Prognostic comparison of the proliferation markers mitotic activity index, phosphohistone H3, Ki67, steroid receptors, HER2, high molecular weight cytokeratins and classical prognostic factors in T 1-2 N 0 M 0 breast cancer

Abstract

The proliferation factors: mitotic activity index (MAI), phosphohistone H3 (PPH3) and Ki67 have strong prognostic value in early breast cancer but their independent value to each other and other prognostic factors has not been evaluated. In 237 T 1-2 N 0 M 0 breast cancers without systemic adjuvant treatment, formalized MAI assessment and strictly standardized, fully automated quantitative immunohistochemistry (IHC) for Ki67, PPH3, estrogen (ER) and progesterone receptor (PR), HER2, cytokeratins-5/6 and -14, and automated digital image analysis (DIA) for measuring PPH3 and Ki67 were performed. Section thickness was measured to further control IHC measurements. All features were measured in the periphery of tumors. The different proliferation assessments and other well-established clinicopathological and biomarker prognostic factors were compared. DIA-Ki67 added prognostically to PPH3. None of the other biomarkers or clinicopathological variables added prognostically to this PPH3/Ki67 combination. However, when PPH3 is replaced by MAI the prognostic value is nearly the same. In early operable node negative breast cancer without adjuvant systemic treatment, Ki67 with a threshold of 6.5% assessed by digital image analysis in the periphery of the tumor is prognostically strong. The combination of either PPH3/Ki67 or MAI/Ki67 overshadowed the prognostic value of all other features including Ki67 alone.

Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma

“…[3][4][5] Therefore, a first aim of this study was to assess the usefulness of phosphohistone H3 immunohistochemical staining (evaluated either manually or with an automated PC-based approach) as a surrogate of morphological mitotic index evaluation. Our data confirm and expand to adrenocortical carcinoma the reported high concordance between morphologically and phospho-histone H3-assessed mitotic counts, with a high statistical significance for both manual and computerassisted 19,[22][23][24][25][26]40 phospho-histone H3 counting. Phospho-histone H3 immunostaining allowed a rapid count of mitotic figures and is also useful for the recognition of atypical mitotic figures, a second relevant parameter included in the Weiss Score (Figure 1).…”

“…Therefore, apart from being a time-consuming exercise, assessment of mitotic figures in 50 high-power fields is often poorly reproducible among observers. Phospho-histone H3 immunostaining has been demonstrated to specifically detect mitotic figures in several human tumors 19,22,27,[30][31][32] but has never been tested in adrenocortical carcinomas, so far. This is surprising, as it is well known that the recognition of this tumor type largely relies on mitotic index evaluation, as one of the nine factors included in the Weiss Score 1 or in other diagnostic algorithms.…”

“…11,12 Phospho-histone H3 immunostaining has been shown to be a reliable and easy method for mitotic index evaluation in melanoma, with both diagnostic [13][14][15][16][17][18] and prognostic 17,[19][20][21] implications. Moreover, it has been also successfully applied in different neoplasms of the breast, [22][23][24][25][26] meninges, [27][28][29] brain, 30 lung, 31 soft tissues, [32][33][34] esophagus, 35 female genital tract, 36,37 prostate, 38 and urothelium, 39 as well as in cytology material from pancreatic endocrine tumors 40 and urothelial carcinoma. 41 The Ki-67 index represents an alternative method for assessing the proliferative potential in adrenocortical tumors and has already been shown to differentiate adrenocortical adenoma from carcinoma, [42][43][44][45][46][47][48][49] and to predict tumor behavior.…”

Application of immunohistochemistry for detection of metastases in sentinel lymph nodes of non-advanced breast cancer patients

“…Among prognostic factors indicating a high correlation with possible unsatisfactory distant treatment results of breast cancer patients (including presence of metastases in regional lymph nodes), Gudlaugsson et al specify mitotic activity index (MAI), phosphohistone H3 (PPH3) and Ki-67 [25]. According to the authors, digital image analysis of PPH3 or MAI combined with Ki-67 is a valuable prognostic tool in the treatment of breast cancer patients with negative lymph nodes.…”

High Phosphohistone H3 Expression Correlates with Adverse Clinical, Biological, and Pathological Factors in Neuroblastomas

“…Phosphohistone H3 (pHH3) is strongly expressed in the late G2-and M-phase (mitotic-phase) of the cell cycle, and high pHH3 expression has been shown to correlate with shorter survival in a variety of tumors such as those of the central nervous system (Colman et al 2006;Kim et al 2007), melanomas (Ladstein et al 2012;Tetzlaff et al 2013) and carcinomas (Aune et al 2011;Gudlaugsson et al 2013;Klintman et al 2013;Nakashima et al 2013;Nowak et al 2014;Skaland et al 2007). Furthermore, in a series of lymph node-negative breast cancer patients, high pHH3 expression emerged as the strongest prognostic variable (Skaland et al 2007).…”