Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects
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Elisa Neubauer1, Ralph M. Wirtz2, Daniel Kaemmerer3, Maria Athelogou4, Lydia Schmidt1, Jörg Sänger5, Amelie Lupp1
1Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
2STRATIFYER Molecular Pathology GmbH Köln, Köln, Germany
3Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany
4DEFINIENS AG, München, Germany
5Laboratory of Cytology and Pathology, Bad Berka, Germany
Elisa Neubauer, email: firstname.lastname@example.org
Keywords: Ki-67, topoisomerase 2 alpha, RacGAP1, lung neuroendocrine neoplasms, IHC/RT-qPCR
Received: March 13, 2016 Accepted: May 16, 2016 Published: May 31, 2016
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.
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