BACKGROUND: Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification. METHODS: TCC was analyzed in 120 H&E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath). RESULTS: Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%. CONCLUSIONS: Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions.
- Kazdal, D.
- Rempel, E.
- Oliveira, C.
- Allgäuer, M.
- Harms, A.
- Singer, K.
- Kohlwes, E.
- Ormanns, S.
- Fink, L.
- Kriegsmann, J.
- Leichsenring, M.
- Kriegsmann, K.
- Stögbauer, F.
- Tavernar, L.
- Leichsenring, J.
- Volckmar, A. L.
- Longuespée, R.
- Winter, H.
- Eichhorn, M.
- Heußel, C. P.
- Herth, F.
- Christopoulos, P.
- Reck, M.
- Muley, T.
- Weichert, W.
- Budczies, J.
- Thomas, M.
- Peters, S.
- Warth, A.
- Schirmacher, P.
- Stenzinger, A.
- Kriegsmann, M.
Keywords
- Digital pathology
- lung adenocarcinoma (lung ADC)
- molecular pathology
- next-generation sequencing (NGS)
- tumor cell content (TCC)
- (available at http://dx.doi.org/10.21037/tlcr-20-1168). DK reports personal fees
- from AstraZeneca, Bristol-Myers Squibb, and Pfizer outside the submitted work. ALV
- reports personal fees from Astra Zeneca, outside the submitted work. RL reports
- grants from Deutsche Forschungsgemeinschaft (DFG), Dietmar Hopp Stiftung, outside
- the submitted work. CPH reports grants from Siemens, Pfizer, MeVis, Boehringer
- Ingelheim, German Center for Lung Research, personal fees from Astellas,
- AstraZeneca, Basilea, Bayer, Boehringer Ingelheim, Bracco MEDA Pharma, Chiesi,
- Covidien, Essex, Fresenius, Gilead, Grifols, Intermune, Lilly, MSD, Novartis,
- Pfizer, Pierre Fabre, Roche, Schering-Plough, Siemens, other from GSK, outside the
- submitted work
- in addition, CPH has a patent Method and Device For Representing the
- Microstructure of the Lungs, IPC8 Class: AA61B5055FI, PAN: 20080208038 issued. FH
- reports personal fees from Uptake, BTG, Olympus, Pulmonx, outside the submitted
- work. PC reports grants and personal fees from Novartis, Roche, AstraZeneca, Takeda,
- and personal fees from Pfizer, Chugai, Boehringer, outside the submitted work. TM
- reports grants and non-financial support from Roche Diagnostics GmbH, Penzberg,
- Germany, outside the submitted work
- in addition, TM has a patent WO2019158460
- pending, a patent WO2019211418 pending, a patent WO2019215223 pending, a patent
- EP3391053 issued, and a patent EP3365679 pending. MR reports personal fees from
- Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Lilly, Celgene, Merck, Mirati, MSD,
- Novartis, Pfizer, Roche, Samsung Bioepis, outside the submitted work. WW reports
- personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer,
- Novartis, Takeda, Amgen, Astellas, Illumina, Agilent, Siemens, Molecular Health and
- grants from Roche, MSD, BMS, Bruker, AstraZeneca, outside the submitted work. JB
- reports grants from German Cancer Aid, outside the submitted work. MT reports
- grants, personal fees and non-financial support from AstraZeneca, Bristol-Myers
- Squibb, Takeda, Roche, personal fees and non-financial support from AbbVie,
- Boehringer Ingelheim, Celgene, Chugai, Lilly, Novartis, Pfizer, outside the
- submitted work. SP reports personal fees from Abbvie, Amgen, AstraZeneca, Bayer,
- Biocartis, Boehringer-Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly,
- F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme,
- Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle
- Genetics and Takeda, Takeda, Bioinvent, Medscape, Phosphoplatin Therapeutics
- non-financial support from Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Clovis, F.
- Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer,
- Phosphoplatin
- outside the submitted work
- all fees to Institution. PS reports
- personal fees from BMS, MSD, Incyte, Janssen, Amgen, Novartis, Roche and AstraZeneca
- outside the submitted work. AS reports grants and personal fees from Bayer, BMS,
- grants from Chugai and personal fees from Astra Zeneca, MSD, Takeda, Seattle
- Genetics, Novartis, Illumina, Thermo Fisher, Eli Lily, Takeda, outside the submitted
- work. The other authors have no conflicts of interest to declare.
