Diagnose und prädiktive Analysen an zytologischen und bioptischen Tumorproben nicht-kleinzelliger Lungenkarzinome: Aktuelle Strategien und Herausforderungen

Zusammenfassung

Personalisierte Medizin wird zunehmend zum Standard in der Behandlung des fortgeschrittenen nicht-kleinzelligen Lungenkarzinoms. Tumorspezifische Therapien auf Basis von Biomarkeranalysen, z. B. dem Nachweis von EGFR Mutationen oder Translokationen des ALK-Genlokus, übertreffen die undifferenziert eingesetzte Kombinationschemotherapie hinsichtlich des klinischen Ansprechens und des progressionsfreien Überlebens deutlich. Der Nachweis prädiktiver molekularer Alterationen erfordert jedoch eine hohe Kompetenz im Umgang mit Zell- und Gewebeproben. Eine Herausforderung ist hierbei häufig die meist geringe Menge an verfügbarem Untersuchungsmaterial, an welchem sowohl eine spezifische Tumorsubtypisierung als auch ergänzende Biomarkeranalysen durchgeführt werden müssen. Aktuell gibt es nur wenige standardisierte und evidenzbasierte Empfehlungen bezüglich der Probengewinnung, der Materialprozessierung, der Analyse und der Befundung. Entsprechende qualitätsoptimierte Verfahren erfordern eine fachübergreifende Zusammenarbeit, um klinische und pathologische Aspekte gleichermaßen zu berücksichtigen. Um hierfür eine Basis zu schaffen, wurden unterschiedliche Verfahren, Methoden und Protokolle interdisziplinär diskutiert und bewertet. Ein Schwerpunkt lag hierbei neben den unterschiedlichen Verfahren der zytologischen und bioptischen Probengewinnung in der Prozessierung des Materials, um den gestiegenen Anforderungen an Diagnostik und Prädiktion gerecht zu werden. Die dargestellten Einflussgrößen der Probengewinnung und -aufarbeitung sind unter dem Aspekt einer qualitativ hochwertigen und standardisierten Diagnostik von wachsender Bedeutung in der multidisziplinären, zunehmend komplexer werdenden Betreuung von Lungenkrebspatienten.

Abstract

Personalised medicine is becoming the standard care for advanced non-small cell lung cancer. Tumour-specific therapies based on biomarker analyses, e. g., EGFR mutations or translocations of the ALK gene locus, result in a superior patient outcome compared to unselected therapy approaches. However, predictive molecular analyses can be challenging and require significant experience with cell- and tissue-based diagnostic methods. The major challenge relates to the sometimes low amount of available tumour material for both diagnostic and predictive analyses. As yet, there are no standardised or evidence-based recommendations concerning biopsies, specimen processing, and analyses. Respective guidelines require combined interdisciplinary actions to consider both clinical and pathological aspects. In order to establish a basis for high quality procedures, different approaches, methods, and protocols were interdisciplinary discussed with an emphasis on cytological specimens. Detailed evaluation of the parameters and consented recommendations might contribute to optimised strategies in the interdisciplinary, more and more complex care of non-small cell lung cancer patients.

