Hum Pathol. 2008 Jun;39(6):857-65. Epub 2008 Apr 8.

Expression of BRCA1 protein in breast cancer and its prognostic significance.

Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO.

Department of Histopathology, The Breast Unit, Nottingham City Hospital, University of Nottingham, NG5 1PB Nottingham, UK. emadrakha@yahoo.com

BRCA1 is a tumor suppressor gene which, when mutated, is associated with the development of hereditary breast cancers. In sporadic tumors, although inherent gene mutations are rare, loss of BRCA1, resulting from reduced expression or incorrect subcellular localization, is postulated to be important. The purpose of the current study was to examine the expression and localization of BRCA1 protein and to assess its prognostic value, in a well-characterized series of unselected breast carcinomas. We have examined BRCA1 in a series of invasive breast carcinoma (1940 cases) using tissue microarray and immunohistochemistry, to evaluate its expression pattern and to correlate this with clinicopathologic variables and patient outcome. In breast cancer, complete loss of nuclear expression was observed in 223 cases (15%) and cytoplasmic expression was found in 541 breast cancers (36.6%). Absent or reduced nuclear BRCA1 expression was observed more frequently in ductal carcinoma of no special type and medullary-like carcinoma and less frequently in lobular and tubular mixed carcinomas. It was also associated with high-grade, advanced lymph node stage, larger size, vascular invasion, negative estrogen receptor, progesterone receptor and androgen receptor expression, and positive p53 and P-cadherin expression, and with the basal-like class of breast cancer. Altered BRCA1 was associated with shorter disease-free interval. Cytoplasmic expression was also associated with development of recurrence and positive EGFR and HER2 expression. It showed an inverse association with survival particularly in low-grade, small-size, and estrogen receptor-positive subgroups. In the grade 1 subgroup, multivariate analysis with adjustment for other prognostic factors showed that cytoplasmic expression of BRCA1 was an independent predictor of disease-free interval. BRCA1 alteration may play a significant role in the development and progression of breast cancer. Immunohistochemical assessment of BRCA1 expression could provide additional clinically relevant information in routine classification of breast cancer.

Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, de Jong D, Van de Vijver MJ, Van't Veer LJ, Peterse JL.

Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands. bweigelt@lbl.gov

Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers are categorized into at least 17 discrete pathological entities; however, whether these also constitute discrete molecular entities remains to be determined. Current therapy decision-making is increasingly governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B, neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic, and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling. Hierarchical clustering analysis confirmed that some histological special types constitute discrete entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one molecular subtype. Our analysis also revealed that some special types associated with a good prognosis, such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome, providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group. Taken together, our results imply that the correct classification of breast cancers of special histological type will allow a more accurate prognostication of breast cancer patients and facilitate the identification of optimal therapeutic strategies

Jacquemier J, Padovani L, Rabayrol L, Lakhani SR, Penault-Llorca F, Denoux Y, Fiche M, Figueiro P, Maisongrosse V, Ledoussal V, Martinez Penuela J, Udvarhely N, El Makdissi G, Ginestier C, Geneix J, Charafe-Jauffret E, Xerri L, Eisinger F, Birnbaum D, Sobol H; European Working Group for Breast Screening Pathology; Breast Cancer Linkage Consortium.

Marseille Cancer Institute, Molecular Oncology Department, UMR599 INSERM and Paoli-Calmettes Institute, Marseille, France. jacquemierj@marseille.fnclcc.fr

Medullary breast cancer (MBC) is a rare, diagnostically difficult, pathological subtype. Despite being high grade, it has a good prognosis. MBC patients have an excess of BRCA1 germ-line mutation and reliable identification of MBC could help to identify patients at risk of carrying germline BRCA1 mutations or in whom chemotherapy could be avoided. The aim of this study was therefore to improve diagnosis by establishing an MBC protein expression profile using immunohistochemistry (IHC) on tissue-microarrays (TMA). Using a series of 779 breast carcinomas ('EC' set), diagnosed initially as MBC, a double-reading session was carried out by several pathologists on all of the histological material to establish the diagnosis as firmly as possible using a 'medullary score'. Only MBCs with high scores, i.e. typical MBC (TMBC) (n=44) and non-TMBC grade III with no or low scores (n=160), were included in the IHC study. To validate the results obtained on this first set, a control series of TMBC (n=17) and non-MBC grade III cases (n=140) ('IPC' set) was studied. The expression of 18 proteins was studied in the 61 TMBCs and 300 grade III cases from the two sets. The global intra-observer concordance of the first reading for the diagnosis of TMBC was 94%, with almost perfect kappa (kappa) of 0.815. TMBC was characterized by a high degree of basal/myoepithelial differentiation. In multivariate analysis with logistic regression, TMBC was defined by the association of P-cadherin (R=2.29), MIB1 > 50 (R=3.80), ERBB2 negativity (R=2.24) and p53 positivity (RR=1.45). Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO, Lee AH.

