Reproducibility of mitosis counting in 2,469 breast cancer specimens: Results from the Multicenter Morphometric Mammary Carcinoma Project

Diest, Paul J. van; Baak, J. P. A.; Matze-Cok, P.; Wisse-Brekelmans, E.C.M.; Galen, C.M. van; Kurver, P.H.J.; Bellot, S.M.; Fijnheer, J.; Gorp, L. H. M. van; Kwee, W. S.; Los, J. M.; Peterse, J.L.; Ruitenberg, H.M.; Schapers, R.F.M.; Schipper, Maria; Somsen, J.G.; Willig, Alissa; Ariëns, A.Th.

doi:10.1016/0046-8177(92)90313-r

Cited by 324 publications

(246 citation statements)

References 11 publications

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“…Concordance in mitotic counts is highest when counts are determined in the same area, using established counting methods and established criteria. [16][17][18][19] Mitotic counts also depend on the quality of the tissue processing and the size of the ocular lens. 16,18,19 Since the registry relies in part upon the ability of the participating pathologists to select the optimum area for mitotic counts, there was no attempt to guide the reviewers to any single designated area on the study slides and this is likely responsible for some of the interobserver disagreement.…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18][19] Mitotic counts also depend on the quality of the tissue processing and the size of the ocular lens. 16,18,19 Since the registry relies in part upon the ability of the participating pathologists to select the optimum area for mitotic counts, there was no attempt to guide the reviewers to any single designated area on the study slides and this is likely responsible for some of the interobserver disagreement. Nevertheless, it is likely that the category-specific k obtained in our study overestimates the level of agreement that would occur during the actual performance of the registry data collection, since the area of determination of mitotic counts is occasionally selected from among several sections of tumor by the registry pathologist during the actual review procedure.…”

Section: Discussionmentioning

confidence: 99%

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Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study

et al. 2006

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Registry of this type; over 37 724 individuals have been enrolled to date. One activity of this Registry is the semicentralized pathologic review of tumors from all probands. Given the semicentralized nature of the review, this study was undertaken to determine the reproducibility, source(s) of classification discrepancies and stratagems to circumvent discrepancies for histologic subtyping and grading of invasive breast cancer among the reviewing pathologists. A total of 13 pathologists reviewed 35 invasive breast cancers and classified them by primary and secondary histologic type, Nottingham grade and score. Lymph-vascular space invasion, circumscribed margins, syncytial growth and lymphocytic infiltrate were also evaluated. A training session using a separate set of slides was conducted prior to the study. General agreement, in terms of categoryspecific j's and percent agreement, and accuracy of classification relative to a reference standard were determined. Classification of histologic subtype was most consistent (and accurate) for mucinous carcinoma (j ¼ 1.0), followed by tubular (j ¼ 0.8) and lobular subtypes (j ¼ 0.8). Classification of medullary subtype was moderate (j ¼ 0.4), but additional evaluation of degree of lymphocytic infiltrate, syncytial growth and circumscribed margins identified most cases. Category-specific j's were moderate to good for Nottingham grade (j ¼ 0.5-0.7), with the greatest agreement obtained in categorizing grade I (j ¼ 0.7), and grade III tumors (j ¼ 0.7). A flexible classification strategy that employs individual and combined criteria provides good interobserver agreement for invasive breast cancers with uniform, unambiguous histology and compensates for classification discrepancies in the more histologically ambiguous or heterogeneous cancers. Keywords: interobserver reproducibility; invasive breast cancer; familial breast cancer; breast/ovarian cancer family registryThe reproducibility of the classification and grading of invasive breast cancer and the cause(s) of interobserver disagreement among pathologists have not been adequately evaluated. Prior studies evaluating interobserver concordance in categorizing breast lesions have documented improved diagnostic agreement when the pathologists involved used agreed-upon criteria, 1 but other potential sources of poor interobserver agreement, such as the difficulties in the application of the individual histologic criteria, the individual pathologist's variation in use of these criteria, and most importantly, the ambiguous or borderline and heterogeneous nature of the

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study

et al. 2006

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“…According to the modified Bloom and Richardson score, 10 most tumors were grade 2 (44%) or grade 3 (32%). Mitotic activity was assessed as before 11 with a mean mitotic index of 12 per 2 mm 2 (range 0-56). For all cases, hormone receptor and HER2 status were reassessed as described previously.…”

