ALK-Testung beim nicht-kleinzelligen Lungenkarzinom (NSCLC): Immunhistochemie (IHC) und/oder Fluoreszenz-in-situ-Hybridisierung (FISH)?^[*]

Zusammenfassung

EML4-ALK-Translokationen spielen eine wichtige Rolle in der Pathogenese des nicht-kleinzelligen Lungenkarzinoms. Die Identifizierung der Translokation und die Einleitung einer zielgerichteten Therapie gegen den alterierten EML4-Alk-Signalweg ist von zentraler Bedeutung für die Patienten. Die zielgerichtete Therapie ist mit einem signifikanten progressionsfreien- und Überlebensvorteil vergesellschaftet. Eine frühe Diagnosesicherung ist unabdingbar. Der Nachweis der EML4-ALK-Translokationen wurde bisher vornehmlich mittels FISH-Technik durchgeführt. Die Untersuchungsmethode zeichnet sich durch einen nicht unerheblichen Untersuchungsaufwand aus. Immunhistochemische Nachweise der Translokationen spielen in Zukunft eine größere Rolle im diagnostischen Algorithmus. Das vorliegende Positionspapier stellt die aktuellen Empfehlungen zur Qualität und Sequenz der EML4-ALK-Testung, basierend auf der aktuellen Literatur, dar.

Abstract

The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as tyrosine kinase inhibitors directed against the EML4-ALK signalling pathway lead to improved progression free and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify the patients in time. While FISH techniques have been implemented to characterize this translocation for some time, the implementation of this testing is hampered by its broad use of resources. Immunohistochemical techniques to identify and screen for EML4-ALK translocations may play an important role in the near future. This consensus paper offers recommendations of the sequence and quality of the respective test approaches which are validated on the basis of the current literature.

^* Diese Stellungnahme erscheint ebenfalls in der Zeitschrift „Der Pathologe“, Springer Verlag, DOI: 10.1007/s00292-016-0152-1