Departments of Histopathology and Surgery, Nottingham University Hospitals, Nottingham, UK.

The new gene expression molecular taxonomy of breast cancer places medullary carcinoma in the basal group. The basal group is considered to have a poor prognosis, but medullary carcinoma is considered to have a better prognosis than other grade 3 carcinomas. The prognostic significance of tumour associated inflammation, an important feature of medullary carcinomas, remains controversial. The aim of this study was to assess the prognostic importance of medullary histological type and inflammation in breast cancer. One thousand five hundred and ninety-seven patients who received no systemic adjuvant treatment and who had a median follow up of 9.5 years were studied. Results: Prominent inflammation was associated with high histological grade and with better survival [relative risk (RR) 0.57, 95% confidence intervals (CI) 0.44-0.74] on multivariate analysis. Typical and atypical medullary carcinomas (n=132) did not have significantly different survival and were grouped together. Medullary carcinoma did not have significantly different prognosis than grade 3 ductal carcinoma with prominent inflammation, but both had a better prognosis than grade 3 ductal carcinoma without prominent inflammation (P<0.0001 and P=0.03). These differences were independent of other prognostic factors. These results question the current separation of typical and atypical medullary carcinoma. Prominent inflammation is associated with a better prognosis, and may explain the better prognosis in medullary carcinoma compared with grade 3 ductal carcinoma without prominent inflammation. The good prognosis of medullary carcinoma emphasises the heterogeneity of basal-like breast carcinomas. Further studies are needed to investigate the difference in survival between medullary carcinoma and other forms of basal carcinomas and the role of inflammation in any such differences in behaviour

Breast Cancer Res. 2007;9(2):R24.

Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity.

Vincent-Salomon A, Gruel N, Lucchesi C, MacGrogan G, Dendale R, Sigal-Zafrani B, Longy M, Raynal V, Pierron G, de Mascarel I, Taris C, Stoppa-Lyonnet D, Pierga JY, Salmon R, Sastre-Garau X, Fourquet A, Delattre O, de Cremoux P, Aurias A.

Department of Tumor Biology, Institut Curie, Paris cedex 05, France. anne.salomon@curie.net

INTRODUCTION: Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC). METHODS: Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs. RESULTS: All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC. CONCLUSION: Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.

Rodríguez-Pinilla SM, Rodríguez-Gil Y, Moreno-Bueno G, Sarrió D, Martín-Guijarro Mdel C, Hernandez L, Palacios J.

Breast and Gynecological Cancer Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.

It is not clear whether invasive breast carcinomas with medullary features (IBCMFs, atypical medullary carcinomas) constitute a specific phenotype of breast cancer that is of biologic significance. Because medullary features are common in BRCA1-associated carcinomas and these tumors frequently show a basal-like phenotype, we examined whether IBCMFs expressed basal/myoepithelial markers and had a basal-like phenotype. We studied the immunohistochemical expression of 15 markers in tissue microarrays containing samples from 35 IBCMFs and 39 grade 3 invasive ductal carcinomas (IDCG3s) of no special type. In addition, we analyzed EGFR, C-MYC, and CCNE gene amplification by fluorescence in situ hybridization, because the expression of these genes is known to be associated with the basal-like phenotype. We defined the basal-like phenotype according to the criteria of Nielsen et al as being those tumors that were ER/HER2-negative and cytokeratin (CK) 5/6- and/or epidermal growth factor receptor-positive. IBCMFs were more frequently hormone receptor- and HER2-negative, but had greater expression of proliferation markers and p53. In addition, IBCMFs more frequently expressed basal/myoepithelial markers, such as CK5/6 and P-cadherin. A basal-like phenotype was found in 62.9% of IBCMFs but in only 18.9% of IDCG3s. No differences in gene amplification were found between IBCMFs and IDCG3s, although C-MYC amplification was more common in tumors without a basal-like phenotype. The identification of IBCMF as an independent group of tumors could be of clinical significance, given the high incidence of cases with a basal-like phenotype, which is a group of tumors with different prognosis and chemotherapy response from those of IDCG3s of no special type.

Matkovic B, Juretic A, Separovic V, Novosel I, Separovic R, Gamulin M, Kruslin B.

