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Modern Pathology : An Official Journal... Mar 2024In recent years, artificial intelligence (AI) has demonstrated exceptional performance in mitosis identification and quantification. However, the implementation of AI in...
In recent years, artificial intelligence (AI) has demonstrated exceptional performance in mitosis identification and quantification. However, the implementation of AI in clinical practice needs to be evaluated against the existing methods. This study is aimed at assessing the optimal method of using AI-based mitotic figure scoring in breast cancer (BC). We utilized whole slide images from a large cohort of BC with extended follow-up comprising a discovery (n = 1715) and a validation (n = 859) set (Nottingham cohort). The Cancer Genome Atlas of breast invasive carcinoma (TCGA-BRCA) cohort (n = 757) was used as an external test set. Employing automated mitosis detection, the mitotic count was assessed using 3 different methods, the mitotic count per tumor area (MCT; calculated by dividing the number of mitotic figures by the total tumor area), the mitotic index (MI; defined as the average number of mitotic figures per 1000 malignant cells), and the mitotic activity index (MAI; defined as the number of mitotic figures in 3 mm area within the mitotic hotspot). These automated metrics were evaluated and compared based on their correlation with the well-established visual scoring method of the Nottingham grading system and Ki67 score, clinicopathologic parameters, and patient outcomes. AI-based mitotic scores derived from the 3 methods (MCT, MI, and MAI) were significantly correlated with the clinicopathologic characteristics and patient survival (P < .001). However, the mitotic counts and the derived cutoffs varied significantly between the 3 methods. Only MAI and MCT were positively correlated with the gold standard visual scoring method used in Nottingham grading system (r = 0.8 and r = 0.7, respectively) and Ki67 scores (r = 0.69 and r = 0.55, respectively), and MAI was the only independent predictor of survival (P < .05) in multivariate Cox regression analysis. For clinical applications, the optimum method of scoring mitosis using AI needs to be considered. MAI can provide reliable and reproducible results and can accurately quantify mitotic figures in BC.
Topics: Humans; Female; Breast Neoplasms; Ki-67 Antigen; Artificial Intelligence; Mitosis; Mitotic Index
PubMed: 38154653
DOI: 10.1016/j.modpat.2023.100416 -
Histopathology Feb 2023Mitotic count in breast cancer is an important prognostic marker. Unfortunately, substantial inter- and intraobserver variation exists when pathologists manually count...
Improving mitotic cell counting accuracy and efficiency using phosphohistone-H3 (PHH3) antibody counterstained with haematoxylin and eosin as part of breast cancer grading.
BACKGROUND
Mitotic count in breast cancer is an important prognostic marker. Unfortunately, substantial inter- and intraobserver variation exists when pathologists manually count mitotic figures. To alleviate this problem, we developed a new technique incorporating both haematoxylin and eosin (H&E) and phosphorylated histone H3 (PHH3), a marker highly specific to mitotic figures, and compared it to visual scoring of mitotic figures using H&E only.
METHODS
Two full-face sections from 97 cases were cut, one stained with H&E only, and the other was stained with PHH3 and counterstained with H&E (PHH3-H&E). Counting mitoses using PHH3-H&E was compared to traditional mitoses scoring using H&E in terms of reproducibility, scoring time, and the ability to detect mitosis hotspots. We assessed the agreement between manual and image analysis-assisted scoring of mitotic figures using H&E and PHH3-H&E-stained cells. The diagnostic performance of PHH3 in detecting mitotic figures in terms of sensitivity and specificity was measured. Finally, PHH3 replaced the mitosis score in a multivariate analysis to assess its significance.
RESULTS
Pathologists detected significantly higher mitotic figures using the PHH3-H&E (median ± SD, 20 ± 33) compared with H&E alone (median ± SD, 16 ± 25), P < 0.001. The concordance between pathologists in identifying mitotic figures was highest when using the dual PHH3-H&E technique; in addition, it highlighted mitotic figures at low power, allowing better agreement on choosing the hotspot area (k = 0.842) in comparison with standard H&E (k = 0.625). A better agreement between image analysis-assisted software and the human eye was observed for PHH3-stained mitotic figures. When the mitosis score was replaced with PHH3 in a Cox regression model with other grade components, PHH3 was an independent predictor of survival (hazard ratio [HR] 5.66, 95% confidence interval [CI] 1.92-16.69; P = 0.002), and even showed a more significant association with breast cancer-specific survival (BCSS) than mitosis (HR 3.63, 95% CI 1.49-8.86; P = 0.005) and Ki67 (P = 0.27).
