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
Van Bockstal, Mieke R.; Beniuga, Gabriela; Craciun, Ligiaet al.
2022 • In Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology, 89 (6), p. 393 - 406
Humans; Immunohistochemistry; Neoplasms; Receptor, trkA; Retrospective Studies; Sarcoma; Tropomyosin; Pathology and Forensic Medicine; Molecular Biology; Cell Biology; General Medicine
Abstract :
[en] 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.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Van Bockstal, Mieke R. ; Department of Pathology, Cliniques Universitaires Saint-Luc (CUSL), Woluwe-Saint-Lambert, Brussels, Belgium ; Institute of Clinical and Experimental Research (IREC), Universite Catholique de Louvain, Brussels, Belgium
Beniuga, Gabriela; Institut de Pathologie et de Genetique (IPG), Charleroi, Belgium
Craciun, Ligia; Department of Pathology, Institut Jules Bordet, Brussels, Belgium
Creytens, David; Department of Pathology, Ghent University Hospital (UZG), Ghent University, Ghent, Belgium ; Cancer Research Institute Ghent, CRIG, Ghent University Hospital, Ghent University, Ghent, Belgium
Dedeurwaerdere, Franceska ; Department of Pathology, AZ Delta, Roeselare, Belgium
Delvenne, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Demetter, Pieter; Department of Pathology, Institut Jules Bordet, Brussels, Belgium
De Wiest, Bart; Department of Pathology, Onze-Lieve-Vrouwziekenhuis (OLV) Aalst, Aalst, Belgium
Dewinne, Koen ; Department of Pathology, Antwerp University Hospital (UZA), Edegem, Belgium
Habran, Lionel ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Pauwels, Patrick ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique ; Department of Pathology, Antwerp University Hospital (UZA), Edegem, Belgium
Theate, Ivan; Institut de Pathologie et de Genetique (IPG), Charleroi, Belgium
Vander Borght, Sara; Department of Pathology, University Hospitals Leuven (UZL), Leuven, Belgium
Van Der Steen, Kris; Department of Pathology, Onze-Lieve-Vrouwziekenhuis (OLV) Aalst, Aalst, Belgium
Weynand, Birgit ; Department of Pathology, University Hospitals Leuven (UZL), Leuven, Belgium
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
Publication date :
December 2022
Journal title :
Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology
Penault-Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol. 2019; 72 (7): 460-7. http://dx.doi.org/10.1136/jclinpath-2018-205679.
Marchio C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M,. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019; 30 (9): 1417-27.
Weiss LM, Funari VA. NTRK fusions and Trk proteins: what are they and how to test for them. Hum Pathol. 2021; 112: 59-69. http://dx.doi.org/10.1016/j.humpath.2021.03.007.
Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018; 15 (12): 731. http://dx.doi.org/10.1038/s41571-018-0113-0.
Solomon JP, Benayed R, Hechtman JF, Ladanyi M. Identifying patients with NTRK fusion cancer. Ann Oncol. 2019; 30 (8): VIII16-22. http://dx.doi.org/10.1093/annonc/mdz384.
Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM,. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018; 19 (5): 705-14.
Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS,. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020; 21 (4): 531-40.
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD,. Efficacy of larotrectinib in TRK fusion: positive cancers in adults and children. N Engl J Med. 2018; 378 (8): 731-9.
Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF,. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020; 21 (2): 271-82.
Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M,. Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer. J Thorac Oncol. 2015; 10 (12): 1670-4.
Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol. 2019; 30 (8): VIII23-30. http://dx.doi.org/10.1093/annonc/mdz282.
Lezcano C, Shoushtari AN, Ariyan C, Hollmann TJ, Busam KJ. Primary and metastatic melanoma with NTRK fusions. Am J Surg Pathol. 2018; 42 (8): 1052-8. http://dx.doi.org/10.1097/PAS.0000000000001070.
Arnold A, Daum S, von Winterfeld M, Berg E, Hummel M, Horst D,. Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry. Pathol Res Pract. 2019; 215 (11): 152662.
Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol. 2019; 32 (1): 147-53. http://dx.doi.org/10.1038/s41379-018-0118-3.
Bocciarelli C, Caumont C, Samaison L, Cariou M, Aline-Fardin A, Doucet L,. MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories. Hum Pathol. 2021; 114: 99-109.
Sholl LM, Zheng M, Nardi V, Hornick JL. Predictive "biomarker piggybacking": an examination of reflexive pan-cancer screening with pan-TRK immunohistochemistry. Histopathology. 2021; 79 (2): 260-4.
