Publications

Facebooktwittergoogle_plusredditpinterestlinkedinFacebooktwittergoogle_plusredditpinterestlinkedin

Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.

Cserni G, Wells CA, Kaya H, Regitnig P, Sapino A, Floris G, Decker T, Foschini MP, van Diest PJ, Grabau D, Reiner A, DeGaetano J, Chmielik E, Cordoba A, Andreu X, Zolota V, Charafe-Jauffret E, Ryska A, Varga Z, Weingertner N, Bellocq JP, Liepniece-Karele I, Callagy G, Kulka J, Bürger H, Figueiredo P, Wesseling J, Amendoeira I, Faverly D, Quinn CM, Bianchi S.

Virchows Arch. 2016 Jan 27. [Epub ahead of print]

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100 % agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Pathological non-response to chemotherapy in a neoadjuvant setting of breast cancer: an inter-institutional study

Balmativola, D., C. Marchio, M. Maule, L. Chiusa, L. Annaratone, F. Maletta, F. Montemurro, J. Kulka, P. Figueiredo, Z. Varga, I. Liepniece-Karele, G. Cserni, E. Arkoumani, I. Amendoeira, G. Callagy, A. Reiner-Concin, A. Cordoba, S. Bianchi, T. Decker, D. Glaser, C. Focke, P. van Diest, D. Grabau, E. Lips, J. Wesseling, R. Arisio, E. Medico, C. Wells and A. Sapino (2014).

Breast Cancer Res Treat 148(3): 511-523.

http://www.ncbi.nlm.nih.gov/pubmed/25395316

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243004/pdf/10549_2014_Article_3192.pdf

To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the adjuvant setting. Sixteen pathologists of the European Working Group for Breast Screening Pathology reviewed the core biopsies of breast cancers treated with NAC and recorded the clinico-pathological findings (histological type and grade; estrogen, progesterone receptors, and HER2 status; Ki67; mitotic count; tumor-infiltrating lymphocytes; necrosis) and data regarding the pathological response in corresponding surgical resection specimens. Analyses were carried out in a cohort of 490 cases by comparing the groups of patients showing pathological complete response (pCR) and partial response (pPR) with the group of non-responders (pathological non-response: pNR). Among other parameters, the lobular histotype and the absence of inflammation were significantly more common in pNR (p < 0.001). By ROC curve analyses, cut-off values of 9 mitosis/2 mm(2) and 18% of Ki67-positive cells best discriminated the pNR and pCR + pPR categories (p = 0.018 and < 0.001, respectively). By multivariable analysis, only the cut-off value of 9 mitosis discriminated the different response categories (p = 0.036) in the entire cohort. In the Luminal B/HER2- subgroup, a mitotic count <9, although not statistically significant, showed an OR of 2.7 of pNR. A lobular histotype and the absence of inflammation were independent predictors of pNR (p = 0.024 and <0.001, respectively). Classical morphological parameters, such as lobular histotype and inflammation, confirmed their predictive value in response to NAC, particularly in the Luminal B/HER2- subgroup, which is a challenging breast cancer subtype from a therapeutic point of view. Mitotic count could represent an additional marker but has a poor positive predictive value.

 

Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values

Cserni, G., A. Voros, I. Liepniece-Karele, S. Bianchi, V. Vezzosi, D. Grabau, A. Sapino, I. Castellano, P. Regitnig, M. P. Foschini, V. Zolota, Z. Varga, P. Figueiredo, T. Decker, C. Focke, J. Kulka, H. Kaya, A. Reiner-Concin, I. Amendoeira, G. Callagy, E. Caffrey, J. Wesseling and C. Wells (2014).

Breast 23(3): 259-263.

http://www.ncbi.nlm.nih.gov/pubmed/24613255

http://www.thebreastonline.com/article/S0960-9776(14)00031-9/abstract

The Ki67 labelling index (LI – proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5.

 

Pathology update. Quality assurance guidelines for pathology. In: European guidelines for quality assurance in breast cancer screening and diagnosis, Supplements.

DOWNLOAD HERE

Wells, C. A., A. I, J. P. Bellocq, S. Bianchi, W. Boecker, B. Borisch, B. Bruun Rasmussen, G. M. Callagy, C. E., A. Cordoba, G. Cserni, T. Decker, J. DeGaetano, M. Drijkoningen, I. O. Ellis, D. R. Faverly, M. P. Foschini, S. Frković-Grazio, D. Grabau, P. Heikkilä, E. Iacovou, J. Jacquemier, H. Kaya, J. Kulka, M. Lacerda, I. Liepniece-Karele, J. Martinez-Penuela, C. M. Quinn, F. Rank, P. Regitnig, A. Reiner, A. Sapino, T. Tot, P. J. Van Diest, Z. Varga, J. Wesseling, V. Zolota and E. Zozaya-Alvarez (2013).