CONCLUSION
Using PHH3-H&E-stained slides can reliably be used in routine scoring of mitotic figures and integrating both techniques will compensate for each other's limitations and improve diagnostic accuracy, quality, and precision.
Topics: Humans; Female; Eosine Yellowish-(YS); Mitotic Index; Breast Neoplasms; Hematoxylin; Reproducibility of Results; Biomarkers, Tumor; Immunohistochemistry; Mitosis; Antibodies; Phosphorylation
PubMed: 36349500
DOI: 10.1111/his.14837 -
Journal of Medical Case Reports Jan 2016Atypical uterine leiomyomas show benign behavior. However, the distinction between leiomyomas and leiomyosarcomas may at times be problematic. We report a rare case of... (Review)
Review
BACKGROUND
Atypical uterine leiomyomas show benign behavior. However, the distinction between leiomyomas and leiomyosarcomas may at times be problematic. We report a rare case of atypical uterine leiomyoma. We try to investigate potential immunohistochemical parameters that could be essential to distinguish cases of malignant smooth muscle tumors and those of uncertain or borderline histology.
CASE PRESENTATION
A 56-year-old white ethnic Albanian woman from Kosovo presented with uterine bleeding because of uterine multiple leiomyomas. A hysterectomy with unilateral adnexectomy was performed. Her hysterectomy specimen contained multiple leiomyomas in submucosal, intramural and subserosal locations. The leiomyomas were well demarcated, firm and white with a whorled cut surface and one had foci of hemorrhage. Histology of most of the leiomyomas showed a whorled (fascicular) pattern of smooth muscle bundles separated by well-vascularized connective tissue. Smooth muscle cells were elongated with eosinophilic or occasional fibrillar cytoplasm and distinct cell membranes. Some of them developed areas of degeneration including hyaline change, with less than five mitotic figures per ten high power fields in most mitotically active areas, and no significant atypia. One leiomyoma was characterized by moderately to severely pleomorphic atypical tumor cells with low mitotic counts and no coagulative tumor cell necrosis. Immunohistochemistry showed strong immunoreactivity for vimentin, smooth muscle actin and desmin, while cyclin-dependent kinase inhibitor 2A (p16), and B-cell lymphoma 2 (bcl-2) showed focal immunoreactivity, estrogen and progesterone were positive, Ki-67 expressed a low proliferation index, whereas p21 and tumor suppressor gene p53 were negative.
CONCLUSIONS
The combination of evaluation of conventional morphologic criteria with cyclin-dependent kinase inhibitor 2A (p16), p21, progesterone, B-cell lymphoma 2, tumor suppressor gene p53 and Ki-67 expression may be of great value in the assessment of uterine smooth muscle tumors of uncertain or borderline histology.
Topics: Diagnosis, Differential; Female; Humans; Leiomyomatosis; Leiomyosarcoma; Middle Aged; Mitotic Index; Uterine Neoplasms
PubMed: 26801982
DOI: 10.1186/s13256-016-0800-3 -
International Journal of Clinical and... Nov 2010fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless, FLHCC has a propensity to recur with...
CONTEXT
fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless, FLHCC has a propensity to recur with limited responsiveness to chemotherapy.
OBJECTIVE
The purpose of this study was to provide insight into the cell cycle biology of FLHCC, as it relates to FLHCC's relatively indolent nature and lack of chemoresponsiveness.
DESIGN
in seven cases of FLHCC, we assessed: 1. immunoexpression of protein analytes indicating cell cycle progression including Ki-67 (G1, S, G2 and M phases) and S-phase kinase-associated protein (Skp) 2 along with the mitotic index (MI); 2.immunoreactivity for cyclin-dependent kinase inhibitors of cell cycle progression from G1 to S phase, p27Kip1 and p16INK4.
RESULTS
the mean percentage of Ki-67 nuclear positivity in neoplastic hepatocytes ranged from 1.0% to 29.7%. Nuclear Skp2 immunoexpression was not observed in any of the cases. The mitotic index was very low (0-1 mitotic figure / 10 high-power fields). All cases showed moderate to strong nuclear p16INK4 positivity (diffuse in five and focal in two). Contras-tively, the adjacent non-neoplastic hepatocytes expressed only mild (2 cases) to no (3 cases) p16INK4.