Elfving H, Broström E, Moens LNJ, Almlöf J, Cerjan D, Lauter G,. Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer. Lung Cancer. 2021; 151: 53-9.
Lee YC, Chen JY, Huang CJ, Chen HS, Yang AH, Hang JF. Detection of NTRK1/3 rearrangements in papillary thyroid carcinoma using immunohistochemistry, fluorescent in situ hybridization, and next-generation sequencing. Endocr Pathol. 2020; 31 (4): 348-58. http://dx.doi.org/10.1007/s12022-020-09648-9.
Yamamoto H, Nozaki Y, Kohashi K, Kinoshita I, Oda Y. Diagnostic utility of pan-Trk immunohistochemistry for inflammatory myofibroblastic tumours. Histopathology. 2020; 76 (5): 774-8. http://dx.doi.org/10.1111/his.14010.
Rudzinski ER, Lockwood CM, Stohr BA, Vargas SO, Sheridan R, Black JO,. Pan-Trk immunohistochemistry identifies ntrk rearrangements in pediatric mesenchymal tumors. Am J Surg Pathol. 2018; 42 (7): 927-35.
Remoue A, Conan-Charlet V, Bourhis A, Flahec GL, Lambros L, Marcorelles P,. Non-secretory breast carcinomas lack NTRK rearrangements and TRK protein expression. Pathol Int. 2019; 69 (2): 94-6.
Hung YP, Fletcher CDM, Hornick JL. Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics. Histopathology. 2018; 73 (4): 634-44. http://dx.doi.org/10.1111/his.13666.
Croce S, Hostein I, Longacre TA, Mills AM, Perot G, Devouassoux-Shisheboran M,. Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms. Mod Pathol. 2019; 32 (7): 1008-22.
Conde E, Hernandez S, Sanchez E, Regojo RM, Camacho C, Alonso M,. Pan-TRK immunohistochemistry. Arch Pathol Lab Med. 2021; 145 (8): 1031-40.
Siozopoulou V, Smits E, De Winne K, Marcq E, Pauwels P. NTRK fusions in sarcomas: diagnostic challenges and clinical aspects. Diagnostics. 2021; 11 (3): 478. http://dx.doi.org/10.3390/diagnostics11030478.
Solomon JP, Linkov I, Rosado A, Mullaney K, Rosen EY, Frosina D,. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol. 2020; 33 (1): 38-46.
Wong DD, Vargas AC, Bonar F, Maclean F, Kattampallil J, Stewart C,. NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm. Pathology. 2020; 52 (4): 401-9.
Berrino E, Bragoni A, Annaratone L, Fenocchio E, Carnevale-Schianca F, Garetto L,. Pursuit of gene fusions in daily practice: evidence from real-world data in wild-type and microsatellite instable patients. Cancers. 2021 Jul; 13 (13): 3376.
Hospital Erasme. Loi relative aux experimentations sur la personne humaine. Monit Belge. 2004;(7): 39516.
De Winne K, Sorber L, Lambin S, Siozopoulou V, Beniuga G, Dedeurwaerdere F,. Immunohistochemistry as a screening tool for NTRK gene fusions: results of a first Belgian ring trial. Virchows Arch. 2021; 478 (2): 283-91.
Vanden Bempt I, Vander Borght S, Sciot R, Spans L, Claerhout S, Brems H,. Comprehensive targeted next-generation sequencing approach in the molecular diagnosis of gastrointestinal stromal tumor. Genes Chromosom Cancer. 2021; 60 (4): 239-49.
Rosen EY, Goldman DA, Hechtman JF, Benayed R, Schram AM, Cocco E,. TRK fusions are enriched in cancers with uncommon histologies and the absence of canonical driver mutations. Clin Cancer Res. 2020; 26 (7): 1624-32.
Hechtman JF, Benayed R, Hyman DM, Drilon A, Zehir A, Frosina D,. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017; 41 (11): 1547-51.
Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998; 18 (2): 184-7. http://dx.doi.org/10.1038/ng0298-184.
Sheng WQ, Hisaoka M, Okamoto S, Tanaka A, Meis-Kindblom JM, Kindblom LG,. Congenital-infantile fibrosarcoma: a clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol. 2001; 115 (3): 348-55.