  1. Perry, M. Broeders, C. de Wolf et al. Luxembourg, European Commission, Office for Official Publications of the European Union.

 

 

Distinction of isolated tumour cells and micrometastasis in lymph nodes of breast cancer patients according to the new Tumour Node Metastasis (TNM) definitions

Cserni, G., I. Amendoeira, S. Bianchi, E. Chmielik, J. Degaetano, D. Faverly, P. Figueiredo, M. P. Foschini, D. Grabau, J. Jacquemier, H. Kaya, J. Kulka, M. Lacerda, I. Liepniece-Karele, J. M. Penuela, C. Quinn, P. Regitnig, A. Reiner-Concin, A. Sapino, P. J. van Diest, Z. Varga, V. Vezzosi, J. Wesseling, V. Zolota, E. Zozaya and C. A. Wells (2011).

Eur J Cancer 47(6): 887-894.

http://www.ncbi.nlm.nih.gov/pubmed/21168328

Isolated tumour cells and micrometastases represent two different staging categories and are often dealt with differently when identified in sentinel lymph nodes of breast cancer patients. The reproducibility of these categories was found to be suboptimal in several studies. The new edition of the TNM (Tumour Node Metastasis) is expected to improve the reproducibility of these categories. Fifty cases of possible low-volume nodal involvement were represented by one to four digital images and were analysed by members of the European Working Group for Breast Screening Pathology (EWGBSP). The kappa value for interobserver agreement of the pN (TNM) staging categories and of the isolated tumour cells category were 0.55 and 0.56 reflecting moderate reproducibility, and the kappa of the micrometastatic category (0.62) reflected substantial reproducibility. This is an improvement over the results gained on the basis of the previous edition of the TNM. Maximal adherence to the category definitions supplemented by explanatory texts in the staging manual should result in more homogeneous nodal staging of breast cancer.

 

Quality indicators in breast cancer care

Del Turco, M. R., A. Ponti, U. Bick, L. Biganzoli, G. Cserni, B. Cutuli, T. Decker, M. Dietel, O. Gentilini, T. Kuehn, M. P. Mano, P. Mantellini, L. Marotti, P. Poortmans, F. Rank, H. Roe, E. Scaffidi, J. A. van der Hage, G. Viale, C. Wells, M. Welnicka-Jaskiewicz, Y. Wengstom and L. Cataliotti (2010).

Eur J Cancer 46(13): 2344-2356.

http://www.ncbi.nlm.nih.gov/pubmed/20675120

To define a set of quality indicators that should be routinely measured and evaluated to confirm that the clinical outcome reaches the requested standards, Eusoma has organised a workshop during which twenty four experts from different disciplines have reviewed the international literature and selected the main process and outcome indicators available for quality assurance of breast cancer care. A review of the literature for evidence-based recommendations have been performed by the steering committee. The experts have identified the quality indicators also taking into account the usability and feasibility. For each of them it has been reported: definition, minimum and target standard, motivation for selection and level of evidence (graded according to AHRO). In overall 17 main quality indicators have been identified, respectively, 7 on diagnosis, 4 on surgery and loco-regional treatment, 2 on systemic treatment and 4 on staging, counselling, follow-up and rehabilitation. Breast Units in Europe are invited to comply with these indicators and monitor them during their periodic audit meetings.

 

Nodal-stage classification in invasive lobular breast carcinoma: influence of different interpretations of the pTNM classification

van Deurzen, C. H., G. Cserni, S. Bianchi, V. Vezzosi, R. Arisio, J. Wesseling, M. Asslaber, M. P. Foschini, A. Sapino, I. Castellano, G. Callagy, D. Faverly, M. D. Martin-Martinez, C. Quinn, I. Amendoeira, J. Kulka, A. Reiner-Concin, A. Cordoba, C. A. Seldenrijk and P. J. van Diest (2010).