CONCLUSION
our analysis has revealed that cell cycle arrest in FLHCC occurs in G0G1 phase and is associated with overexpression of the cell cycle regulator, p16INK4 in tumoral cell nuclei compared with non-neoplastic hepatocytes. In conjunction with our previous immunohistochemical demonstration of a constitutively activated nuclear factor (NF)-kappaB pathway and stemness characteristics of FLHCC with limited differentiation, this cell cycle arrest elucidates the biology of FLHCC's indolent nature and relative chemoresistance.
Topics: Adult; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Nucleus; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Female; Humans; Ki-67 Antigen; Liver Neoplasms; Male; Mitotic Index; Prognosis; Young Adult
PubMed: 21151393
DOI: No ID Found -
PloS One 2013Dyskerin is a highly conserved, nucleolar RNA-binding protein with established roles in small nuclear ribonucleoprotein biogenesis, telomerase and telomere maintenance...
Dyskerin is a highly conserved, nucleolar RNA-binding protein with established roles in small nuclear ribonucleoprotein biogenesis, telomerase and telomere maintenance and precursor rRNA processing. Telomerase is functional during S phase and the bulk of rRNA maturation occurs during G1 and S phases; both processes are inactivated during mitosis. Yet, we show that during the course of cell cycle progression, human dyskerin expression peaks during G2/M in parallel with the upregulation of pro-mitotic factors. Dyskerin redistributed from the nucleolus in interphase cells to the perichromosomal region during prometaphase, metaphase and anaphase. With continued anaphase progression, dyskerin also localized to the cytoplasm within the mid-pole region. Loss of dyskerin function via siRNA-mediated depletion promoted G2/M accumulation and this was accompanied by an increased mitotic index and activation of the spindle assembly checkpoint. Live cell imaging further revealed an array of mitotic defects including delayed prometaphase progression, a significantly increased incidence of multi-polar spindles, and anaphase bridges culminating in micronucleus formation. Together, these findings suggest that dyskerin is a highly dynamic protein throughout the cell cycle and increases the repertoire of fundamental cellular processes that are disrupted by absence of its normal function.
Topics: Cell Cycle; Cell Cycle Proteins; Cell Line; Cell Nucleolus; Gene Expression; Humans; M Phase Cell Cycle Checkpoints; Micronuclei, Chromosome-Defective; Mitosis; Mitotic Index; Nuclear Proteins; Nucleophosmin; Protein Transport; Spindle Apparatus
PubMed: 24303026
DOI: 10.1371/journal.pone.0080805 -
Romanian Journal of Morphology and... 2014Histopathological and immunohistochemical study of prognostic factors in anterior skull base meningiomas in order to determine the post-operative management.
AIM
Histopathological and immunohistochemical study of prognostic factors in anterior skull base meningiomas in order to determine the post-operative management.
MATERIALS AND METHODS
The studied material consisted in resection specimens from 65 patients with anterior skull base meningiomas hospitalized in Clinic of Neurosurgery, National Institute of Neurology and Neurovascular Diseases, Bucharest, Romania, and diagnosed in the Department of Pathology of the same Institute, between 2007 and 2013. The biological material was processed by standard histological technique with Hematoxylin and Eosin staining which allowed the classification of tumors according to WHO 2007 system and the assessment of the morphological parameters of known prognostic value. Subsequently, the tumor fragments were submitted to immunohistochemistry to evaluate the proliferative activity (Ki-67 labeling index) and progesterone hormone receptor (PR) status.
RESULTS
83.07% of the 65 anterior skull base meningiomas were WHO grade I tumors; the grade II tumors accounted 15.38%, while the grade III tumors were rare (1.53%). Mitotic activity was variable, reaching up to 14 mitoses/10 HPF (high-power field) in atypical and anaplastic tumors; mitoses were absent in 64.81% of grade I tumors; the average mitotic index in grade II tumors was 5.15 mitoses/10 HPF. Both mitotic activity and infiltrative and invasive tumor growth (the latter found in 36.92% of cases) were correlated with tumor grade. Ki-67 labeling index ranged between 1.1% and 7.7%, with the highest value found in anaplastic tumor; progesterone receptors (PR) were expressed with variable index in 84.61% of cases. The immunonegative PR tumors were represented by 16.66% of grade I tumors and by the only grade III tumor. In contrast to PR, Ki-67 expression was statistically correlated with tumor grade. The comparison between the expression of Ki-67 and PR revealed an inverse relationship between the level of PR expression and the proliferative activity intensity.