Davis JL, Lockwood CM, Stohr B, Boecking C, Al-Ibraheemi A, Dubois SG,. Expanding the spectrum of pediatric NTRK-rearranged mesenchymal tumors. Am J Surg Pathol. 2019; 43 (4): 435-45.
Anderson WJ, Hornick JL. Immunohistochemical correlates of recurrent genetic alterations in sarcomas. Genes Chromosomes Cancer. 2019; 58 (2): 111-23. http://dx.doi.org/10.1002/gcc.22700.
Zhao M, Yin M, Kuick CH, Chen H, Aw SJ, Merchant K,. Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6-NTRK3 fusion, and the rare KLHL7-BRAF fusion. Histopathology. 2020; 77 (4): 611-21.
Harrison BT, Fowler E, Krings G, Chen Y, Bean GR, Vincent-salomon A,. Pan-TRK immunohistochemistry: a useful diagnostic adjunct for secretory carcinoma of the breast. Am J Surg Pathol. 2019; 43 (12): 1693-700.
Bell D, Ferrarotto R, Liang L, Goepfert RP, Li J, Ning J,. Pan-Trk immunohistochemistry reliably identifies ETV6-NTRK3 fusion in secretory carcinoma of the salivary gland. Virchows Arch. 2020; 476 (2): 295-305.
Hung YP, Jo VY, Hornick JL. Immunohistochemistry with a pan-TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma. Histopathology. 2019; 75 (1): 54-62. http://dx.doi.org/10.1111/his.13845.
Yamamoto H, Nozaki Y, Sugii A, Taguchi K, Hongo T, Jiromaru R,. Pan-tropomyosin receptor kinase immunoreactivity, ETV6-NTRK3 fusion subtypes, and RET rearrangement in salivary secretory carcinoma. Hum Pathol. 2021; 109: 37-44.
Csanyi-Bastien M, Lanic MD, Beaussire L, Ferric S, François A, Meseure D,. Pan-TRK immunohistochemistry is highly correlated with NTRK3 gene rearrangements in salivary gland tumors. Am J Surg Pathol. 2021; 45 (11): 1487-98.
Xu B, Haroon Al Rasheed MR, Antonescu CR, Alex D, Frosina D, Ghossein R,. Pan-Trk immunohistochemistry is a sensitive and specific ancillary tool for diagnosing secretory carcinoma of the salivary gland and detecting ETV6-NTRK3 fusion. Histopathology. 2020; 76 (3): 375-82.
Brčic I, Godschachner TM, Bergovec M, Igrec J, Till H, Lackner H,. Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions. Mod Pathol. 2021; 34 (2): 396-407.
Zhao X, Kotch C, Fox E, Surrey LF, Wertheim GB, Baloch ZW,. NTRK fusions identified in pediatric tumors: the frequency, fusion partners, and clinical outcome. JCO Precis Oncol. 2021 Jan; 1: 20.
Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon A,. NTRK3 kinase fusions in Spitz tumours. J Pathol. 2016 Nov; 240 (3): 282.
Vandenboom T, Quan VL, Zhang B, Garfield EM, Kong BY, Isales MC,. Genomic fusions in pigmented spindle cell nevus of reed. Am J Surg Pathol. 2018; 42 (8): 1042-51.
Yeh I, Busam KJ, McCalmont TH, LeBoit PE, Pissaloux D, Alberti L,. Filigree-like rete ridges, lobulated nests, rosette-like structures, and exaggerated maturation characterize spitz tumors with NTRK1 fusion. Am J Surg Pathol. 2019; 43 (6): 737-46.
Strohmeier S, Brcic I, Popper H, Liegl-Atzwanger B, Lindenmann J, Brcic L. Applicability of pan-TRK immunohistochemistry for identification of NTRK fusions in lung carcinoma. Sci Rep. 2021; 11 (1): 9785-7. http://dx.doi.org/10.1038/s41598-021-89373-3.
Zhao R, Yao F, Xiang C, Zhao J, Shang Z, Guo L,. Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population. J Pathol Clin Res. 2021; 7 (4): 375-84.
Cocco E, Benhamida J, Middha S, Zehir A, Mullaney K, Shia J,. Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions. Cancer Res. 2019; 79 (6): 1047-53.
Chou A, Fraser T, Ahadi M, Fuchs T, Sioson L, Clarkson A,. NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas: a study of 4,569 cases. Mod Pathol. 2020; 33 (5): 924-32.
Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Tejpar S, Sartore-Bianchi A,. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst. 2017 Dec; 109 (12.