J Clin Oncol 28(6): 999-1004.

http://www.ncbi.nlm.nih.gov/pubmed/20085942

http://jco.ascopubs.org/content/28/6/999.full.pdf

PURPOSE Application of current nodal status classification is complicated in lobular breast carcinoma metastases. The aim of this study was to define the optimal interpretation of the pTNM classification in sentinel node (SN) -positive patients to select patients with limited or with a high risk of non-SN involvement. PATIENTS AND METHODS SN metastases of 392 patients with lobular breast carcinoma were reclassified according to interpretations of the European Working Group for Breast Screening Pathology (EWGBSP) and guidelines by Turner et al, and the predictive power for non-SN involvement was assessed. Results Reclassification according to definitions of EWGBSP and Turner et al resulted in different pN classification in 73 patients (19%). The rate of non-SN involvement in the 40 patients with isolated tumor cells according to Turner et al and with micrometastases according to EWGBSP was 20%, which is comparable to the established rate for micrometastases. The rate of non-SN involvement in the 29 patients with micrometastases according to Turner et al and with macrometastases according to EWGBSP was 48%, which is comparable to the established rate for macrometastases. Therefore, the EWGBSP method to classify SN tumor load better reflected the risk of non-SN involvement than the Turner et al system. CONCLUSION Compared with the guidelines by Turner et al, the EWGBSP definitions better reflect SN metastatic tumor load and allow better differentiation between patients with lobular breast carcinoma who have a limited or a high risk of non-SN metastases. Therefore, we suggest using the EWGBSP definitions in these patients to select high-risk patients who may benefit from additional local and/or systemic therapy.

 

Variations in sentinel node isolated tumour cells/micrometastasis and non-sentinel node involvement rates according to different interpretations of the TNM definitions

Cserni, G., S. Bianchi, V. Vezzosi, P. van Diest, C. van Deurzen, I. Sejben, P. Regitnig, M. Asslaber, M. P. Foschini, A. Sapino, I. Castellano, G. Callagy, E. Arkoumani, J. Kulka and C. A. Wells (2008).

Eur J Cancer 44(15): 2185-2191.

http://www.ncbi.nlm.nih.gov/pubmed/18691877

Breast cancers with nodal isolated tumour cells (ITC) and micrometastases are categorised as node-negative and node-positive, respectively, in the tumour node metastasis (TNM) classification. Two recently published interpretations of the TNM definitions were applied to cases of low-volume sentinel lymph node (SLN) involvement and their corresponding non-SLNs for reclassification as micrometastasis or ITC. Of the 517 cases reviewed, 82 had ITC and 435 had micrometastasis on the basis of one classification, and the number of ITC increased to 207 with 310 micrometastases on the basis of the other. Approximately 24% of the cases were discordantly categorised. The rates of non-SLN metastases associated with SLN ITCs were 8.5% and 13.5%, respectively. Although the second interpretation of low-volume nodal stage categories has better reproducibility, it may underestimate the rate of non-SLN involvement. The TNM definitions of low-volume nodal metastases need to be better formulated and supplemented with visual information in the form of multiple sample images.

 

Guidelines on the standards for the training of specialised health professionals dealing with breast cancer

Cataliotti, L., C. De Wolf, R. Holland, L. Marotti, N. Perry, K. Redmond, M. Rosselli Del Turco, H. Rijken, N. Kearney, I. O. Ellis, A. Di Leo, R. Orecchia, A. Noel, M. Andersson, W. Audretsch, N. Bjurstam, R. W. Blamey, M. Blichert-Toft, H. Bosmans, A. Burch, G. Bussolati, M. R. Christiaens, M. Colleoni, G. Cserni, T. Cufer, S. Cush, J. Damilakis, M. Drijkoningen, P. Ellis, J. Foubert, M. Gambaccini, E. Gentile, F. Guedea, J. Hendriks, R. Jakesz, J. Jassem, B. A. Jereczek-Fossa, O. Laird, E. Lartigau, W. Mattheiem, N. O’Higgins, E. Pennery, D. Rainsbury, E. Rutgers, M. Smola, E. Van Limbergen, K. von Smitten, C. Wells, R. Wilson and Eusoma (2007).

Eur J Cancer 43(4): 660-675.

http://www.ncbi.nlm.nih.gov/pubmed/17276672

According to EUSOMA position paper ‘The requirements of a specialist breast unit’, each breast unit should have a core team made up of health professionals who have undergone specialist training in breast cancer. In this paper, on behalf of EUSOMA, authors have identified the standards of training in breast cancer, to harmonise and foster breast care training in Europe. The aim of this paper is to contribute to the increase in the level of care in a breast unit, as the input of qualified health professionals increases the quality of breast cancer patient care.