• Literatur

• 1 Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90
• 2 Warth A, Muley T, Meister M et al. The novel histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival. J Clin Oncol 2012; 30: 1438-1446
• 3 Warth A, Muley T, Herpel E et al. Large-scale comparative analyses of immunomarkers for diagnostic subtyping of non-small-cell lung cancer biopsies. Histopathology 2012; 61: 1017-1025
• 4 Mok TS. Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol 2011; 8: 661-668
• 5 Penzel R, Schirmacher P, Warth A. A Novel EML4-ALK Variant: Exon 6 of EML4 Fused to Exon 19 of ALK. J Thorac Oncol 2012; 7: 1198-1199
• 6 Warth A, Macher-Goeppinger S, Muley T et al. Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy. Eur Respir J 2012; 39: 1437-1442
• 7 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
• 8 Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957
• 9 Soda M, Choi YL, Enomoto M et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561-566
• 10 Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239-246
• 11 Penzel R, Sers C, Chen Y et al. EGFR mutation detection in NSCLC--assessment of diagnostic application and recommendations of the German Panel for Mutation Testing in NSCLC. Virchows Arch 2011; 458: 95-98
• 12 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977; 74: 5463-5467
• 13 Molina-Vila MA, Bertran-Alamillo J, Reguart N et al. A sensitive method for detecting EGFR mutations in non-small cell lung cancer samples with few tumor cells. J Thorac Oncol 2008; 3: 1224-1235
• 14 Do H, Dobrovic A. Limited copy number-high resolution melting (LCN-HRM) enables the detection and identification by sequencing of low level mutations in cancer biopsies. Mol Cancer 2009; 8: 82
• 15 Fassina A, Gazziero A, Zardo D et al. Detection of EGFR and KRAS mutations on trans-thoracic needle aspiration of lung nodules by high resolution melting analysis. J Clin Pathol 2009; 62: 1096-1102
• 16 Morinaga R, Okamoto I, Fujita Y et al. Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer. Cancer Sci 2008; 99: 2455-2460
• 17 Marchetti A, Martella C, Felicioni L et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005; 23: 857-865
• 18 Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res 2007; 13: 4954-4955
• 19 Pirker R, Herth FJ, Kerr KM et al. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. J Thorac Oncol 2010; 5: 1706-1713
• 20 Thunnissen E, Kerr KM, Herth FJ et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer 2012; 76: 1-18
• 21 Petersen I, Schnabel PA. [What’s new in lung pathology: minutes from the Pulmonary Pathology Working Group of the German Society of Pathology]. Pathologe 2011; 32: 351-357
• 22 Schnabel PA, Petersen I, Junker K. [Current issues in pulmonary pathology: Report of the working group on pulmonary pathology of the German Society of Pathology]. Pathologe 2012; 33 (Suppl. 02) 351-354
• 23 Shure D, Fedullo PF. Transbronchial needle aspiration in the diagnosis of submucosal and peribronchial bronchogenic carcinoma. Chest 1985; 88: 49-51
• 24 Kacar N, Tuksavul F, Edipoglu O et al. Effectiveness of transbronchial needle aspiration in the diagnosis of exophytic endobronchial lesions and submucosal/peribronchial diseases of the lung. Lung Cancer 2005; 50: 221-226
• 25 Micames CG, McCrory DC, Pavey DA et al. Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis. Chest 2007; 131: 539-548
• 26 Herth FJ, Krasnik M, Kahn N et al. Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer. Chest 2010; 138: 790-794
• 27 Gellert AR, Rudd RM, Sinha G et al. Fibreoptic bronchoscopy: effect of multiple bronchial biopsies on diagnostic yield in bronchial carcinoma. Thorax 1982; 37: 684-687
• 28 Popovich Jr J, Kvale PA, Eichenhorn MS et al. Diagnostic accuracy of multiple biopsies from flexible fiberoptic bronchoscopy. A comparison of central versus peripheral carcinoma. Am Rev Respir Dis 1982; 125: 521-523
• 29 Hetzel J, Eberhardt R, Herth FJ et al. Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial. Eur Respir J 2012; 39: 685-690
• 30 Laurent F, Latrabe V, Vergier B et al. Percutaneous CT-guided biopsy of the lung: comparison between aspiration and automated cutting needles using a coaxial technique. Cardiovasc Intervent Radiol 2000; 23: 266-272
• 31 Levine MS, Weiss JM, Harrell JH et al. Transthoracic needle aspiration biopsy following negative fiberoptic bronchoscopy in solitary pulmonary nodules. Chest 1988; 93: 1152-1155
