Morphometric grading in breast cancer: Tfor mitotic counts

doi:10.1016/S0046-8177(98)90017-X

Human Pathology

Volume 29, Issue 12, December 1998, Pages 1462-1468

https://doi.org/10.1016/S0046-8177(98)90017-X Get rights and content

Abstract

Three hundred sixty-four cases of invasive ductal breast cancer diagnosed during the years 1988 to 1991 were analyzed to determine quantitative thresholds for mitotic activity. Mitotic counts were calculated in each sample and expressed as standardized mitotic index (SMI) and mitotic activity index (MAI). Based on Kaplan-Meier curves, univariate and multivariate analysis of Cox's regression, and maximum efficiencies of ROC analysis, optimal thresholds were determined on the basis of survival and recurrence of disease. In our material, with a follow-up time of 5 years 9 months, we found two thresholds-a lower and a higher-for both SMI (17 mitoses/mm²and 32 mitoses/mm²) and MAI (13 mitoses/10 HPF and 35 mitoses/10 HPF). The thresholds were the same in the whole material and in subgroups divided according to the patients' age and axillary lymph node status at the time of diagnosis, and tumor size. The thresholds clearly separated patients with favorable, intermediate, and unfavourable outcome of disease. In our material, the risk of breast cancer death associated with the determined thresholds (ranging from 4.7 to 3.8) clearly exceeded those of menopausal status, axillary lymph node status and tumor size. The risk of breast cancer death associated with the determined thresholds was still emphasized in the groups of premenopausal and axillary lymph node-negative patients, and with tumor size less than 2 cm in diameter (risk ratios, 11.8, 6.0, and 6.7, respectively). The results suggest that the presented quantitative thresholds could be applied in grading of invasive ductal breast cancer.