University Hospital for Tumors, Zagreb, Croatia.

AIMS AND BACKGROUND: Recent publications of breast cancer classification based on gene expression profile analyses indicate that medullary breast carcinomas (MBC) may be considered part of the basal-like carcinoma spectrum made up of ER-negative, PR-negative and HER-2-negative cells ("triple-negative phenotype"). On the other hand, there are also data showing that a proportion of MBC and atypical MBC (AMBC) is ER, PR and/or HER-2 positive. Therefore, we have decided to immunohistochemically analyze ER, PR, HER-2 and basal/myoepithelial markers CK 5/6, p63 and EGFR expression in our archival paraffin-embedded MBC and AMBC samples from 48 patients. METHODS: Immunohistochemical evaluation of samples which were derived from patients operated on at our two hospitals between 1999 and 2005. RESULTS: Typical MBC was found in 39 patients and AMBC in 9 patients. The patients ranged in age from 32 to 84 years (median 55). Modified radical mastectomy with axillary dissection was performed in 30/48 patients (63%) while breast segmentectomy with axillary dissection was performed in 18/48 patients (37%). Metastases in axillary lymph nodes were observed in 15/48 patients (31%). ER positivity was present in 3/48 patients (6%), PR positivity in 8/48 (17%), and a positive HER-2 reaction was present in 14/48 patients (29%). CK 5/6 was positive in 20/48, p63 in 24/48 and EGFR in 8/48 patients. Adjuvant therapy was applied in all but 2 patients. Alive were 45/48 (94%) of patients. With the exception of PR expression, 39 patients with typical MBC and 9 patients with AMBC were comparable in the analyzed parameters. Positive HER-2 antigen expression in the analyzed sample was not found to be associated to a statistically significant degree with the MBC or AMBC histological tumor type, tumor size, axillary lymph node metastases, ER and PR status nor with patient survival. CONCLUSIONS: The data from our study seem to be generally comparable with the relatively scarce published data on clinicopathological parameters of MBC and AMBC.

Eichhorn JH.

James Homer Wright Pathology Laboratories, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA. JEICHHORN@PARTNERS.ORG

The recent observation that studies of BRCA1-associated tumors contain a high proportion of medullary carcinomas and ductal carcinomas with medullary features has re-introduced pathologists to an old diagnostic problem. The term "medullary carcinoma" dates to the 19th century, but the modern entity was introduced in 1949 by Moore and Foote, who described a carcinoma with a lymphoid infiltrate, a favorable prognosis, and low frequency of metastasis. Almost three decades later, Ridolfi et al proposed specific criteria for diagnosis, resulting in an entity with an even more favorable prognosis and a lower incidence. The reproducibility and clinical relevance of the diagnosis have been questioned recently, and new criteria have been proposed and compared. The tumors typically express cytokeratin 7, often vimentin and S100-protein, but not cytokeratin 20. The usual ones are positive for p53 and negative for estrogen receptor, Her2/neu, and bcl-2. Medullary carcinomas express e-cadherin and beta-catenin more often than ordinary high-grade ductal carcinomas, and the former have genetic differences from the latter. The lymphoid infiltrate of medullary carcinomas is related to beta-actin fragments exposed by apoptotic cells. The present review discusses historical and recent developments and emphasizes diagnostic criteria.

Also for wfbjwt :Your reading is so fast.

Basically basal-like ca and medullary ca are two different calssification systems. We cannot say the dx of MA should exclude basal-like ca.

In fact most cases of MA belong to the category of basal-like ca.

I am pasting some related abstracts here.

 WHO 2003 关于髓样癌有5个诊断特征 as abin mention above.

Syncytial growth (large than 75%)

No glnadular structure

Diffuse lymphplasmacytic infiltrate

Nuclear pleomorphism, moderate to marked

Complete histologic curcumscription.

  This is the important paper. In the past almost 20 y, people use this criteria for MA

Br J Cancer. 1991 Apr;63(4):591-5.   Pedersen L from Denmark did a lot of work on MA

 Find some original paper abstrats about classification systems for medullary carcinoma (MA). They are similar, but with some difference. I am pasting some paper abstracts for some ones who have good English and are interested to this area.

Cancer. 1977 Oct;40(4):1365-85.

Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up.

 非常好的病例！主要是两种意见：髓样癌；基底细胞样型乳腺癌。

我的观点是：诊断基底细胞样型乳腺癌应该有免疫组化结果的支持；诊断髓样癌必须1、形态典型。2、排除基底细胞样型乳腺癌。