• Literatur

• 1 Lindeman NI, Cagle PT, Beasley MB et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 2013; 137: 828-860
• 2 Thunnissen E, Bubendorf L, Dietel M et al. Consensus statement on testing for EML4-ALK in non-small-cell carcinomas of the lung. Virch Arch 2012; 461: 245-257
• 3 Kerr KM, Bubendorf L, Edelman MJ et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 2014; 25: 1681-1690
• 4 Sebastian M, Niederle N, Thomas M et al. Molekulargenetische Untersuchungen bei fortgeschrittenem nicht-kleinzelligem Lungenkarzinom: praktische Relevanz. Dtsch Med Wochenschr 2014; 139: 2096-2100
• 5 Shaw AT, Yeap BY, Solomon BJ et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011; 12: 1004-1012
• 6 Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363: 1693-1703
• 7 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm
• 8 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002489/WC500134761.pdf
• 9 Yi ES, Boland JM, Maleszewski JJ et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 2011; 6: 459-465
• 10 von Laffert M, Warth A, Penzel R et al. Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC): Results of a multi-centre ALK-testing. Lung Cancer 2013; 81: 200-206
• 11 Blackhall FH, Peters S, Bubendorf L et al. Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project. J Clin Oncol 2014; 32: 2780-2787
• 12 von Laffert M, Warth A, Penzel R et al. Multicenter Immunohistochemical ALK-Testing of Non-Small-Cell Lung Cancer Shows High Concordance after Harmonization of Techniques and Interpretation Criteria. J Thorac Oncol 2014; 9: 1685-1692
• 13 Nitta H, Tsuta K, Yoshida A et al. New methods for ALK status diagnosis in non-small-cell lung cancer: an improved ALK immunohistochemical assay and a new, Brightfield, dual ALK IHC-in situ hybridization assay. J Thorac Oncol 2013; 8: 1019-1031
• 14 Wynes MW, Sholl LM, Dietel M et al. An international interpretation study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators. J Thorac Oncol 2014; 9: 631-638
• 15 Ilie MI, Bence C, Hofman V et al. Discrepancies between FISH and immunohistochemistry for assessment of the ALK status are associated with ALK ‘borderline’-positive rearrangements or a high copy number: a potential major issue for anti-ALK therapeutic strategies. Ann Oncol 2015; 26: 238-244
• 16 Ilie M, Hofman P. Reply to the letter to the editor “ALK FISH rearranged and amplified tumor with negative immunohistochemistry: a rare and challenging case concerning ALK status screening in lung cancer” by Uguen et al. Ann Oncol 2015; 26: 1802
• 17 Savic S, Diebold J, Zimmermann AK et al. Screening for ALK in non-small cell lung carcinomas: 5A4 and D5F3 antibodies perform equally well, but combined use with FISH is recommended. Lung Cancer 2015; 89: 104-109
• 18 Sholl LM, Weremowicz S, Gray SW et al. Combined Use of ALK Immunohistochemistry and FISH for Optimal Detection of ALK-Rearranged Lung Adenocarcinomas. J Thorac Oncol 2013; 8: 322-328
• 19 Minca EC, Portier BP, Wang Z et al. ALK status testing in non-small cell lung carcinoma: correlation between ultrasensitive IHC and FISH. J Mol Diagn 2013; 15: 341-346
• 20 Hutarew G, Hauser-Kronberger C, Strasser F et al. Immunohistochemistry as a screening tool for ALK rearrangement in NSCLC: evaluation of five different ALK antibody clones and ALK FISH. Histopathology 2014; 65: 398-407
• 21 Cutz JC, Craddock KJ, Torlakovic E et al. Canadian anaplastic lymphoma kinase study: a model for multicenter standardization and optimization of ALK testing in lung cancer. J Thorac Oncol 2014; 9: 1255-1263
• 22 Gruber K, Kohlhäufl M, Friedel G et al. A novel, highly sensitive ALK antibody 1A4 facilitates effective screening for ALK rearrangements in lung adenocarcinomas by standard immunohistochemistry. J Thorac Oncol 2015; 10: 713-716
• 23 Peled N, Palmer G, Hirsch FR et al. Next-Generation Sequencing Identifies and Immunohistochemistry Confirms a Novel Crizotinib-Sensitive ALK Rearrangemnet in a Patient with Metastatic Non-Small-Cell Lung Cancer. J Thorac Oncol 2012; 7: e14-e16
• 24 Ren S, Hirsch FR, Varella-Garcia M et al. Atypical negative ALK break-apart FISH harboring a crizotinib-responsive ALK rearrangement in non-small-cell lung cancer. J Thorac Oncol 2014; 9: e21-e23
• 25 Pekar-Zlotin M, Hirsch FR, Soussan-Gutman L et al. Fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. Oncologist 2015; 20: 316-322
• 26 McLeer-Florin A, Lantuéjoul S. Why technical aspects rather than biology explain cellular heterogeneity in ALK-positive non-small cell lung cancer. J Thorac Dis 2012; 4: 240-241
• 27 von Laffert M, Stenzinger A, Hummel M et al. ALK-FISH Borderline Cases in Non-Small Cell Lung Cancer: Implications for Diagnostics and Clinical Decision Making. Lung Cancer 23.10.2015; pii: S0169-5002(15)30066-0. [Epub ahead of print].
• 28 Kawahara A, Azuma K, Taira T et al. Heterogeneity of anaplastic lymphoma kinase gene rearrangement in non-small-cell lung carcinomas: a comparative study between small biopsy and excision samples. J Thorac Oncol 2015; 10: 800-805
• 29 Cabillic F, Gros A, Dugay F et al. Parallel FISH and immunohistochemical studies of ALK status in 3244 non-small-cell lung cancers reveal major discordances. J Thorac Oncol 2014; 9: 295-306
• 30 Jung Y, Kim P, Jung Y et al. Discovery of ALK-PTPN3 gene fusion from human non-small cell lung carcinoma cell line using next generation RNA sequencing. Genes Chromosomes Cancer 2012; 51: 590-597
• 31 Alì G, Proietti A, Pelliccioni S et al. ALK rearrangement in a large series of consecutive non-small cell lung cancers: comparison between a new immunohistochemical approach and fluorescence in situ hybridization for the screening of patients eligible for crizotinib treatment. Arch Pathol Lab Med 2014; 138: 1449-1458
• 32 Gao X, Sholl LM, Nishino M et al. Clinical Implications of Variant ALK FISH Rearrangement Patterns. J Thorac Oncol 2015; 10: 1648-1652
• 33 Pfarr N, Stenzinger A, Penzel R et al. High-throughput diagnostic profiling of clinically actionable gene fusions in lung cancer. Genes Chromosomes Cancer 2015; [Epub ahead of print]
• 34 Selinger CI, Rogers TM, Russell PA et al. Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol 2013; 26: 1545-1553
• 35 Conde E, Suárez-Gauthier A, Benito A et al. Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry. PLoS One 2014; 9: e107200