Robust linear regression model of Ki‑67 for mitotic rate in gastrointestinal stromal tumors

Kemmerling,Ralf; Weyland,Denis; Kiesslich,Tobias; Illig,Romana; Klieser,Eckhard; Jäger,Tarkan; Dietze,Otto; Neureiter,Daniel

doi:10.3892/ol.2014.1802

Robust linear regression model of Ki‑67 for mitotic rate in gastrointestinal stromal tumors

Authors:
- Ralf Kemmerling
- Denis Weyland
- Tobias Kiesslich
- Romana Illig
- Eckhard Klieser
- Tarkan Jäger
- Otto Dietze
- Daniel Neureiter
View Affiliations

Affiliations: Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria, Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria, Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria
Published online on: January 15, 2014 https://doi.org/10.3892/ol.2014.1802
Pages: 745-749

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Risk stratification of gastrointestinal stromal tumors (GISTs) by tumor size, lymph node and metastasis status is crucially affected by mitotic activity. To date, no studies have quantitatively compared mitotic activity in hematoxylin and eosin (H&E)‑stained tissue sections with immunohistochemical markers, such as phosphohistone H3 (PHH3) and Ki‑67. According to the TNM guidelines, the mitotic count on H&E sections and immunohistochemical PHH3‑stained slides has been assessed per 50 high‑power fields of 154 specimens of clinically documented GIST cases. The Ki‑67‑associated proliferation rate was evaluated on three digitalized hot spots using image analysis. The H&E‑based mitotic rate was found to correlate significantly better with Ki‑67‑assessed proliferation activity than with PHH3‑assessed proliferation activity (r=0.780; P<0.01). A linear regression model (analysis of variance; P<0.001) allowed reliable predictions of the H&E‑associated mitoses based on the Ki‑67 expression alone. Additionally, the Ki‑67‑associated proliferation revealed a higher and significant impact on the recurrence and metastasis rate of the GIST cases than by the classical H&E‑based mitotic rate. The results of the present study indicated that the mitotic rate may be reliably and time‑efficiently estimated by immunohistochemistry of Ki‑67 using only three hot spots.

View Figures

View References

1	Tran T, Davila JA and El-Serag HB: The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 100:162–168. 2005. View Article : Google Scholar : PubMed/NCBI
2	Miettinen M and Lasota J: Histopathology of gastrointestinal stromal tumor. J Surg Oncol. 104:865–873. 2011. View Article : Google Scholar : PubMed/NCBI
3	Tannapfel A and Wittekind C: The current TNM system for gastrointestinal tumors part II. Pathologe. 31:348–352. 2010.(In German).
4	Fletcher CD, Berman JJ, Corless C, et al: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 33:459–465. 2002. View Article : Google Scholar : PubMed/NCBI
5	Yamaguchi U, Hasegawa T, Sakurai S, et al: Interobserver variability in histologic recognition, interpretation of KIT immunostaining, and determining MIB-1 labeling indices in gastrointestinal stromal tumors and other spindle cell tumors of the gastrointestinal tract. Appl Immunohistochem Mol Morphol. 14:46–51. 2006. View Article : Google Scholar
6	Hasegawa T, Yamamoto S, Nojima T, et al: Validity and reproducibility of histologic diagnosis and grading for adult soft-tissue sarcomas. Hum Pathol. 33:111–115. 2002. View Article : Google Scholar
7	Brown DC and Gatter KC: Ki67 protein: the immaculate deception? Histopathology. 40:2–11. 2002. View Article : Google Scholar
8	Hendzel MJ, Wei Y, Mancini MA, et al: Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 106:348–360. 1997. View Article : Google Scholar
9	Wang X, Mori I, Tang W, et al: Helpful parameter for malignant potential of gastrointestinal stromal tumors (GIST). Jpn J Clin Oncol. 32:347–351. 2002. View Article : Google Scholar : PubMed/NCBI
10	Seidal T and Edvardsson H: Expression of c-kit (CD117) and Ki67 provides information about the possible cell of origin and clinical course of gastrointestinal stromal tumours. Histopathology. 34:416–424. 1999. View Article : Google Scholar
11	Nakamura N, Yamamoto H, Yao T, et al: Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol. 36:828–837. 2005. View Article : Google Scholar
12	Wong NA, Young R, Malcomson RD, et al: Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach. Histopathology. 43:118–126. 2003. View Article : Google Scholar : PubMed/NCBI
13	Miettinen M and Lasota J: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 23:70–83. 2006. View Article : Google Scholar : PubMed/NCBI
14	Illig R, Fritsch H and Schwarzer C: Breaking the seals: efficient mRNA detection from human archival paraffin-embedded tissue. RNA. 15:1588–1596. 2009. View Article : Google Scholar : PubMed/NCBI
15	Illig R, Fritsch H and Schwarzer C: Spatio-temporal expression of HOX genes in human hindgut development. Dev Dyn. 242:53–66. 2013. View Article : Google Scholar : PubMed/NCBI
16	Kemmerling R, Stintzing S, Muhlmann J, et al: Primary testicular lymphoma: A strictly homogeneous hematological disease? Oncol Rep. 23:1261–1267. 2010.PubMed/NCBI
17	Yerushalmi R, Woods R, Ravdin PM, et al: Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 11:174–183. 2010. View Article : Google Scholar : PubMed/NCBI
18	Gould Rothberg BE and Rimm DL: Biomarkers: the useful and the not so useful--an assessment of molecular prognostic markers for cutaneous melanoma. J Invest Dermatol. 130:1971–1987. 2010.