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

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

doi:10.3892/ol.2014.1802

Cited by 25 publications

(26 citation statements)

References 17 publications

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“…Furthermore, we were unable to confirm the role of differentiation and cell-cycle regulatory proteins, such as Bcl-2, P16 and P53, as well as CD44, as prognostic factors, similar to previous studies (8,(21)(22)(23)(24). The reasons may be different antibodies, antigen retrieval or inter-observer variations of the immunohistochemical staining (10,11,15).…”

Section: Discussioncontrasting

confidence: 44%

“…a Significant differences between GIST sub-localizations using analysis of variance. b Analyzed as previously described (15). GIST, gastrointestinal stromal tumor; I, intensity; E, extent; S, quickscore; HPFs, high-power fields; SD, standard deviation; Bcl-2, B-cell lymphoma 2; DOG-1, discovered on GIST 1; PDGFRα, platelet-derived growth factor receptor α; PHH3, phosphohistone H3; SMA, smooth muscle actin.…”

Section: Multivariate Analysis Of Clinicopathological Histomorphologmentioning

confidence: 99%

“…PHH3-positive cells were manually counted in 50 HPFs. The Ki-67-based proliferation rate was assessed by the optimized particle analysis module according to the software manual (Image Access 9 Enterprise; Imagic Bildverarbeitung AG, Glattbrugg, Switzerland) on three digitized hot spot areas and related to the total number of cells, as previously described (15).…”

Section: Morphologymentioning

confidence: 99%

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Back to the start: Evaluation of prognostic markers in gastrointestinal stromal tumors

Klieser

Pichelstorfer

Weyland

et al. 2016

Molecular and Clinical Oncology

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Abstract. The aim of this study was to provide a standardized risk stratification model for gastrointestinal stromal tumors (GISTs) based on tumor localization, tumor size, involved lymph nodes and metastases, as well as mitotic activity and other morphological and molecular markers, in order to improve the risk evaluation scheme for recurrence, metastatic spread and survival for patients with GIST. A total of 201 cases of patients with GIST were investigated according to standardized morphological markers, including nuclear pleomorphism, tumor cell necrosis, mucosal infiltration, ulceration, skeinoid fibers and growth pattern. In addition, all cases were immunohistochemically analyzed using a tissue microarray platform for various markers of differentiation (CD34, CD44, CD117, desmin, discovered on GIST 1, platelet-derived growth factor receptor α, S-100 and smooth muscle actin) and proliferation (B-cell lymphoma 2, P16, P53, phosphohistone H3 and Ki-67). These findings were correlated by uni-and multivariable analyses with clinicopathological characteristics, including recurrence, metastasis and survival. The general clinicopathological parameters of this GIST specimen cohort were comparable to previous studies. While several parameters exhibited clear associations to each other and to the defined clinical endpoints, the multivariate analysis reduced the number of relevant prognostic variables to localization, margin status, growth pattern and hematoxylin and eosin-based mitosis̸Ki-67-based proliferation of GISTs. With the exception of CD34, none of the applied markers of differentiation and proliferation were found to be independent prognostic markers in GIST and the classical risk factors of GIST remain important prognostic factors. Additionally, growth pattern may predict the risk of recurrence and metastasis in GIST patients. Additional independent molecular prognostic markers remain to be identified and validated.

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Section: Discussioncontrasting

confidence: 44%

Section: Multivariate Analysis Of Clinicopathological Histomorphologmentioning

confidence: 99%

Section: Morphologymentioning

confidence: 99%

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Back to the start: Evaluation of prognostic markers in gastrointestinal stromal tumors

Klieser

Pichelstorfer

Weyland

et al. 2016

Molecular and Clinical Oncology

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“…Reproducibility of mitotic counts can be improved using mitosisspecific staining techniques. An approach that has already provided promising results in a variety of tumor types, including GISTs, is immunohistochemical staining of phospho-histone H3 using a commercially available antibody [18][19][20][21][22][23][24][25][26]. This antibody targets a phosphorylated serine amino acid in position 10 of the core histone protein H3, which is detectable at maximum level during chromosome condensation in early prophase of mitosis and minimally in any other phase of the cell cycle and in apoptosis [27][28][29].…”

