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

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.

Current management of lobular in situ neoplasia.

Although the term of lobular neoplasia was first proposed in 1978 and the term Lobular In situ Neoplasia (LIN) has been incorporated in the current World Health Organisation (WHO) classification to cover both atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), the clinical significance and the natural history of lobular neoplasia is far from being fully understood. Furthermore problems and confusion still remain surrounding (1) the most appropriate terminology and classification for these lesions, (2) the best course of long-term management after diagnosis.This article summarizes the opinions on LCIS management of a group of Belgian experts.

[Vertical reduction mammaplasty for gigantomastia with massive fibroadenomatosis: a case report]. / Réduction mammaire selon la technique verticale pour gigantomastie avec fibroadénomatose massive: à propos d'un cas clinique.

Vertical reduction mammaplasty is one of the most debated << short-scar >> breast reduction technique. Advantages and drawbacks of the technique are discussed; most of the authors do not accept it as the technique of choice for high glandular resection weights. In our case report we achieve it for a resection weight up to two kilograms with an areolar transposition distance of more than ten centimetres. We show that it is reasonable to realize it dealing with gigantomastia. The massive fibroadenomatosis is observed following immunosuppressive treatment for kidney transplantation. Cyclosporine intake, even sporadic, is at the origin of the growth of these multiple, bilateral and large fibroadenomas. Drug-induced cytokines stimulate their development.

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.

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.

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.

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.

MR findings of a primary intramedullary malignant melanoma: case report and literature review.

A case of primary malignant melanoma of the conus medullaris depicted at MR imaging is presented. Tumoral histoimmunologic analysis revealed features of malignant melanoma. Because findings for primary melanoma outside the spinal cord were negative, the diagnosis of primary intramedullary malignant melanoma was established. This rare tumor should be suspected when T1-weighted images show signal hyperintensity and T2-weighted images show signal iso- or hypointensity, with mild contrast enhancement of the lesion. However, these features may vary depending on intratumoral bleeding and melanin content.

Consequences of a National Mammography Screening Program on diagnostic procedures and tumor sizes in breast cancer. A retrospective study of 1540 cases diagnosed and histologically confirmed between 1995 and 1997.

In 1992, a national screening mammography program, including female patients between 50 and 64 years of age, was launched in Luxembourg. The effects of this campaign on the different diagnostic procedures, especially fine needle aspirations (FNA), large core needle biopsies (LCNB), and surgical specimens, were analyzed. From 1983 to 1997, the National Cancer Registry recorded 3167 new cases of invasive female breast cancer, all histologically diagnosed in one central pathology department. In 1996, the population consisted of 418,300 inhabitants (212,900 females). The number of breast cancer, tumor size, the nature of the diagnostic procedures, their diagnostic value as well as the number of physicians, "aspirators", and "biopsists" were evaluated. Between 1992 and 1994, the incidence of invasive breast cancers increased, concomitant with the launching of a National Screening Mammography Program. The diagnosis of in situ cancers tripled, and the mean size of invasive breast cancer decreased from 2.1-2.4 cm to 1.1-1.4 cm. Since 1994, the number of FNA had remained stable, LCNB had increased by 417.5%, and surgical biopsies had decreased by 18.95%. Between 1995 and 1997, 28.37% of 1075 FNA, and only 9.6% of 465 LCNB yielded inadequate samples. FNA were done by 77 different doctors (53.25% being gynecologists) and LCNB by 34 (52.94% being radiologists). The first diagnoses of all invasive cancers (n = 790) were made by using frozen sections from surgical specimens in 58.35% (n = 461), LCNB in 18.23% (n = 144), mastectomy in 10.13% (n = 80), formalin-fixed biopsies in 9.49% (n = 75), and FNA in 3.17% (n = 25). There are beneficial effects (increase in the number of diagnoses of in situ cancer; decrease in tumor sizes) not only for the "target" age group (50-64 years), but also for all female age groups (> 15 years). For quality assurance purposes, it is absolutely recommended to carry out pathological, radiological, and diagnostic work in specialized centers.

Accuracy of frozen section diagnoses of breast lesions after introduction of a national programme in mammographic screening.

