TY - JOUR
T1 - ALK-FISH borderline cases in non-small cell lung cancer
T2 - Implications for diagnostics and clinical decision making
AU - von Laffert, Maximilian
AU - Stenzinger, Albrecht
AU - Hummel, Michael
AU - Weichert, Wilko
AU - Lenze, Dido
AU - Warth, Arne
AU - Penzel, Roland
AU - Herbst, Hermann
AU - Kellner, Udo
AU - Jurmeister, Philipp
AU - Schirmacher, Peter
AU - Dietel, Manfred
AU - Klauschen, Frederick
N1 - Publisher Copyright:
© 2015 Elsevier Ireland Ltd.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Background: Fluorescence in-situ hybridization (FISH) for the detection of ALK-rearrangements in non-small cell lung cancer (NSCLC) is based on at first sight clear cut-off criteria (≥15% of tumor cells) for split signals (SS) and single red signals (SRS). However, NSCLC with SS-counts around the cut-off may cause interpretation problems. Material and methods: Tissue microarrays containing 753 surgically resected NSCLCs were independently tested for ALK-alterations by FISH and immunohistochemistry (IHC). Our analysis focused on samples with SS/SRS in the range between 10% and 20% (ALK-FISH borderline group). To better understand the role of these samples in routine diagnostics, we performed statistical analyses to systematically estimate the probability of ALK-FISH-misclassification (false negative or positive) for different numbers of evaluated tumor cell nuclei (30, 50, 100, and 200). Results: 94.3% (710/753) of the cases were classified as unequivocally (<10% or ≥20%) ALK-FISH-negative (93%; 700/753) or positive (1.3%; 10/753) and showed concordant IHC results.5.7% (43/753) of the samples showed SS/SRS between 10% and 20% of the tumor cells. Out of these, 7% (3/43; ALK-FISH: 14%, 18% and 20%) were positive by ALK-IHC, while 93% (40/43) had no detectable expression of the ALK-protein. Statistical analysis showed that ALK-FISH misclassifications occur frequently for samples with rearrangements between 10% and 20% if ALK-characterization is based on a sharp cut-off point (15%). If results in this interval are defined as equivocal (borderline), statistical sampling-related ALK-FISH misclassifications will occur in less than 1% of the cases if 100 tumor cells are evaluated. Conclusion: While ALK status can be determined robustly for the majority of NSCLC by FISH our analysis showed that ~6% of the cases belong to a borderline group for which ALK-FISH evaluation has only limited reliability due to statistical sampling effects. These cases should be considered equivocal and therapy decisions should include additional tests and clinical considerations.
AB - Background: Fluorescence in-situ hybridization (FISH) for the detection of ALK-rearrangements in non-small cell lung cancer (NSCLC) is based on at first sight clear cut-off criteria (≥15% of tumor cells) for split signals (SS) and single red signals (SRS). However, NSCLC with SS-counts around the cut-off may cause interpretation problems. Material and methods: Tissue microarrays containing 753 surgically resected NSCLCs were independently tested for ALK-alterations by FISH and immunohistochemistry (IHC). Our analysis focused on samples with SS/SRS in the range between 10% and 20% (ALK-FISH borderline group). To better understand the role of these samples in routine diagnostics, we performed statistical analyses to systematically estimate the probability of ALK-FISH-misclassification (false negative or positive) for different numbers of evaluated tumor cell nuclei (30, 50, 100, and 200). Results: 94.3% (710/753) of the cases were classified as unequivocally (<10% or ≥20%) ALK-FISH-negative (93%; 700/753) or positive (1.3%; 10/753) and showed concordant IHC results.5.7% (43/753) of the samples showed SS/SRS between 10% and 20% of the tumor cells. Out of these, 7% (3/43; ALK-FISH: 14%, 18% and 20%) were positive by ALK-IHC, while 93% (40/43) had no detectable expression of the ALK-protein. Statistical analysis showed that ALK-FISH misclassifications occur frequently for samples with rearrangements between 10% and 20% if ALK-characterization is based on a sharp cut-off point (15%). If results in this interval are defined as equivocal (borderline), statistical sampling-related ALK-FISH misclassifications will occur in less than 1% of the cases if 100 tumor cells are evaluated. Conclusion: While ALK status can be determined robustly for the majority of NSCLC by FISH our analysis showed that ~6% of the cases belong to a borderline group for which ALK-FISH evaluation has only limited reliability due to statistical sampling effects. These cases should be considered equivocal and therapy decisions should include additional tests and clinical considerations.
KW - Anaplastic lymphoma kinase (ALK)
KW - Fluorescence in-situ hybridization (FISH)
KW - Immunohistochemistry (IHC)
KW - Non-small cell lung cancer (NSCLC)
KW - Statistical analysis
UR - https://www.scopus.com/pages/publications/84949184917
U2 - 10.1016/j.lungcan.2015.09.022
DO - 10.1016/j.lungcan.2015.09.022
M3 - Article
C2 - 26547803
AN - SCOPUS:84949184917
SN - 0169-5002
VL - 90
SP - 465
EP - 471
JO - Lung Cancer
JF - Lung Cancer
IS - 3
ER -
