Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast.

Pleomorphic lobular carcinoma of the breast is a variant of infiltrating lobular carcinoma that has poor prognosis. The pleomorphic appearance of this variant hinders its correct identification and differentiation from ductal carcinoma. The analysis of E-cadherin glycoprotein expression is a powerful tool for distinguishing lobular from ductal carcinomas, because complete loss of E-cadherin expression occurs in most infiltrating lobular tumors and lobular carcinomas in situ, but not in ductal tumors. In the present study, we have evaluated E-cadherin expression by immunohistochemistry in a series of 29 pleomorphic lobular breast carcinomas, including 7 cases with an in situ component. Complete loss of E-cadherin expression was observed in all the cases (29/29, 100%), in invasive and in situ components. To understand better the mechanisms underlying E-cadherin inactivation in this tumor type, the frequency of loss of heterozygosity at the E-cadherin gene locus (16q22.1) was analyzed. All informative tumors (27/27, 100%) showed loss of heterozygosity, thus implying a strong association between loss of E-cadherin expression and loss of heterozygosity at 16q22.1. Moreover, loss of heterozygosity was detected in all in situ components analyzed. These results imply that in terms of E-cadherin inactivation, pleomorphic lobular tumors are identical to classic infiltrating lobular carcinomas and distinct from ductal tumors, and therefore they should be considered a variant of lobular carcinoma of the breast, despite their aggressive behavior.     

Comparative expressed sequence hybridization reveals differential gene expression in morphological breast cancer subtypes

In this study, comparative expressed sequence hybridization (CESH) has been used to compare gene expression patterns in three morphologically different breast cancer subtypes: classic-type invasive lobular carcinoma (ILC), poorly differentiated ERBB2-negative invasive ductal carcinoma-not otherwise specified (IDC-NOS), and poorly differentiated ERBB2-positive IDC-NOS. CESH allows global detection of chromosomal regions with differential gene expression in a way similar to that of comparative genomic hybridization (CGH). Eight cases of each breast cancer subtype were included in the study. For each subtype, two pools of four cases each were constructed. CESH was used to compare both pools within the same morphological subtype, followed by a comparison of pools belonging to different subtypes. This revealed three chromosomal regions that were differentially expressed in ductal and lobular carcinomas, including relative overexpression at 8q13-q23 and 16q22, and relative underexpression at 8p21-p22. In addition, an expression signature characterized by relative overexpression at 3q24-q26.3, 14q23-31, 17q12, and 20q12-13 was identified for ERBB2-positive IDC-NOS. In summary, CESH analysis highlights chromosomal regions of differential gene expression that are associated with morphologically defined breast cancer subtypes and suggests that regions on chromosome 8 are of interest in the discrimination between ductal and lobular carcinomas. In addition, using CESH, it was possible to identify an ERBB2 expression signature, comprising four chromosomal regions with potential significance in the aggressive behaviour of ERBB2-positive IDC-NOS.     

Expression of PC-cell-derived growth factor in benign and malignant human breast epithelium

PC-cell-derived growth factor (PCDGF, progranulin) is a novel autocrine growth factor that is overexpressed in human breast cancer cell lines. We have examined immunohistochemical PCDGF expression in 206 paraffin-embedded human breast lesions and investigated its association with clinicopathological variables. PCDGF staining was observed in breast carcinoma, whereas it was almost always negative in benign breast epithelium. PCDGF expression was more common in invasive ductal carcinoma (80% cases positive) than in invasive lobular carcinoma (53% positive). PCDGF staining was almost never observed in lobular carcinoma in situ. Ductal carcinoma in situ expressed PCDGF in 66% of the cases, and this expression correlated strongly with nuclear grade. Similar correlation was observed between PCDGF expression and histologic grade of invasive ductal carcinoma. Average Ki-67 index of PCDGF-negative/weakly positive invasive carcinomas (30.3) was significantly lower than that of strongly PCDGF-positive tumors (48.8, P=0.01). A larger percentage of tumors that expressed PCDGF with a staining intensity of 2+ or 3+ were p53 positive (44%) than were PCDGF-negative tumors (25%), P=0.02. PCDGF expression was independent of c-erbB-2 overexpression and of ER and PR status. Our study provides the first evidence of high incidence of PCDGF expression in human breast cancer in which it correlates with clinicopathological variables such as tumor grade, proliferation index, and p53 expression. These characteristics, as well as the virtual absence of expression in benign breast tissue, suggest an important role of PCDGF in breast cancer pathogenesis and make it a potential novel target for the treatment of breast cancer.     

