Isabelle de Mascarel

Distinction between isolated tumor cells and micrometastases in breast cancer: is it reliable and useful?

In routine practice, the distinction between isolated tumor cells (ITC) and micrometastases (MIC) in patients with breast cancer is sometimes difficult to discern. The authors assessed differences in classifying patients according to the American Joint Commission on Cancer (AJCC) and the International Union Against Cancer (UICC) definitions and method of sizing.

Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations

IntroductionBreast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers.MethodsWe first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data.ResultsUnsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma.ConclusionsThese data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features.

Prise en charge des atypies épithéliales du sein

Resume En attendant une classification moleculaire des atypies epitheliales du sein, les auteurs font une mise au point sur leur prise en charge, a la lumiere des travaux de la litterature et de leur experience a l’institut Bergonie. Leur experience repose sur l’analyse de 2 833 biopsies chirurgicales effectuees pour micro-calcifications sans tumeur palpable, etudiees en coupes macroscopiquement seriees (26 blocs en moyenne par biopsie) chez des patientes avec un long suivi median (160 mois). Cette mise au point concerne l’application de la classification OMS des lesions proliferantes atypiques non invasives du sein, la mesure des hyperplasies canalaires atypiques, la prise en charge des patientes avec des atypies epitheliales diagnostiquees sur microbiopsies, et enfin l’examen des biopsies chirurgicales de re-excision a la recherche d’un petit cancer concomitant de voisinage associe, retrouve dans un tiers des cas environ. En effet, il semblerait que les atypies epitheliales soient davantage un marqueur de risque de cancer concomitant que de cancer secondaire.

Immunohistochemically detected lymph node metastases from breast carcinoma: practical considerations about the new American Joint Committee on Cancer classification.

The authors applied the sixth edition of the American Joint Committee on Cancer (AJCC) classification system to their previously published group of patients with breast carcinoma who had immunohistochemically detected lymph node metastases.

An array CGH based genomic instability index (G2I) is predictive of clinical outcome in breast cancer and reveals a subset of tumors without lymph node involvement but with poor prognosis.

BackgroundDespite entering complete remission after primary treatment, a substantial proportion of patients with early stage breast cancer will develop metastases. Prediction of such an outcome remains challenging despite the clinical use of several prognostic parameters. Several reports indicate that genomic instability, as reflected in specific chromosomal aneuploidies and variations in DNA content, influences clinical outcome but no precise definition of this parameter has yet been clearly established.MethodsTo explore the prognostic value of genomic alterations present in primary tumors, we performed a comparative genomic hybridization study on BAC arrays with a panel of breast carcinomas from 45 patients with metastatic relapse and 95 others, matched for age and axillary node involvement, without any recurrence after at least 11 years of follow-up. Array-CGH data was used to establish a two-parameter index representative of the global level of aneusomy by chromosomal arm, and of the number of breakpoints throughout the genome.ResultsApplication of appropriate thresholds allowed us to distinguish three classes of tumors highly associated with metastatic relapse. This index used with the same thresholds on a published set of tumors confirms its prognostic significance with a hazard ratio of 3.24 [95CI: 1.76-5.96] pu2009=u20096.7x10-5 for the bad prognostic group with respect to the intermediate group. The high prognostic value of this genomic index is related to its ability to individualize a specific group of breast cancers, mainly luminal type and axillary node negative, showing very high genetic instability and poor outcome. Indirect transcriptomic validation was obtained on independent data sets.ConclusionAccurate evaluation of genetic instability in breast cancers by a genomic instability index (G2I) helps individualizing specific tumors with previously unexpected very poor prognosis.

Comprehensive prognostic analysis in breast cancer integrating clinical, tumoral, micro-environmental and immunohistochemical criteria

Significant morphological, clinical and biological prognostic factors vary according to molecular subtypes of breast tumors, yet comprehensive analysis of such factors linked to survival in each group is lacking. Clinicopathological and micro-environmental criteria, estrogen (ER), progesterone (PR) receptors, HER2, Ki67, basal markers, CD24, CD44, ALDH1, BCL2, E-Cadherin and Trio were assessed in 1070 primary operable breast cancers from a single center according to five main molecular subtypes and associations with distant metastasis-free survival (DMFS) were examined. There were 682 (64xa0%) luminal A (LA), 166 (16xa0%) Luminal B HER2 negative (LBH−), 47 (4xa0%) Luminal B HER2 positive (LBH+), 108 (10xa0%) triple negative (TN) and 67 (6xa0%) HER2-enriched tumors (H2+). Median follow-up was 13.7xa0years. At 5xa0years, DMFS in LA (90xa0%) was better than in LBH− (80.9xa0%), hazard ratio (HR)xa0=xa02.22 [1.44–3.43] Pxa0<xa00.001; LBH+ (74.5xa0%), HRxa0=xa03.14 [1.69–5.84] Pxa0<xa00.001, TN (71.5xa0%) HRxa0=xa03.63 [2.34–5.63], Pxa0<xa00.001; and H2+ (65.2xa0%), HRxa0=xa04.69 [2.90–7.59], Pxa0<xa00.001. In multivariable analysis, factors associated with shorter DMFS varied according to molecular subtype, with tumor size being associated with shorter DMFS in the LBH−, LBH+ and TN groups and the Rho GEF Trio and BCL2 phenotypes in TN tumors only. These findings help to define new clinicophenotypic models and to identify new therapeutic strategies in the specific molecular subgroups.

L’examen cytologique a-t-il encore sa place dans l’analyse extemporanée du ganglion sentinelle dans le cancer du sein ?

