Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects.
The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
Elisa
E
Neubauer
STRATIFYER Molecular Pathology GmbH Köln, Köln, Germany.
Ralph M
RM
Wirtz
Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany.
Daniel
D
Kaemmerer
DEFINIENS AG, München, Germany.
Maria
M
Athelogou
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
Lydia
L
Schmidt
Laboratory of Cytology and Pathology, Bad Berka, Germany.
Jörg
J
Sänger
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
Amelie
A
Lupp
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002276:Carcinoid Tumor / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D018287:Carcinoma, Large Cell / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D020690:GTPase-Activating Proteins; D019394:Ki-67 Antigen; D000075223:Poly-ADP-Ribose Binding Proteins; C115995:mgcRacGAP; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
IHC/RT-qPCR; Ki-67; RacGAP1; lung neuroendocrine neoplasms; topoisomerase 2 alpha