AIMS: By introducing mammography screening programmes, the size of the detected breast lesions became smaller and the histopathological interpretation problems greater. The study's aim was to analyse the risks and possible limitations of the frozen section method. METHODS AND RESULTS: Frozen section consultations of breast lesions (n=559) 2 years before and 6 years after launching a national mammographic screening programme in 1992 were evaluated in regard of the benign/malignant ratio, tumour size, preoperative frozen section results and final permanent section diagnoses. The breast frozen section examinations of 1990 compared with those from 1998 declined from 70.7% (299/423) to 62.2% (260/418) (P < 0.01), the benign/malignant ratio from 1.09 to 0.54 (P < 0.0001), the rate of the conclusive, correct frozen section diagnoses from 96.3% to 91.9% (P < 0.03). The sensitivity dropped from 92.3% to 87.6%, the negative predictive value from 95.7% to 88.3%, whereas the negative likelihood ratio rose from 0.08 to 0.12. The 'small' (< or = 10 mm) invasive breast carcinomas increased from 14.2% to 22.3% (P < 0.01) and the 'in situ' carcinomas from 2.1% to 6.6% (P < 0.05). CONCLUSIONS: The declining sizes of breast tumours (< or = 10 mm), especially from radiologically detected lesions and sometimes without a macroscopic correlate, create new limitations and changing indications in the histopathological interpretation. Considering the performance of new diagnostic methods (i.e. large core needle biopsies), frozen sections of surgical specimens should not be the primary diagnostic procedure for breast lesions and should be performed only after other preoperative methods have failed.

Breast carcinomas of limited extent: frequency, radiologic-pathologic characteristics, and surgical margin requirements.

BACKGROUND: Clinical trials established the value of breast-conserving treatment (BCT) including the macroscopic removal of the tumor followed by local radiation therapy (RT) for Stage I and II invasive carcinomas. The occurrence of local tumor recurrence is related to the extent and multifocality of the tumor. Various studies aim to identify those tumors that could be proper candidates for conventional BCT. Furthermore, recent studies have focused on the identification of tumors that may be treated by breast-conserving surgery alone without RT. Small, localized tumors theoretically should be the potential candidates for this type of treatment. The mammographic and pathologic criteria for the identification of tumors with limited extent are not yet established; furthermore, the optimal extent of the surgical excision and the method for margin examination are controversial. METHODS: Surgical breast-conserving procedures were simulated in a review of 135 mastectomy specimens of patients treated for an invasive carcinoma (> or = 4 cm in size, all pathologic types except invasive lobular carcinoma) who were theoretically eligible for conservative treatment. Tumor spread including possible multifocality and multicentricity was studied by the technique of correlated specimen radiography and pathology. Breast carcinoma of limited extent (BCLE), the proper tumor profile for BCT, was defined as having no invasive carcinoma, ductal carcinoma in situ, and lymphatic emboli foci beyond 1 cm from the edge of the dominant mass. RESULTS: Fifty-three percent of the patients in this series had a BCLE. No statistically significant relation was found between BCLE and patient age, pathologic size, type and grade of the tumor, lymph node status, mode of detection, and mammographic aspect of the index tumor. Based on mammography, the absence of calcification or tumor density beyond the edge of index tumor appears to be the best predictor for BCLE (P < 0.0001). A 1-cm microscopically tumor free margin as the outer rim of a macroscopic surgical margin of 2 cm gives the best positive predictive value based on pathology (P < 0.0001). By applying the above conditions, 72 of the 135 cancers were identified as being potential BCLE cases in this series. However, whereas 64 of these 72 tumors (89%) were correctly identified as being true BCLE, 8 (11%) were erroneously identified as such (non-BCLE cases), having "residual" tumor foci beyond 2 cm from the edge of the dominant tumor. CONCLUSIONS: We conclude, that approximately 50% of invasive ductal carcinomas may have limited extent. The accuracy of identifying this group of cancers, the proper candidates for BCT, by applying state-of-the-art mammography and pathology may be as high as 90%. A subset of these tumors might represent the potential candidates for treatment with surgery alone without RT. As a result, the routine application of BCT complemented by RT would have led to the overtreatment of 89% of the patients with a BCLE in this series; conversely, 11% of the tumors may have recurred without the use of RT. Considering that these conclusions are based on a theoretic morphologic model, further clinical studies with facilities for high quality team approach in diagnosis and therapy are needed to evaluate the impact of BCLE on BCT strategies. The results of this study should not justify the withholding of RT outside the context of clinical trials.

Breast cancer screening pathology: an assessment of the practise and needs in Belgium and Luxembourg.

Education and quality assurance (QA) in breast screening pathology have been encouraged by the Europe Against Cancer programme. As a prerequisite for the set-up of a QA programme in Belgium and in the Grand Duchy of Luxembourg, an inquiry was initiated to evaluate the daily practise in breast pathology, the modalities in handling and analysing breast specimens and the willingness of the pathologists to participate in a QA scheme. Of the 278 mailed questionnaires, 109 confidential and valid questionnaires were returned, meaning a participation rate of 40%. All 109 respondents indicated their willingness to voluntarily participate in the further QA programme. Segmental resections for conservative surgery and excision biopsies ranked first and second, respectively, in examination requests. Of the respondents, 50% complained about the lack of clinical information on the pathology request form. A multidisciplinary team approach for the diagnosis of screen-detected lesions was deemed desirable by 87% of the respondents, but only 16% of them actually participate in such pre-operative meetings. Even more puzzling is that 75% of the respondents report regular unavailability of the control radiogram of the surgical specimen removed for non-palpable lesions. One-quarter to one-third of the pathologists still regularly perform frozen sections on microcalcifications or tumours smaller than 1 cm. However, 81% of the respondents estimate that pre-operative diagnosis is not appropriate for this type of lesion. The results of this inquiry show that the guidelines for the diagnosis of screen-detected breast lesions are not yet fully applied in daily practise. The development of local comprehensive breast teams involving a pathologist should improve the co-ordination between the medical disciplines, represent an important way of disseminating the guidelines on breast screening pathology and stimulate the relay unit to conduct QA programmes.