 

European guidelines for quality assurance in breast cancer screening and diagnosis

DOWNLOAD HERE

Perry, N., M. Broeders, C. de Wolf, S. Törnberg, R. Holland, L. von Karsa and E. Puthaar (2006). European Comission.

 

 

Improving the reproducibility of diagnosing micrometastases and isolated tumor cells

Cserni, G., S. Bianchi, W. Boecker, T. Decker, M. Lacerda, F. Rank, C. A. Wells and P. European Working Group for Breast Screening Pathology (2005).

Cancer 103(2): 358-367.

http://www.ncbi.nlm.nih.gov/pubmed/15593354

http://onlinelibrary.wiley.com/store/10.1002/cncr.20760/asset/20760_ftp.pdf?v=1&t=ibcb6rq1&s=d9c56f658379aaca4aa608de6571d3e71332134a

BACKGROUND: The latest edition of the tumor-lymph node-metastasis (TNM) classification of malignant tumors distinguishes between isolated tumor cells (pN0) and micrometastases (pN1mi). The reproducibility of these categories has not been assessed previously. METHODS: Digital images from 50 cases with low-volume lymph node involvement from axillary sentinel lymph nodes were circulated twice for evaluation (Evaluation Rounds 1 and 2) among the members of the European Working Group for Breast Screening Pathology, and the members were asked to categorize lesions as micrometastasis, isolated tumor cells, or something else and to classify each case into a pathologic lymph node (pN) category of the pathologic TNM system. Methods for improving the low reproducibility of the categorizations were discussed between the two evaluation rounds. kappa Statistics were used for the assessment of interobserver variability. RESULTS: The kappa value for the consistency of categorizing low-volume lymph node load into micrometastasis, isolated tumor cells, or neither of those changed from 0.39 to 0.49 between Evaluation Rounds 1 and 2, but it was slightly lower for the pN categories (0.35 and 0.44, respectively). Interpretation of the definitions of isolated tumor cells (especially with respect to their localization within the lymph node), lack of guidance on how to measure them if they were multiple, and lack of any definitions for multiple simultaneous foci of lymph node involvement were listed among the causes of discordant diagnoses. CONCLUSIONS: The results of the current study indicated that the definitions available have minor contradictions and do not permit a reproducible distinction between micrometastases and isolated tumor cells. Refinement of these definitions, therefore, is required. One refinement that may improve reproducibility is suggested in this report.

 

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology

Cserni, G., I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, W. Boecker, B. Borisch, C. E. Connolly, T. Decker, P. Dervan, M. Drijkoningen, I. O. Ellis, C. W. Elston, V. Eusebi, D. Faverly, P. Heikkila, R. Holland, H. Kerner, J. Kulka, J. Jacquemier, M. Lacerda, J. Martinez-Penuela, C. De Miguel, J. L. Peterse, F. Rank, P. Regitnig, A. Reiner, A. Sapino, B. Sigal-Zafrani, A. M. Tanous, S. Thorstenson, E. Zozaya, G. Fejes and C. A. Wells (2004).

J Clin Pathol 57(7): 695-701.

http://www.ncbi.nlm.nih.gov/pubmed/15220360

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770358/pdf/jcp05700695.pdf

AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

 

Consistency of staining and reporting of oestrogen receptor immunocytochemistry within the European Union–an inter-laboratory study

Wells, C. A., J. P. Sloane, D. Coleman, C. Munt, I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, W. Boecker, G. Bussolati, C. E. Connolly, P. Dervan, M. Drijkoningen, I. O. Ellis, C. W. Elston, V. Eusebi, D. Faverly, P. Heikkila, R. Holland, J. Jacquemier, M. Lacerda, J. Martinez-Penuela, C. De Miguel, J. L. Peterse, F. Rank, A. Reiner, E. Saksela, B. Sigal-Zafrani, M. Sylvan, B. Borisch, G. Cserni, T. Decker, H. Kerner, J. Kulka, P. Regitnig, A. Sapino, A. M. Tanous, S. Thorstenson, E. Zozaya and P. European Working Group for Breast Screening (2004).

Virchows Arch 445(2): 119-128.

http://www.ncbi.nlm.nih.gov/pubmed/15221370

To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.

 

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines

Cserni, G., I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, G. Bussolati, W. Boecker, B. Borisch, C. E. Connolly, T. Decker, P. Dervan, M. Drijkoningen, I. O. Ellis, C. W. Elston, V. Eusebi, D. Faverly, P. Heikkila, R. Holland, H. Kerner, J. Kulka, J. Jacquemier, M. Lacerda, J. Martinez-Penuela, C. De Miguel, J. L. Peterse, F. Rank, P. Regitnig, A. Reiner, A. Sapino, B. Sigal-Zafrani, A. M. Tanous, S. Thorstenson, E. Zozaya, C. A. Wells and P. European Working Group for Breast Screening (2003).