Section: Phh3 Immunostaining Improves Mitosis Countingmentioning

confidence: 99%

Immunostaining of phospho-histone H3 and Ki-67 improves reproducibility of recurrence risk assessment of gastrointestinal stromal tumors

et al. 2015

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Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial tumors in the digestive tract. Beyond surgery, therapeutic management depends on risk of recurrence. Risk evaluation of GIST takes into account location and size of the tumor, whether or not the tumor was intact or ruptured and mitotic index. The mitotic index lacks in intra- and interobserver reproducibility. In this study, we evaluated on 61 GISTs, the reproducibility of mitotic counting using classical hematoxylin-eosin-saffron (HES) staining, and its correlation with the mitotic count obtained through immunohistochemical staining for phospho-histone H3 (PHH3) and the proliferation index based upon Ki-67 immunostaining. Mitotic counts by HES and PHH3 staining and Ki-67 proliferation index were evaluated twice by three independent observers taking into account interpretation times per tumor for each technique. HES-based and PHH3-based mitotic counts and Ki-67 proliferation index correlated well and presented good intra- and interobserver reproducibility. PHH3 staining resulted in a slight but statistically significant difference of about two more mitotic figures per 5 mm(2) than the HES-based count, which might have put some borderline tumors in a different risk category. Immunohistochemical staining for PHH3 and Ki-67 allowed more rapid interpretation than mitotic counts based upon HES staining, but only PHH3 staining allows counting of mitoses. Immunostaining using anti-PHH3 and anti-Ki-67 antibodies will eventually provide improved recurrence risk stratification of GIST and may become effective ancillary tools in deciding on optimal therapeutic management.

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“…Especially in cases with a higher grade based on Ki-67 than on the mitotic index [87 of 362 cases (24%) in this study], the mitotic index is less accurate than the Ki-67 index in predicting survival. Although some studies have shown that mitoses and the Ki-67 index are closely related in several tumor types [22,23], it has also been demonstrated that this is not always the case [23,24] and might be tumor type specific due to differences in cell cycle kinetics. In our study, however, the tumor type of cases with discordance between these two indexes is similar to that with concordant indexes, e.g.…”

Section: Discussionmentioning

confidence: 99%

Grading of Neuroendocrine Neoplasms: Mitoses and Ki-67 Are Both Essential

Velthuysen¹,

Groen²,

Noort

et al. 2014

Neuroendocrinology

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Background: The current WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract requires Ki-67 and mitotic index for grading. However, both indexes might be conflicting as far as grade is concerned. In this study, we investigate which of the two indexes is most informative to predict survival. Methods: We assessed 362 patients with NEN of gastrointestinal (n = 148), pancreatic (n = 29), lung (n = 77), unknown primary site (n = 102) and of miscellaneous (n = 6) origin. Follow-up and proliferative indexes were recorded. Results: Survival was clearly correlated with both proliferative indexes (p < 0.001). One hundred and nineteen samples (34%) showed discordance in grading between the Ki-67 and the mitotic index, of which 74 (62%) were biopsies and 45 (38%) resection specimens (p = 0.001). In 86% of these cases, survival matched with the highest proliferative index, which was the Ki-67 index in 87% of these cases. Seventeen cases had a mitotic index of 2 (threshold grade 2) and a Ki-67 index of <3% (grade 1). For these cases, survival curve matched that of patients with concordant indexes of grade 1. Conclusion: Grading NEN using two proliferative markers results in discordance between these indexes in one third of cases, more often in biopsy material than in resection specimens. If results are discordant, survival is for the most part associated with the grade of the highest index, for the most part Ki-67. Thus, grading with two proliferative indexes is useful as it highlights cases where one of these indexes may be incongruent.

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

Cited by 25 publications

References 17 publications

Back to the start: Evaluation of prognostic markers in gastrointestinal stromal tumors

Back to the start: Evaluation of prognostic markers in gastrointestinal stromal tumors

Immunostaining of phospho-histone H3 and Ki-67 improves reproducibility of recurrence risk assessment of gastrointestinal stromal tumors

Grading of Neuroendocrine Neoplasms: Mitoses and Ki-67 Are Both Essential

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