CONCLUSIONS
We found that PR expression decreases as the biological behavior of tumor becomes more aggressive; it may be related with an increased risk of recurrence, making the postoperative surveillance more rigorous in these patients.
Topics: Adult; Aged; Female; Humans; Ki-67 Antigen; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Mitotic Index; Neoplasm Grading; Prognosis; Receptors, Progesterone; Skull Base
PubMed: 25607386
DOI: No ID Found -
Archives of Pathology & Laboratory... Nov 2020Mitotic count is an important histologic criterion for grading and prognostication in phyllodes tumors (PTs). Counting mitoses is a routine practice for pathologists...
CONTEXT.—
Mitotic count is an important histologic criterion for grading and prognostication in phyllodes tumors (PTs). Counting mitoses is a routine practice for pathologists evaluating neoplasms, but different microscopes, variable field selection, and areas have led to possible misclassification.
OBJECTIVE.—
To determine whether 10 high-power fields (HPFs) or whole slide mitotic counts correlated better with PT clinicopathologic parameters using digital pathology (DP). We also aimed to find out whether this study might serve as a basis for an artificial intelligence (AI) protocol to count mitosis.
DESIGN.—
Representative slides were chosen from 93 cases of PTs diagnosed between 2014 and 2015. The slides were scanned and viewed with DP. Mitotic counting was conducted on the whole slide image, before choosing 10 HPFs and demarcating the tumor area in DP. Values of mitoses per millimeter squared were used to compare results between 10 HPFs and the whole slide. Correlations with clinicopathologic parameters were conducted.
RESULTS.—
Both whole slide counting of mitoses and 10 HPFs had similar statistically significant correlation coefficients with grade, stromal atypia, and stromal hypercellularity. Neither whole slide mitotic counts nor mitoses per 10 HPFs showed statistically significant correlations with patient age and tumor size.
CONCLUSIONS.—
Accurate mitosis counting in breast PTs is important for grading. Exploring machine learning on digital whole slides may influence approaches to training, testing, and validation of a future AI algorithm.
Topics: Adult; Artificial Intelligence; Breast Neoplasms; Cytodiagnosis; Female; Humans; Microscopy; Middle Aged; Mitosis; Mitotic Index; Pathology, Clinical; Phyllodes Tumor; Reproducibility of Results; Sensitivity and Specificity
PubMed: 32150458
DOI: 10.5858/arpa.2019-0435-OA -
The New England Journal of Medicine Apr 1990Measures of the proliferative activity of tumor cells have prognostic value in patients with node-negative breast cancer. We studied 367 women in southern Sweden who had...
Measures of the proliferative activity of tumor cells have prognostic value in patients with node-negative breast cancer. We studied 367 women in southern Sweden who had undergone surgical resection for such cancer. Tumor specimens were analyzed with DNA flow cytometry in order to estimate both the DNA content (ploidy) and the fraction of cells in the synthetic phase of the cell cycle (S phase). The median duration of follow-up was four years; 28 percent of the patients received adjuvant therapy, usually with tamoxifen (n = 83). A multivariate analysis based on complete data on 250 patients included the following covariates: age (greater than or equal to 75, 50 to 74, and less than or equal to 49 years), tumor size (less than or equal to 20 vs. greater than 20 mm), concentration of estrogen and progesterone receptors (less than 10 vs. greater than or equal to 10 fmol per milligram of protein), ploidy (diploid vs. nondiploid), and S-phase category (fraction of cells in S phase: less than 7.0 percent, 7.0 to 11.9 percent, and greater than or equal to 12 percent). The S-phase fraction yielded the most prognostic information, followed by progesterone-receptor status and tumor size. A prognostic model based on these three variables identified 37 percent of the patients as constituting a high-risk group with a fourfold increased risk of distant recurrence. In the remaining 63 percent of the patients, the five-year overall survival rate (92 +/- 4 [+/- SE] percent) did not differ from the expected age-adjusted rate for Swedish women. We conclude that a prognostic index that includes indicators of the proliferative activity of tumor cells may be able to identify women with node-negative breast cancer in whom the risk of recurrence is sufficiently low that adjuvant chemotherapy can be avoided.