Eur J Cancer 39(12): 1654-1667.

http://www.ncbi.nlm.nih.gov/pubmed/12888359

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

 

Causes of inconsistency in diagnosing and classifying intraductal proliferations of the breast. European Commission Working Group on Breast Screening Pathology

Elston, C. W., J. P. Sloane, I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, W. Boecker, G. Bussolati, D. Coleman, C. E. Connolly, P. Dervan, M. Drijkoningen, V. Eusebi, D. Faverly, R. Holland, J. Jacquemier, M. Lacerda, J. Martinez-Penuela, C. de Miguel, S. Mossi, C. Munt, J. L. Peterse, F. Rank, A. Reiner, M. Sylvan, C. A. Wells and B. Zafrani (2000).

Eur J Cancer 36(14): 1769-1772.

http://www.ncbi.nlm.nih.gov/pubmed/10974624

It is now widely recognised that classifying ductal carcinoma in situ (DCIS) of the breast and diagnosing atypical ductal hyperplasia are associated with significant interobserver variation. Two possible reasons for this inconsistency are differences in the interpretation of specified histological features and field selection where morphology is heterogeneous. In order to investigate the relative contribution of these two factors to inconsistent interpretation of intraductal proliferations, histological sections of 32 lesions were sent to 23 European pathologists followed 3 years later by images of small parts of these sections. Kappa statistics for diagnosing hyperplasia of usual type, atypical ductal hyperplasia and ductal carcinoma in situ were 0.54, 0.35 and 0.78 for sections and 0.47, 0.29 and 0.78 for images, respectively, showing that most of the inconsistency is due to differences in morphological interpretation. Improvements can thus be expected only if diagnostic criteria or methodology are changed. In contrast, kappa for classifying DCIS by growth pattern was very low at 0.23 for sections and better at 0.47 for images, reflecting the widely recognised variation in the growth pattern of DCIS. Higher kappa statistics were obtained when any mention of an individual growth pattern was included in that category, thus allowing multiple categories per case; but kappa was still higher for images than sections. Classifying DCIS by nuclear grade gave kappa values of 0.36 for sections and 0.49 for images, indicating that intralesional heterogeneity has hitherto been underestimated as a cause of inconsistency in classifying DCIS by this method. More rigorous assessment of the proportions of the different nuclear grades present could lead to an improvement in consistency.

 

[Breast cytology guidelines for a mammographic screening program. Report edited by the working group on “Breast Pathology in the Mammographic Screening Program” of the European Union]

Sapino, A., S. Bianchi and G. Bussolati (1999).

Pathologica 91(3): 203-208.

http://www.ncbi.nlm.nih.gov/pubmed/10536467

 

Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas. European Commission Working Group on Breast Screening Pathology

Sloane, J. P., I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, W. Boecker, G. Bussolati, D. Coleman, C. E. Connolly, V. Eusebi, C. De Miguel, P. Dervan, R. Drijkoningen, C. W. Elston, D. Faverly, A. Gad, J. Jacquemier, M. Lacerda, J. Martinez-Penuela, C. Munt, J. L. Peterse, F. Rank, M. Sylvan, V. Tsakraklides and B. Zafrani (1999).

Virchows Arch 434(1): 3-10.