Section: Patient Materialsmentioning

confidence: 99%

Analysis of copy number changes on chromosome 16q in male breast cancer by multiplex ligation-dependent probe amplification

et al. 2013

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Gene copy number changes have an important role in carcinogenesis and could serve as potential biomarkers for prognosis and targets for therapy. Copy number changes mapping to chromosome 16 have been reported to be the most frequent alteration observed in female breast cancer and a loss on 16q has been shown to be associated with low grade and better prognosis. In the present study, we aimed to characterize copy number changes on 16q in a group of 135 male breast cancers using a novel multiplex ligation-dependent probe amplification kit. One hundred and twelve out of 135 (83%) male breast cancer showed copy number changes of at least one gene on chromosome 16, with frequent loss of 16q (71/135; 53%), either partial (66/135; 49%) or whole arm loss (5/135; 4%). Losses on 16q were thereby less often seen in male breast cancer than previously described in female breast cancer. Loss on 16q was significantly correlated with favorable clinicopathological features such as negative lymph node status, small tumor size, and low grade. Copy number gain of almost all genes on the short arm was also significantly correlated with lymph node negative status. A combination of 16q loss and 16p gain correlated even stronger with negative lymph node status (n ¼ 112; P ¼ 0.012), which was also underlined by unsupervised clustering. In conclusion, copy number loss on 16q is less frequent in male breast cancer than in female breast cancer, providing further evidence that male breast cancer and female breast cancer are genetically different. Gain on 16p and loss of 16q identify a group of male breast cancer with low propensity to develop lymph node metastases.

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“…The mitotic activity index is insensitive to variations in tissue processing. [21][22][23] All hematoxylin and eosin-stained sections from the tumors (median 4, range: 3-6) were reviewed and two sections were chosen for immunohistochemical analysis on the basis of: highest percentage of tumor, impression of possible lymphovascular invasion, and least tissue processing artefacts.…”

Section: Pathologymentioning

confidence: 99%

D2-40/p63 defined lymph vessel invasion has additional prognostic value in highly proliferating operable node negative breast cancer patients

et al. 2011

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Phosphohistone H3 assessed proliferation has strong prognostic value. Lymph vessel invasion by D2-40 is also prognostic, but D2-40 þ myoepithelial expression in small ducts completely filled by solid-pattern ductal carcinoma in situ can mimic lymphovascular invasion. As myoepithelial cells are also p63 positive, we have investigated whether lymph vessel invasion identified by combined D2-40/p63 is stronger prognostically than by D2-40 alone, and whether it has independent prognostic value to phosphohistone H3. In 240 operable T 1-2 N 0 M 0 node negative invasive breast cancer patients o71 years, phosphohistone H3 was determined by quantitative immunohistochemistry and lymph vessel invasion by D2-40/p63 double immunostaining. Correlation analysis between the clinico-pathologic factors and lymph vessel invasion, and univariate and multivariate prognostic survival analysis were performed. With median 117 (range: 12-192) months follow-up, 36 patients (15%) developed and 28 (12%) died of distant metastases. Ten of the 61 patients (16%) with cancer cells surrounded by D2-40 were p63 positive and none of these 'false lymph vessel invasion' recurred. D2-40 þ / p63À lymph vessel invasion occurred in 51/239 (21%) cases and correlated with grade, mitotic activity index, phosphohistone H3, ER, cytokeratin14, and HER2. D2-40 þ /p63À lymph vessel invasion was strongly prognostic, but far more in women Z55 than those o55 years (Po0.0001 and 0.04). With multivariate analysis, phosphohistone H3 proliferation was the strongest single prognosticator. Lymph vessel invasion had additional prognostic value to phosphohistone H3 only in women Z55. This group of patients, without/with lymph vessel invasion, had 10-year survival rates of 83 and 50%, respectively (hazard ratio-lymph vessel invasion ¼ 3.0, P ¼ 0.04; hazard ratio-phosphohistone H3 ¼ 6.9, P ¼ 0.002). Where age was o55 years, only phosphohistone H3 had independent prognostic value. Combinations of other features had no additional value. In conclusion, T 1-2 N 0 M 0 invasive breast cancer patients Z55 years with phosphohistone H3Z13, D2-40 þ /p63À defined lymph vessel invasion identifies a subgroup with a high risk of distant metastases.

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Reproducibility of mitosis counting in 2,469 breast cancer specimens: Results from the Multicenter Morphometric Mammary Carcinoma Project

Cited by 324 publications

References 11 publications

Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study

Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study

Analysis of copy number changes on chromosome 16q in male breast cancer by multiplex ligation-dependent probe amplification

D2-40/p63 defined lymph vessel invasion has additional prognostic value in highly proliferating operable node negative breast cancer patients

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