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

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.

Contribution of hook-guided breast biopsy to the pathological diagnosis of mammographic lesions.

This study was carried out to evaluate the reliability of a diagnostic approach with close cooperation between radiologists and surgeons for minimal breast disease. From 1993 to 1995, 152 evaluable patients with non palpable breast lesions were examined by mammography and their lesion was localized with a hook wire before being referred to the surgeon for biopsy. Comparison of mammography findings with pathological diagnosis indicated a good predictive value for benign lesions with only 8% non concordant diagnosis and a rather low predictive value in case of suspect mammograms with only 64% positive diagnosis. With hook-guided breast biopsy, a correct diagnosis was established in 93% of the cases. The remaining breast samples were either non contributory or necessitated a second biopsy. Several recommendations are proposed for improving accuracy of breast sampling such as securing the hook into the gland, orienting the limits of resection, sending specimen for X-ray study and inking the margins for the pathologist. This field experience revealed that some progress are to be made in diagnosis in particular by standardization of mammography and pathological criteria, more precise localization of the lesions with the hook and more refined surgical techniques for breast biopsy.

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.

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.

[Central reparative giant cell granuloma of the maxilla. Apropos of a case]. / Granulome réparateur central à cellules géantes des maxillaires. A propos d'un cas.

Central giant cell granulomas are uncommon, locally aggressive and benign tumors of the maxillofacial skeleton. The authors report a case of tumor arising from the maxilla and present a review of essential characteristics of the lesion.

Ductal carcinoma in situ: a proposal for a new classification.

Details of a proposed new classification for ductal carcinoma in situ (DCIS) are presented. This is based, primarily, on cytonuclear differentiation and, secondarily, on architectural differentiation (cellular polarisation). Three categories are defined. First is poorly differentiated DCIS composed of cells with very pleomorphic, irregularly spaced nuclei, with coarse, clumped chromatin, prominent nucleoli, and frequent mitoses. Architectural differentiation is absent or minimal. The growth pattern is solid or pseudo-cribriform and -micropapillary (without cellular polarisation). Necrosis is usually present. Calcification, when present, is amorphous. Second, at the other end of the spectrum is well-differentiated DCIS, composed of cells with monomorphic, regularly spaced nuclei containing fine chromatin, inconspicuous nucleoli, and few mitoses. The cells show pronounced polarisation with orientation of their apical border towards intercellular spaces usually resulting in cribriform, micropapillary and clinging patterns, although a solid pattern of well-differentiated DCIS also occurs. Necrosis is uncommon. Calcifications, when present, are usually psammomatous. The third category, intermediately differentiated DCIS, is composed of cells showing some pleomorphism but not so marked as in the poorly differentiated group. There is, however, always evidence of polarization around intercellular spaces, although this is not so pronounced as in the well-differentiated group. These two criteria, cytonuclear differentiation and architectural differentiation, have been found to be more consistent throughout a DCIS lesion than previously employed criteria of architectural pattern or the presence or absence of necrosis.

Three dimensional imaging of mammary ductal carcinoma in situ: clinical implications.

The conservation treatment of ductal carcinoma in situ (DCIS) is based on the surgical excision of the tumour together with irradiation of the remaining breast. Because short-term recurrence is almost certainly caused by residual tumour, an attempt should be made to verify the adequacy of the excision by assessing the specimen margin. The reliability of histologic margin assessment is influenced by the growth pattern of DCIS within the ductal tree and by the distance between tumour foci. Using an original stereoscopic technique, the present study of 60 mastectomy specimens shows that continuous and multifocal growth patterns are usual. A multifocal distribution (defined as gap of 4 cm or more between tumour foci) was found in only a single case. The growth pattern is related to DCIS type. Poorly-differentiated DCIS shows continuous growth, in contrast to the well-differentiated DCIS, which has a multicentric distribution. Irrespective of histologic type, however, only 8% of DCIS have a multifocal distribution with gaps greater than 10 mm. Therefore, with careful assessment, the likelihood of a false free margin seems theoretically low and should encourage the use of conserving treatment for eradicable DCIS.