Topics: Age Factors; Aged; Analysis of Variance; Breast Neoplasms; DNA; Female; Flow Cytometry; Humans; Lymph Nodes; Middle Aged; Mitotic Index; Ploidies; Prognosis; Receptors, Estrogen; Receptors, Progesterone
PubMed: 2320064
DOI: 10.1056/NEJM199004123221505 -
Brazilian Journal of Biology = Revista... 2021For many centuries human populations have been suffering and trying to fight with disease-bearing mosquitoes. Emerging and reemerging diseases such as Dengue, Zika, and...
For many centuries human populations have been suffering and trying to fight with disease-bearing mosquitoes. Emerging and reemerging diseases such as Dengue, Zika, and Chikungunya affect billions of people around the world and recently has been appealing to control with chemical pesticides. Malathion (MT) is one of the main pesticides used against mosquitoes, the vectors of these diseases. This study aimed to assess cytotoxicity and mutagenicity of the malathion for the bioindicator Allium cepa L. using a multivariate and integrative approach. Moreover, an appendix table was compiled with all available literature of insecticides assessed by the Allium cepa system to support our discussion. Exposures during 48h to 0.5 mg mL-1 and 1.0 mg mL-1 MT were compared to the negative control (distilled water) and positive control (MMS solution at 10 mg L-1). The presence of chromosomal aberrations, micronuclei frequency, and mitotic index abnormalities was evaluated. Anaphase bridges were the alterations with higher incidence and presented a significantly elevated rate in the concentration of 0.5 mg mL-1, including when compared to the positive control. The integrative discriminant analysis summarizes that MT in assessed concentrations presented effects like the positive control, corroborating its potential of toxicity to DNA. Therefore, it is concluded that MT in its pure composition and in realistic concentrations used, has genotoxic potential in the biological assessment of A. cepa cells. The multivariate integrative analysis was fundamental to show a whole response of all data, providing a global view of the effect of MT on DNA.
Topics: Animals; Chromosome Aberrations; DNA Damage; Humans; Insecticides; Malathion; Mitotic Index; Mosquito Vectors; Onions; Plant Roots; Zika Virus; Zika Virus Infection
PubMed: 34133488
DOI: 10.1590/1519-6984.240118 -
Cancer Apr 2002Cell proliferation is a major determinant of the biologic behavior of breast carcinoma. MIB-1 monoclonal antibody is a promising tool for determining cell proliferation... (Comparative Study)
Comparative Study Review
BACKGROUND
Cell proliferation is a major determinant of the biologic behavior of breast carcinoma. MIB-1 monoclonal antibody is a promising tool for determining cell proliferation on routine histologic material. The objectives of this study were to compare MIB-1 evaluation to other methods of measuring cell proliferation, with a view to refining the cutoff used to classify tumors with low and high proliferation rates in therapeutic trials.
METHODS
One hundred eighty-five invasive breast carcinomas were evaluated for cell proliferation by determining monoclonal antibody MIB-1 staining, histologic parameters (Scarff-Bloom-Richardson grade and mitotic index) on paraffin sections, S-phase fraction (SPF) by flow cytometry, and thymidine-kinase (TK) content of frozen samples.
RESULTS
There was a high correlation (P = 0.0001) between the percentage of MIB-1 positive tumor cells and SPF, TK, histologic grade, and the mitotic index. Multivariate analyses including MIB-1 at 5 different cutoffs (10%, 15%, 17% [median], 20%, 25%) and the other proliferative markers showed that the optimal MIB-1 cutoff was 25% and that the mitotic index was the proliferative variable that best discriminated between low and high MIB-1 samples. A MIB-1 cutoff of 25% adequately identified highly proliferative tumors. Conversely, with a MIB-1 cutoff of 10%, few tumors with low proliferation were misclassified.
CONCLUSIONS
The choice of MIB-1 cutoff depends on the following clinical objective: if MIB-1 is used to exclude patients with slowly proliferating tumors from chemotherapeutic protocols, a cutoff of 10% will help to avoid overtreatment. In contrast, if MIB-1 is used to identify patients sensitive to chemotherapy protocols, it is preferable to set the cutoff at 25%. The MIB-1 index should be combined with some other routinely used proliferative markers, such as the mitotic index.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antigens, Nuclear; Biomarkers, Tumor; Biopsy; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Division; DNA, Neoplasm; Female; Flow Cytometry; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Middle Aged; Mitotic Index; Neoplasm Invasiveness; Neoplasm Staging; Nuclear Proteins; Predictive Value of Tests; Receptors, Estrogen; Receptors, Progesterone; Thymidine Kinase
PubMed: 12001111
DOI: 10.1002/cncr.10458