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Citation Excerpt :
Mitosis, the cell generating process in humans, runs at the nuclei level and, as such, there is an interest in studying the nuclei of cells with the purpose of detecting cancerous cells.18 The reliability and reproducibility of mitotic counts has recently also been improved by elaboration of quantitative methods19 of which image processing favors the detection of mitotic figures to achieve successful discrimination between mitoses and other objects such as artifacts and nuclei of inflammatory cells.20 Methodological errors are of great concern when establishing mitotic activity.21
Mitosis is a process of cell division resulting in two genetically equivalent daughter cells. Excessive proliferation of cells due to mitosis is the hallmark in pre cancer and cancer.
This study was conducted to count the number of mitotic figures in normal oral mucosa, oral epithelial dysplasia and squamous cell carcinoma in both Hematoxylin and Eosin (H&E) and Crystal Violet stained sections. Also the overall number of mitotic figures with both stains were compared along with the evaluation of staining efficacy of both the stains.
The present study was conducted on 20 specimens each of the three categories. These were further divided into two groups for staining with H&E and with 1% Crystal Violet respectively. Images were captured and analyzed using image analysis software Dewinter Biowizard 4.1.
Comparison of mitotic figure count in three categories in sections stained with both stains showed statistically significant difference (p < 0.001). The mean number of mitotic figures seen in Crystal Violet reagent were significantly higher as seen in H&E stain (p < 0.001). The overall diagnostic efficacy of Crystal Violet was 87.6%. Crystal Violet scored over H&E stain and also helped to better appreciate metaphases in Squamous cell carcinoma and telophases in dysplasia.
Number of mitotic figures progressively increase with the advancement of the pathology. Use of 1% Crystal Violet provides better appreciation of mitotic figures and can be employed as a selective stain in routine histopathology.
Prognostic value of mitotic counts in axillary node negative breast cancer patients with predominantly well-differentiated tumours
2005, European Journal of Surgical Oncology
In axillary node negative (ANN) breast cancer patients additional prognostic markers are needed to decide whether adjuvant systemic treatment might be useful.
In the present study, the prognostic relevance of mitotic counts and Bloom–Richardson grade (BR-grade) was evaluated in 164 ANN breast cancer patients. No adjuvant systemic treatment was given to any of these patients. Mitotic counts were determined twice, in routine practice and in revision.
A substantial reproducibility of mitotic counts was found, provided that the cut-off value chosen was high enough. After a median follow-up of 10 years, mitotic counts had no prognostic significance for survival at any cut-off value. A trend towards a significant worse survival was found for patients with Bloom–Richardson grade II or III in comparison with grade I.
Based on data in the literature a positive association between both mitotic counts and BR-grade and survival in ANN breast cancer may exist, but the extent of this putative association and its clinical relevance can be argued, particularly in a group of patients with predominantly well differentiated tumours.
Prognostic Relevance of Mitotic Activity in Patients with Node-Negative Breast Cancer
2003, Modern Pathology
The prognostic relevance of mitotic activity was analyzed in a series of 306 patients with node-negative breast cancer treated with locoregional therapy alone, until early relapse. Mitotic activity was evaluated as the number of mitotic figures per 10 high-power fields (mitotic activity index) or per 1000 tumor cells (mitotic index). Counting was carried out blindly by two observers. A high correlation was observed between the two determinations (r_s = .96, P < .001). For clinical analysis, three mitotic activity index subgroups (mitotic figures/field ≤ 9, 10–19 and more than 19, according to grading criteria) and three mitotic index subgroups (percentage of mitotic figures less than 0.10, 0.11–0.50 and more than 0.50, according to tertile criteria) were considered. No relation was observed between mitotic variables and 6-year disease-free survival, whereas distant disease-free survival was strongly related to mitotic figures per 10 fields (85%, 89% and 70%, P = .012) and to the percentage of mitotic figures out of a total 1000 tumor cells (87%, 86% and 75%, P = .017). Similarly, both mitotic indices were significantly related to 6-year overall survival (99%, 95% and 77%, P < .001, for mitotic figures per 10 fields and 99%, 93% and 82%, P < .001, for the percentage of mitotic figures). These findings were particularly evident in patients with tumors of 1–2 cm. In conclusion, a high number of mitotic figures is associated with a higher probability of developing distant metastases and a shorter survival. The critical point remains the standardization of the preanalytical and analytical steps within quality control programs.
What the clinician needs from the pathologist: Evidence-based reporting in breast cancer
2001, European Journal of Cancer
Histopathology has a vital role in determining breast cancer management and pathologists must be part of the clinical team. Carcinoma size, grade, and especially lymph node status remain the best available prognostic factors. Metastatic carcinoma in axillary nodes is more important than any other prognostic factor presently available. ER status is an important predictor of response to endocrine manipulation, but its independent prognostic significance, and that of micrometastatic disease, circulating carcinoma cells and other molecular factors, even well-studied ones such as HER2 status, are less clear.
Pathology is the first clinical speciality to subject its practice to rigorous scientific analysis, and it has stood up well. However, workers without appropriate experience in Pathology or scientific design have created difficulties by undertaking poorly planned studies with ill-defined end-points, lacking appropriate quality control. New analytical techniques and therapeutic targets make it essential that we learn from past mistakes and integrate pathologists into the research teams pursing clinical trials and the assessment of new bio-markers. Without this, input resource will be wasted on false leads that could have been curtailed. Morphology alone will not be enough to select patients likely to benefit in trials of new therapies, but selection ‘tests’ must be appropriate. The confusion of tests for selection of patients to receive Herceptin shows what happens when this process fails. Much of the microarray data being put into data-bases has no quality control, and meta-analysis of this data will produce even more conflict than the clinical trials. This can be avoided, as the ability to standardise is available.
Quantitative thresholds for mitotic counts in histologic grading: Confirmation in nonfrozen samples of invasive ductal breast cancer
2000, Annals of Diagnostic Pathology
Increasing evidence in the medical literature suggests that freezing a sample before fixation causes changes in the histologically observed mitotic activity. In a recent study we determined quantitative thresholds for mitotic counts in invasive ductal breast cancer in both nonfrozen and frozen formalin-fixed specimens. Survival-and recurrence-based analyses of this study material indicated grading thresholds of 17 and 32 mitoses/mm² for standardized mitotic index (SMI) and 13 and 35 mitoses/10 high-power fields for mitotic activity index (MAI). The purpose of the present study is to confirm and adjust the introduced thresholds in only nonfrozen formalin-fixed samples. The SMI and MAI in 202 cases of nonfrozen formalin-fixed samples were analyzed to determine optimal cutpoints for prognostication of invasive breast cancer on the basis of mitotic activity. The SMI thresholds were identical in both the present nonfrozen specimens and the previous combined specimens. The optimal MAI thresholds in the nonfrozen material changed to 11 and 37 mitoses/10 high-power field. The confirmation and adjustment of the mitotic thresholds improved the prognostic significance of the method in the nonfrozen material, which will contribute to the clinical applicability of a morphometric grading system.
Counting mitoses [1] (multiple letters)
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^☆: Supported by grants from the Cancer Foundation of South-West Finland.