http://www.ncbi.nlm.nih.gov/pubmed/10071228

A detailed analysis of the consistency with which pathologists from 12 different European countries diagnose and classify breast disease was undertaken as part of the quality assurance programme of the European Breast Screening Pilot Network funded by the Europe against Cancer Programme. Altogether 107 cases were examined by 23 pathologists in 4 rounds. Kappa statistics for major diagnostic categories were: benign (not otherwise specified) 0.74, atypical ductal hyperplasia (ADH) 0.27, ductal carcinoma in situ (DCIS) 0.87 and invasive carcinoma 0.94. ADH was the majority diagnosis in only 2 cases but was diagnosed by at least 2 participants in another 14, in 9 of which the majority diagnosis was benign (explaining the relatively low kappa for this category). DCIS in 4 (all low nuclear grade) and invasive carcinoma (a solitary 1-mm focus) in 1. The histological features of these cases were extremely variable; although one feature that nearly all shared was the presence of cells with small, uniform, hyperchromatic nuclei and a high nucleo-cytoplasmic ratio. The majority diagnosis was DCIS in 33 cases; kappa for classifying by nuclear grade was 0.38 using three categories and 0.46 when only two (high and other) were used. When ADH was included with low nuclear grade DCIS there was only a slight improvement in kappa. Size measurement of DCIS was less consistent than that of invasive carcinoma. The majority diagnosis was invasive carcinoma in 57 cases, the size of the majority being 100% in 49. The remainder were either special subtypes (adenoid cystic, tubular, colloid, secretory, ductal/medullary) or possible microinvasive carcinomas. Subtyping was most consistent for mucinous (kappa, 0.92) and least consistent for medullary carcinomas (kappa, 0.56). Consistency of grading using the Nottingham method was moderate (kappa=0.53) and consistency of diagnosing vascular invasion, fair (kappa=0.38). There was no tendency for consistency to improve from one round to the next, suggesting that further improvements are unlikely without changes in guidelines or methodology.

 

Consistency achieved by 23 European pathologists in categorizing ductal carcinoma in situ of the breast using five classifications. European Commission Working Group on Breast Screening Pathology

Sloane, J. P., I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, W. Boecker, G. Bussolati, D. Coleman, C. E. Connolly, P. Dervan, V. Eusebi, C. De Miguel, M. Drijkoningen, C. W. Elston, D. Faverley, A. Gad, J. Jacquemier, M. Lacerda, J. Martinez-Penuela, C. Munt, J. L. Peterse, F. Rank, M. Sylvan, V. Tsakraklides and B. Zafrani (1998).

Hum Pathol 29(10): 1056-1062.

http://www.ncbi.nlm.nih.gov/pubmed/9781641

The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening, the greater use of breast-conserving surgery, and the recognition that certain histological subtypes are associated with a greater risk of local recurrence has led to the formulation of several new classifications of DCIS in recent years. There are, however, no data concerning the degree of consistency with which these schemes can be applied by reasonable numbers of pathologists. Thirty-three cases of DCIS were thus examined by a working group of 23 European pathologists who categorized them using five recently published classifications: (1) that of the European Pathologists’ Working Group based on differentiation (a combination of nuclear grade and cell polarization) with categories of poorly, intermediately, and well differentiated; (2) one based entirely on nuclear grade with categories of high, intermediate, and low, currently in use in the UK national and EC-funded breast screening programs; (3) the same classification in which only two categories, high nuclear grade and other, were used; (4) the Van Nuys system in which lesions are divided into high grade, non-high grade with necrosis and non-high grade without necrosis; and (5) a two-category classification based entirely on the presence or absence of comedo necrosis. Of the three systems with three categories, Van Nuys gave the highest overall kappa statistic of 0.42. Others gave similar values of 0.37 and 0.35 showing that assessing cell polarization in addition to nuclear grade neither improves nor worsens consistency. In all three systems, the middle category was associated with the lowest value for kappa. Of the two systems with two categories, that based on nuclear grade gave the highest overall kappa of 0.46 and that based on comedo necrosis the lowest of 0.34. The most robust histological features were thus high- and low-grade nuclei and necrosis as long as the latter did not involve the recognition of a comedo growth pattern. These values probably represent the maximum achievable, at least by reasonable numbers of pathologists in everyday practice. They are better than those previously reported for classification based entirely on architecture, but further improvement is needed.

 

[Guidelines concerning breast pathology in the course of mammographic screening programs. Working group on “Breast pathology in mammographic screening programs” of the European Communities]

Bianchi, S., A. Sapino and G. Bussolati (1997).

Pathologica 89(3): 234-255.

http://www.ncbi.nlm.nih.gov/pubmed/9380418

 

[Guidelines for pathology–supplement to European guidelines for quality assurance in mammography screening. Report by the Pathology Working Group of the European Community]

Sloane, J. P., I. Amendoeira, N. Apostolikas, J. P. Bellocq, S. Bianchi, W. Bocker, G. Bussolati, C. E. Connolly, C. De Miguel, P. Dervan, R. Drijkoningen, C. W. Elston, D. Faverly, A. Gad, R. Holland, J. Jacquemier, M. Lacerda, A. Lindgren, J. Martinez-Penuela, J. L. Peterse, F. Rank, V. Tsakraklides, C. de Wolf and B. Zafrani (1997).

Pathologe 18(1): 71-88.

http://www.ncbi.nlm.nih.gov/pubmed/9157408