NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm

Wong, Daniel; Vargas, Ana Cristina; Bonar, Fiona; Maclean, Fiona; Kattampallil, Joseph; Stewart, Colin J.R.; Sulaiman, Ban; Santos, Leonardo D.; Gill, Anthony J.

doi:10.1016/j.pathol.2020.02.004

Cited by 41 publications

(50 citation statements)

References 34 publications

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“…According to a recent review of TRK fusion-positive mesenchymal tumours, the morphological characteristics indicative of a higher probability of harbouring an NTRK gene fusion were inflammatory myofibroblastic tumour-like, fibrosarcoma/malignant peripheral nerve sheath tumour-like, or lipofibromatosis-like morphological patterns, particularly if combined with S100 and CD34 co-expression [ 92 ].…”

Section: Soft Tissue Sarcomamentioning

confidence: 99%

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

et al. 2021

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The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.

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Section: Soft Tissue Sarcomamentioning

confidence: 99%

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

et al. 2021

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“…With the increasing use of RNA‐sequencing, NTRK fusions are increasingly being recognized in mesenchymal tumors including new entities such as lipofibromatosis‐like neural tumor, spindle cell sarcomas with hemangiopericytic or myopericytoma‐like pattern, spindle cell tumor with S100 and CD34 co‐expression resembling malignant peripheral nerve sheath tumor (MPNST), and soft tissue tumors with inflammatory myofibroblastic tumor‐like and fibrosarcoma‐like morphologies 33,34 . In the majority of reported cases, NTRK fusions are associated with Trk protein expression detectable by immunohistochemistry (pan‐Trk, TrkA, B, C); these are useful surrogate markers of NTRK fusions with a sensitivity ranging from 75‐100% 35 and a specificity from 93% 11 to 100% 36,37 …”

Section: Ntrk Fusion Uterine Sarcomamentioning

confidence: 99%

“…In 2018, Chiang et al first reported NTRK fusions in four uterine sarcomas, three of them located in the cervix 11 . Including the initial four cases described by Chiang et al, there have been a total of 19 NTRK fusion associated uterine sarcomas reported and their clinicopathological, immunohistochemical and molecular characteristics are summarized in Table 1 12,34,35,39‐42 . Some of the tumors reported by Croce et al 12 were included in the original paper by Mills et al 38…”

Section: Ntrk Fusion Uterine Sarcomamentioning

confidence: 99%

NTRK and other recently described kinase fusion positive uterine sarcomas: A review of a group of rare neoplasms

Croce

Hostein

McCluggage

2020

Genes Chromosomes & Cancer

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The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high‐grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of “new” entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1‐PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a “fibrosarcoma‐like” appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm.

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“…Tumours harbouring recurrent oncogenic genetic fusions or ITDs typically have a relatively clean genomic background with a simple karyotype, and these include low-grade endometrial stromal sarcomas (LGESSs) (JAZF1-SUZ12 and JAZF1-PHF1), 1,2 high-grade endometrial stromal sarcomas (HGESSs) (YWHAE-NUTM2A/B, ZC3H7B-BCOR, and BCOR ITD), [3][4][5][6][7][8][9][10] inflammatory myofibroblastic tumours (IMTs) (ALK fusion), [11][12][13] and NTRK1/ 2/3-fusion-associated uterine sarcomas. [14][15][16][17][18][19] In contrast, uterine leiomyosarcomas (LMSs) and undifferentiated uterine sarcomas (UUSs) (mostly of the pleomorphic type) frequently show a degree of structural aberration and/or copy number variation across their genomes, and typically do not harbour recurrent genetic fusions/ITDs. [20][21][22] TP53 mutations, as demonstrated by sequencing and/or by p53 immunohistochemistry, are present in the majority of these tumours.…”

Section: Introductionmentioning

confidence: 99%

p53 immunohistochemical analysis of fusion‐positive uterine sarcomas

et al. 2021

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p53 immunohistochemical analysis of fusion-positive uterine sarcomas Aims: Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas. Methods and results: We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/ rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression. Conclusion: p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours.

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NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm

Cited by 41 publications

References 34 publications

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

NTRK and other recently described kinase fusion positive uterine sarcomas: A review of a group of rare neoplasms

p53 immunohistochemical analysis of fusion‐positive uterine sarcomas

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