Intraoperative examination of sentinel lymph nodes (SLN) in breast cancer can avoid a new surgical procedure in case of positive SLN, but its value, efficacy and the methods used are still controversial. The aim of our study was to evaluate the imprint cytology intraoperative method of SLN analysis performed at our institution. We did a retrospective study of the sentinel lymph node procedures performed during a period of 24 u200amonths on cT1N0 unifocal breast cancers. Intraoperative procedure was mainly by imprint cytology (touch prep). A SLN procedure was performed on 187 women with 360 SLN. Two hundred and seventy-seven SLN among 156 women were analyzed intraoperatively by touch prep. 19/48 positive SLN were detected by intraoperative touch prep (sensitivity 39.6%; specificity 100%; positive predictive value 100%; negative predictive value 88.7%, accuracy 89.5%). False negative rate of cytological intraoperative examination of SLN was 11,2% by SLN and 18,3% by patient. By univariate analysis, this rate significantly increased with lymphovascular invasion, tumor size cT1b and c and histological SBR grade 2 or 3. By multivariate analysis, only lymphovascular invasion was a predictive factor of intraoperative touch prep failure (ORu200a=u200a3.3; IC 1.3-8.4). Intraoperative imprint cytology of SLN in breast cancer is associated with a high rate of false negativity that questions its use in this setting.

Epithelial Atypia: A Marker Risk of Concomitant or Subsequent Breast Carcinoma?

breast cancer risk associated with epithelial atypia. In this study, 66 breast cancers (19.9%) occurred among 331 women with ductal and/or lobular atypia (mean follow-up of 13.7 years) from an initial cohort of 9,376 women with benign lesions who underwent surgery between 1967 and 1991. Epithelial atypia were diagnosed on surgical biopsiesthathadbeensampledwithameanof3.2slidesperspecimen. In a recent study, we found a lower absolute risk 2 associated with epithelial atypia in a series of 2,833 surgical biopsies for microcalcifi- cations without any palpable mass, performed at BergonieInstitute between 1975 and 2003. The surgical biopsies in our series were mac- roscopically sectioned every 2 mm (median number of slides per biopsy, 26) and ductal and/or lobular atypia were recorded in 971 cases. 2 A concomitant small ( 5 mm) and low-grade cancer was associated with epithelial atypia in 301 (31%) of 971 of the surgical biopsies. Thus epithelial atypia was isolated, without a concomitant cancer, in 670 of 971 biopsies concerning 415 patients with one or several biopsies and without any previous or synchronous carci- noma in the same or contralateral breast. All these patients were untreated and monitored at our institute (mean follow-up, 13.3 years). Among them, only 18 patients had a subsequent breast cancer (4.3%). Therefore, at 5 and 10 years, the probabilities of developing invasive breast cancer were 2.8% (9 5% CI, 1.4 to 5.5) and 5.5% (95% CI, 3.3 to 9.9), respectively. In light of our experi- ence, we think that the pathologic management of surgical breast biopsies with epithelial atypia is determinant in the estimation of long-term absolute risk of breast cancer. In the study of Degnim et al, 1 as in the other series in the literature, 3-13 estimations of risk associated with epithelial atypia were based on a relatively small number of surgical biopsies with epithelial atypia (n 60 to 332),

La numérisation d’images en anatomie-pathologique : application à l’assurance qualité pour le diagnostic de cancer

Resume Objectifs Tester un systeme de double lecture histologique fonde sur l’image numerique pour le diagnostic de cancer. Materiel et methodes Un systeme de numerisation d’images integre au systeme de gestion informatise du laboratoire permet d’illustrer en temps reel l’aspect histologique pour les cas de cancer diagnostiques dans le laboratoire et traites dans notre Centre. Une double lecture de ces cas a ete realisee par l’examen des images numerisees sur une periode de 30 jours d’activite. Les cas revus ont ete classes en tumeur maligne avec type histologique precise, tumeur maligne sans autre indication (SAI) et diagnostic de malignite douteux sur l’aspect des images numerisees. Resultats Pendant la periode d’etude, 204 cas de cancer ont ete diagnostiques dont 178 ont ete numerises (87%). Parmi les cas numerises, 119 (67%) ont ete classes en tumeur maligne avec type histologique precise, 53 (30%) en tumeur maligne SAI et 6 (3%) en diagnostic de malignite douteux. Ces derniers cas ont ete revus histologiquement et correspondaient bien a une tumeur maligne. Le temps passe a une telle relecture a ete d’environ 2 heures par semaine d’activite. Conclusion Le systeme de numerisation d’images peut participer a l’assurance qualite du diagnostic de cancer en permettant une double lecture rapide et efficace.

Automate à inclusion rapide : l’expérience bordelaise

Resume Le conditionnement actuel des prelevements tissulaires en pathologie, base sur la fixation formolee et l’inclusion par un automate sous vide, n’est plus adapte aux normes sanitaires, a la necessite de preserver les acides nucleiques et a la reduction des delais de rendu des diagnostics. Nous testons depuis 3 ans une nouvelle methode de conditionnement tissulaire basee sur une fixation alcoolique dans le Molecular Fixative ® (MF) et l’automate Xpress ® a inclusion rapide de Sakura™. En utilisant ce systeme, il est possible de traiter les fragments tissulaires en une a deux heures, a condition d’adapter leur prise en charge macroscopique. Le rendu morphologique varie peu de celui des tissus fixes au formol et se traduit par une retraction cellulaire et tissulaire variable selon le tissu et son epaisseur. Des ajustements protocolaires permettent les analyses immunohistochimiques et FISH de la meme facon qu’avec les fixateurs classiques. Les differentes techniques montrent l’integrite de l’ADN et de l’ARN des tissus fixes dans le MF et conditionnes dans l’Xpress ® .