• 32 Fassina A, Corradin M, Zardo D et al. Role and accuracy of rapid on-site evaluation of CT-guided fine needle aspiration cytology of lung nodules. Cytopathology 2011; 22: 306-312
• 33 O'Neill AC, McCarthy C, Ridge CA et al. Rapid needle-out patient-rollover time after percutaneous CT-guided transthoracic biopsy of lung nodules: effect on pneumothorax rate. Radiology 2012; 262: 314-319
• 34 Kazerooni EA, Lim FT, Mikhail A et al. Risk of pneumothorax in CT-guided transthoracic needle aspiration biopsy of the lung. Radiology 1996; 198: 371-375
• 35 Khan MF, Straub R, Moghaddam SR et al. Variables affecting the risk of pneumothorax and intrapulmonal hemorrhage in CT-guided transthoracic biopsy. Eur Radiol 2008; 18: 1356-1363
• 36 Fernandez-Villar A, Gonzalez A, Leiro V et al. [Effect of different bronchial washing sequences on diagnostic yield in endoscopically visible lung cancer]. Arch Bronconeumol 2006; 42: 278-282
• 37 van der Drift MA, van der Wilt GJ, Thunnissen FB et al. A prospective study of the timing and cost-effectiveness of bronchial washing during bronchoscopy for pulmonary malignant tumors. Chest 2005; 128: 394-400
• 38 Mak VH, Johnston ID, Hetzel MR et al. Value of washings and brushings at fibreoptic bronchoscopy in the diagnosis of lung cancer. Thorax 1990; 45: 373-376
• 39 Totsch M, Guzman J, Theegarten D et al. [Bronchoalveolar lavage]. Pathologe 2007; 28: 346-353
• 40 Thunnissen FB. Sputum examination for early detection of lung cancer. J Clin Pathol 2003; 56: 805-810
• 41 Karahalli E, Yilmaz A, Turker H et al. Usefulness of various diagnostic techniques during fiberoptic bronchoscopy for endoscopically visible lung cancer: should cytologic examinations be performed routinely?. Respiration 2001; 68: 611-614
• 42 Govert JA, Kopita JM, Matchar D et al. Cost-effectiveness of collecting routine cytologic specimens during fiberoptic bronchoscopy for endoscopically visible lung tumor. Chest 1996; 109: 451-456
• 43 Lee HS, Lee GK, Kim MS et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of non-small cell lung cancer: how many aspirations per target lymph node station?. Chest 2008; 134: 368-374
• 44 Travis WD, Brambilla E, Noguchi M et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244-285
• 45 Weihmann J, Weichert C, Petersen I et al. [Evaluation of a cell block method in cytological diagnostics]. Pathologe 2012; 33: 553-559
• 46 Bubendorf L, Feicher G, Obermann P et al. Zytopathologie, Pathologie Band 9. Berlin, Heidelberg: Springer Verlag; 2011
• 47 Riaz SP, Luchtenborg M, Jack RH et al. Variation in surgical resection for lung cancer in relation to survival: population-based study in England 2004-2006. Eur J Cancer 2012; 48: 54-60
• 48 Lau KK, Rathinam S, Waller DA et al. The effects of increased provision of thoracic surgical specialists on the variation in lung cancer resection rate in England. J Thorac Oncol 2013; 8: 68-72
• 49 Savic S, Bihl MP, Bubendorf L. [Non-small cell lung cancer : Subtyping and predictive molecular marker investigations in cytology]. Pathologe 2012; 33: 301-307
• 50 Tapia C, Savic S, Bihl M et al. [EGFR mutation analysis in non-small-cell lung cancer: Experience from routine diagnostics]. Pathologe 2009; 30: 384-392
• 51 Zlobec I, Raineri I, Schneider S et al. Assessment of mean EGFR gene copy number is a highly reproducible method for evaluating FISH in histological and cytological cancer specimens. Lung Cancer 2010; 68: 192-197
• 52 Savic S, Tapia C, Grilli B et al. Comprehensive epidermal growth factor receptor gene analysis from cytological specimens of non-small-cell lung cancers. Br J Cancer 2008; 98: 154-160
• 53 Bruno P, Mariotta S, Ricci A et al. Reliability of direct sequencing of EGFR: comparison between cytological and histological samples from the same patient. Anticancer Res 2011; 31: 4207-4210
• 54 Rekhtman N, Brandt SM, Sigel CS et al. Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. J Thorac Oncol 2011; 6: 451-458
• 55 Solomon SB, Zakowski MF, Pao W et al. Core needle lung biopsy specimens: adequacy for EGFR and KRAS mutational analysis. AJR Am J Roentgenol 2010; 194: 266-269
• 56 Chowdhuri SR, Xi L, Pham TH et al. EGFR and KRAS mutation analysis in cytologic samples of lung adenocarcinoma enabled by laser capture microdissection. Mod Pathol 2012; 25: 548-555