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Original contributionMorphometric grading in breast cancer: Tfor mitotic counts☆

Abstract

Nuclear morphometry and mitotic indexes as prognostic factors in breast cancer

Eur J Surg

Mitotic indexes as prognostic predictors in female breast cancer

J Cancer Res Clin Oncol

The value of morphometry to classic prognosticators in breast cancer

Cancer

Pathologic correlates of survival in 378 lymph node negative infiltrating ductal breast carcinomas: Mitotic count is the best single predictor

Cancer

Prediction of prognosis of breast cancer: Multivariate analysis of mitotic index, lymph node status, and tumour size

The value of mitotic counting in the assessment of prognosis and proliferation in human tumours

J Pathol

Scope and conceipts of quantitative histopathology

Acta Stereol

Prospective evaluation of prognostic value of morphometry in patients with primary breast cancer

J Clin Pathol

Correlation between morphometrical parameters and disease-free survival in ductal breast cancer treated only by surgery

Appl Pathol

Further evaluation of the prognostic value of morphometric and flow cytometric parameters in breast cancer patients with long follow-up

Int J Cancer

Standardized mitotic counts in breast cancer: Evaluation of the method

Pathol Res Pract

Volume corrected mitotic index (M/V-INDEX)

Heterogenity of mitotic activity in breast cancer

Histopathology

Comparison of the prognostic value of four methods to assess mitotic activity in 186 invasive breast cancer patients: Classical and random mitotic activity assessment with correction for volume percentage of epithelium

Hum Pathol

Use of the mitotic counts for the prognosis and grading of breast cancer: Method evaluation study

Pathol Res Pract

The impact of mitotic index on predicting outcome in breast carcinoma: A comparison of different counting methods in patients with different lymph node status

Mod Pathol

Can you count on the mitotic index?

Hum Pathol

The clinical assessment of proliferation and growth in human tumours: Evaluation of methods and applications as prognostic variables

J Pathol

Histologic grading of breast carcinoma: A reproducibility study

Cancer

Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up

Histopathology

Status of breast cancer prognostication based on histopathologic data

Am J Clin Pathol

Breast cancer prognostication: Morphometric thresholds for nuclear grading

Br J Cancer

Histological grading and prognosis in breast cancer

Br J Cancer

The position of histology in the prognosis of carcinoma of the breast

Lancet

Histological typing of breast tumours

Aggressiveness of breast cancers found with and without screening

BMJ

Mammography screening interval and the frequency of interval cancers in a population-based screening

Br J Cancer

A Manual of Morphometry in Diagnostic Pathology

The Multicenter Morphometric Mammary Carcinoma Project (MMMCP): A nationwide prospective study on reproducibility and prognostic power of routine quantitative assessments in the Netherlands

Pathol Res Pract

Mitotic counts in breast cancer: The influence of training performance

Pathol Res Pract

Maximum utilization of the life table method in analyzing survival

J Chron Dis

Beyond normality

Beyond normality

Original contribution
Morphometric grading in breast cancer: Tfor mitotic counts☆