Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index

Jalava, Päivi; Kuopio, Teijo; Juntti-Patinen, L; Kotkansalo, Tero; Kronqvist, Pauliina; Collan, Yrjö

doi:10.1111/j.1365-2559.2006.02402.x

Cited by 151 publications

(122 citation statements)

References 27 publications

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“…In this regard, it is interesting to note that previous studies found the level of positive TUNEL staining to be relatively high not only in salivary glands malignancies but also in oral cancer (Loro et al, 1999;Nagler et al, 1999Nagler et al, ,2003. Our results are also supported by multiple recent studies of various nonsalivary malignancies which demonstrated that high scores of Ki67 and p53 staining predict a higher tumourogenic grade, a higher rate of metastasis spread and a poorer prognosis, whereas low scores of Ki67 and p53 are associated with prognostically better histopathologic features (Saleh et al, 2000;Ben-Izhak et al, 2001Jalava et al, 2006). Furthermore, in gastric cancer significant relationships between TUNEL, Ki67 and grade have been reported (Jesionek-Kupnicka et al, 2002), whereas in oral leukoplakia higher levels of TUNEL, Ki67 and p53 have been reported, indicating increased instability of the genome and higher severity of the dysplasia and the clinical stage (Kovesi and Szende, 2004).…”

Section: Discussionsupporting

confidence: 78%

“…This may lead to finding a cellular target (associated or non-associated with p53 and/or Ki67), which might be used for anti-carcinogenetic therapy. Finally, it is noteworthy to mention a paper published recently by Jalava et al (2006), which seems to show that mitotic activity and apoptotic activity are related in breast cancer and that Ki-67 may not be the best possible proliferation-associated prognosticator but rather the mitotic count. Furthermore, in 2000 this group (Jalava et al, 2000) showed that Bcl-2 immunostaining could potentially replace TUNEL as its prognostic value is well-established in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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TUNEL – an efficient prognosis predictor of salivary malignancies

et al. 2007

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Biological markers are necessary for predicting prognosis of salivary malignancies and better understanding the pathogenesis of salivary cancer. We analysed terminal deoxynucleotidyl transferase (TdT)-mediated biotinylated deoxyuridine-triphosphate (dUTP)-biotin nick-end labelling (TUNEL), p53 and Ki67 expression in 66 patients with malignant salivary tumours by immonohistochemistry, and correlated the data with survival, disease-free survival, tumour grade, stage, and local and distant metastasis. TUNEL efficiently predicted poor prognosis in salivary malignancies. The 5-year (5Y) survival probability dropped significantly with the level of TUNEL staining (from 83% in negatively stained tumours to 57 and 24% in TUNEL positively stained levels 1 and 2, respectively), (P ¼ 0.042). Extensive Ki67 staining (in addition to TUNEL) reduced the 5Y-survival rate even further and addition of positively stained p53 dropped the 5Y-survival rate to 0. The correlation rates between TUNEL and Ki67 was 58% (P ¼ 0.0001), and between TUNEL and p53 it was 50% (P ¼ 0.035). Concurrently, TUNEL correlated with metastasis, extracapsular spread, grade and stage. The correlation between TUNEL, p53 and Ki67 staining and survival probabilities, and the pathological grade, stage and metastasis spread of salivary malignancies makes this a highly effective tool in patient follow-up and prognosis.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

TUNEL – an efficient prognosis predictor of salivary malignancies

et al. 2007

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“…The prognostic power of mitotic activity and traditional proliferation markers, such as standardised mitotic counts and Ki-67, is established in pathological practice. To benefit individual breast cancer patients, the potential of the traditional prognostic features could still be intensified by additional methods (Olivotto et al, 1999;Michels et al, 2003;Oestreicher et al, 2004;Warwick et al, 2004;Jalava et al, 2006).…”

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confidence: 99%

Proliferation marker securin identifies favourable outcome in invasive ductal breast cancer

et al. 2008

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We introduce a new proliferation marker, securin (pituitary tumour-transforming 1 (PTTG1)), analysed in invasive ductal breast carcinomas by cDNA microarrays and immunohistochemistry. In cDNA microarray of a total of 4000 probes of genes, securin was revealed with a significant change in expression among the several proliferation-related genes studied. The value of securin as a proliferation marker was verified immunohistochemically (n ¼ 44) in invasive ductal breast cancer. In follow-up analyses of the sample of patients, the prognostic value of securin was compared with the established markers of breast cancer proliferation, Ki-67 and mitotic activity index (MAI). Our results of a small sample of patients suggest that low securin expression identifies a distinct subgroup of more favourable outcome among patients with high Ki-67 immunoexpression or high MAI. In univariate analysis of Cox's regression, 10-unit increment of securin immunopositivity was associated with a 2.3-fold overall risk of death due to breast cancer and a 7.1-fold risk of death due to breast cancer in the sample of patients stratified according to the cutoff points of 10 and 20% of securin immunopositivity. We suggest that securin immunostaining is a promising and clinically applicable proliferation marker. The finding urges further prognostic studies with a large sample of patients.

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“…Various studies have shown that a high expression of Ki67 or cyclin A is correlated with a worse prognosis in breast cancer (Bukholm et al, 2001;Kuhling et al, 2003;Poikonen et al, 2005;Baldini et al, 2006;Ahlin et al, 2007;de Azambuja et al, 2007;Railo et al, 2007). However, evidence has also been obtained that the prognostic value of proliferation markers varies significantly depending on clinical characteristics of the tumour disease, for example, lymph node status (Jalava et al, 2006;Trere et al, 2006). Thus, to obtain more detailed information regarding the prognostic contribution of proliferation markers in breast cancer, patients have to be subgrouped according to clinical features, for example, tumour size and lymph node status.…”

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confidence: 99%

Genomic instability and proliferative activity as risk factors for distant metastases in breast cancer

Zhou

et al. 2008

Br J Cancer

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The role of genomic instability and proliferative activity for development of distant metastases in breast cancer was analysed, and the relative contribution of these two risk factors was quantified. A detailed quantitative comparison was performed between Ki67 and cyclin A as proliferative markers. The frequency of Ki67 and cyclin A-positive cells was scored in the same microscopic areas in 428 breast tumours. The frequency of Ki67-positive cells was found to be highly correlated with the frequency of cyclin A-positive cells, and both proliferation markers were equally good to predict risk of distant metastases. The relative contribution of degree of aneuploidy and proliferative activity as risk markers for developing distant metastases was studied independently. Although increased proliferative activity in general was associated with an increased risk of developing distant metastases, ploidy level was found to be an independent and even stronger marker when considering the group of small (T1) node negative tumours. By combining proliferative activity and ploidy level, a large group of low risk breast tumours (39%) could be identified in which only a few percentage of the tumours (5%) developed distant metastases during the 9-year follow-up time period.

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Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index

Abstract: We have found a 'wrong positive' Ki67 group with favourable prognosis. SMI cannot be replaced by Ki67 because of the danger of misclassification of some patients.

Cited by 151 publications

References 27 publications

TUNEL – an efficient prognosis predictor of salivary malignancies

TUNEL – an efficient prognosis predictor of salivary malignancies

Proliferation marker securin identifies favourable outcome in invasive ductal breast cancer

Genomic instability and proliferative activity as risk factors for distant metastases in breast cancer

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