiation of SC from AciCC. Material and methods An electronic search was carried out using MEDLINE by PubMed, Scopus, Google scholar, Trip, Cochrane library and EMBASE databases. Articles in which SC assessed with pan‐TRK immunohistochemical expressions were included for systematic review and their staining pattern (cytoplasmic, nuclear and/or combined), sensitivity, specificity, positive as well as negative predictive were gathered. Risk of bias was analyzed for each study using QUADAS‐2 tool. Results Thirteen eligible articles were included for the quantitative analysis, which revealed positive immunostaining of pan‐TRK by nearly all the ETV6::NTRK3 fusion prevalent SCs alongside negative expression in almost all the cases of AciCC with 100% of sensitivity as well as specificity. Conclusion The evidence from the included studies supports that pan‐TRK immunostaining could be used as a reliable preliminary screening tool for discerning SC from AciCC. PROSPERO No: CRD42022308913.

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Section: Resultsmentioning

confidence: 99%

“…The included studies were conducted between 2017 and 2022, in more than 5 different countries: 4 in the USA, 7,12-14 2 in France, 16,18 3 in Japan, 8,15,21 2 in China 19,20 1 in Taiwan, 22 and 1 was multicentric. 17 A total of 623 different SGTs including 255 SCs and 82 AciCCs were identified.…”

Section: Resultsmentioning

confidence: 99%

Diagnostic accuracy of pan‐TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland—A systematic review

Sharma

Sivakumar

Pandiar

2022

J Oral Pathology Medicine

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“…The fusion transcript joined exon 6 of ETV6 gene and exon 12 of RET gene, consistent with the literature. 6 To our knowledge, only 26 cases of SC 6,10,[25][26][27][28] were reported to harbor ETV6::RET in the English literature so far. The two patients in our study both suffered multiple relapses, regional lymph node metastasis, and distal metastasis, then one lived with disease at the latest follow-up (49 months from initial surgery) and the other one underwent disease-related death at 307 months after initial surgery.…”

Section: Discussionmentioning

confidence: 95%

Atypical/unbalanced ETV6/NTRK3 rearrangement in salivary secretory carcinoma with a focus on the incidence, the patterns, and the clinical implications

Sun

Tian

et al. 2022

J Oral Pathology Medicine

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Background: Atypical/unbalanced rearrangement in salivary secretory carcinoma was observed and its incidence, patterns, and clinical significance remain unknown.Methods: One hundred and ninety-six cases of diagnosed secretory carcinoma were retrospectively reviewed. Fluorescence in situ hybridization for NTRK3/ ETV6::NTRK3 was conducted on cases carrying the atypical ETV6 fluorescence in situ hybridization signals. Cases without ETV6::NTRK3 were selected for nextgeneration sequencing to reveal novel partner. Immunohistochemistry and follow-up were performed.Results: Twenty-seven cases were confirmed to carry the atypical ETV6 fluorescence in situ hybridization signal patterns. The most common type of abnormality was the duplication of ETV6 5 0 end (1Y1GnR, n ≥ 2) with the incidence of 81.5% (22/27). Seventeen of 19 were identified with ETV6::NTRK3 and 2 with ETV6::RET. The immunophenotype was similar to the typical secretory carcinoma group. TrkC exhibited 68.8% sensitivity and 100% specificity for NTRK3 fusion. Microscopically, 5 out of 21 were accompanied by necrosis and 3 out of 21 showed neural invasion. Four out of 19 patients showed local relapse, 2 developed distant metastasis, and 1 died of disease. The patients with distant metastasis and even dead were both harbored ETV6::RET rearrangement. Statistical analysis revealed that there were no significant differences in disease-free survival, relapse-free survival, and distant metastasis-free survival between atypical and typical groups.Conclusion: Gene rearrangement can be identified although the fluorescence in situ hybridization signals were atypical, which was instructive for secretory carcinoma diagnosis in clinical practice. The signals of partners were also always atypical which may have an impact to the efficacy of targeted drugs. There was no statistical evidence that this group possessed worse prognosis. However, secretory carcinomas with ETV6::RET have dismal prognosis than those with ETV6::NTRK3.Jingjing Sun and Jiang Li contributed equally to this study.

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“…Our series does not contain these tumor types, but we did identify four salivary gland secretory carcinomas. Two of these presented with the commonly detected ETS transcription factor variant 6-NTRK3 fusion [40][41][42][43][44], which was accompanied by weak to strong cytoplasmic pan-TRK immunoreactivity. The remaining two salivary gland secretory carcinomas harbored an NTRK1 rearrangement with the interferon regulatory factor 2-binding protein 2 gene as a fusion partner.…”

Section: Discussionmentioning

confidence: 99%

The Use of Pan-Tropomyosin Receptor Kinase Immunohistochemistry as a Screening Tool for the Detection of Neurotrophic Tropomyosin-Related Kinase Fusions: Real-World Data from a National Multicentric Retrospective Study

et al. 2022

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Introduction: The neurotrophic tropomyosin-related kinase (NTRK) genes encode the tropomyosin receptor kinases (TRKs). Patients with solid tumors harboring an oncogenic NTRK fusion are eligible for treatment with TRK inhibitors. NTRK fusion is often associated with TRK overexpression. Pan-TRK immunohistochemistry (IHC) is used to screen for NTRK fusions, but immunoreactivity patterns are poorly defined. Methods: Data on pan-TRK immunoreactivity patterns in 2,669 solid tumors (comprising carcinomas, sarcomas, and melanocytic lesions) were retrospectively collected by nine laboratories and comprised tumor type, percentage of pan-TRK-positive tumor cells, staining intensity, cytoplasmic, membrane and/or nuclear staining pattern, and the presence or absence of NTRK fusion. Results: Overall, 2,457 tumors (92%) were pan-TRK negative and 212 neoplasms (8%) were pan-TRK positive. Twenty-two pan-TRK-positive tumors (0.8%) harbored an NTRK fusion, representing 10% of all pan-TRK-positive tumors. Cytoplasmic immunoreactivity was most often observed, followed by membrane immunoreactivity. Nuclear pan-TRK positivity was least frequent, but was most often (33%) associated with NTRK fusion. Conclusion: Pan-TRK IHC can be used to screen for NTRK fusions, especially in commonly diagnosed solid tumors with low NTRK fusion prevalence. In case of pan-TRK immunoreactivity, regardless of its intensity and tumor cell percentage, subsequent molecular tests should be performed to formally confirm the presence or absence of NTRK fusions.

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Pan-tropomyosin receptor kinase immunoreactivity, ETV6-NTRK3 fusion subtypes, and RET rearrangement in salivary secretory carcinoma

Cited by 10 publications

References 30 publications

Diagnostic accuracy of pan‐TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland—A systematic review

Diagnostic accuracy of pan‐TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland—A systematic review

Atypical/unbalanced ETV6/NTRK3 rearrangement in salivary secretory carcinoma with a focus on the incidence, the patterns, and the clinical implications

The Use of Pan-Tropomyosin Receptor Kinase Immunohistochemistry as a Screening Tool for the Detection of Neurotrophic Tropomyosin-Related Kinase Fusions: Real-World Data from a National Multicentric Retrospective Study

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