Histopathological and clonal study of combined lobular and ductal carcinoma of the breast

Lobular carcinoma in situ (LCIS) clinically constitutes a risk factor for the subsequent development of either invasive lobular carcinoma (ILC) or invasive ductal carcinoma (IDC). In order to approach the possibility of this common precursor of both ILC and IDC, we investigated combined lobular and ductal carcinomas. Thirty‐two cases of lobular carcinoma were picked up out of 773 cases of operated breast carcinomas. The histopathological detailed re‐examination using immunostain of E‐cadherin and β‐catenin revealed a rather high frequency of combined lobular carcinomas than previous reports. Clinicopathologically, combined lobular carcinomas were younger and smaller than pure lobular carcinomas, and the cytological atypia was relatively low. These results suggested that combined lobular carcinomas could be detected in the earlier stage of breast cancer. Furthermore, the lobular and ductal components of combined carcinomas coexisted in the neighborhood and were distributed contiguously. The immunohistochemical phenotypes of both components were accorded in most combined cases. A genetic analysis using methylation‐specific PCR on the HUMARA gene demonstrated that the same allele was inactivated in both lobular and ductal components in all detectable cases of combined carcinoma. Therefore, it is reasonable to assume that both lobular and ductal components of combined carcinomas are clonal and derived from the LCIS as the common precursor lesion, which may contradict the conventional concept that the lobular and ductal carcinomas arise from distinct differentiation pathways.     

Genetic pathways in the evolution of breast ductal carcinoma in situ

The patterns of allelic loss in 28 cases of pure ductal carcinoma in situ (DCIS) and 25 cases of DCIS associated with invasive ductal carcinoma (IDC) were compared, in order to define whether pure DCIS represented an earlier stage than DCIS associated with IDC in the progression of breast carcinoma. To this aim, the polymerase chain reaction (PCR) was performed on microdissected normal and neoplastic breast tissue, formalin-fixed and paraffin-embedded. Fifteen microsatellite markers were examined, on chromosomes 1p, 3p, 7q, 11q, 12p, 13q, 16q and 17q, mostly focused on regions altered in breast cancer. Loss of heterozygosity (LOH) was greater in pure DCIS than in the DCIS component associated with IDC for 11 out of 15 markers. The difference was statistically significant for D13S260 and D17S800 (p=0.008 and p=0.01, respectively). DCIS associated with IDC showed a lesser degree of alteration than the synchronous IDC component for ten out of 15 markers. In contrast, LOH at D11S1816 and D16S318 was lower in pure DCIS than in DCIS associated with IDC and even greater in the IDC component. These results confirm that DCIS is a possible but not an obligate precursor of invasive breast cancer and suggest that pure DCIS and DCIS associated with IDC may be genetically distinct. The evolution from DCIS to IDC may follow multiple pathways and not a linear model.     

In situ and invasive lobular neoplasia of the breast

Lobular neoplasia of the breast represents a group of related malignancies with clinical implications ranging from risk lesions [atypical lobular hyperplasia and lobular carcinoma in situ (LCIS)] through to aggressive invasive lesions, notably invasive pleomorphic lobular carcinoma. The diversity in lobular carcinoma is evident at the morphological level, at the molecular marker level and in cytogenetic profiles. Research in these areas is already changing the face of the disease group, for example suggesting that some lobular and ductal carcinomas are closely related and even that one of the lobular group, the tubulo-lobular carcinomas, should, in fact, be regarded as a ductal cancer. More research is required to understand the long-term pathogenic implications of a diagnosis of in situ lobular neoplasia, particularly pleomorphic LCIS , and to understand the genetics behind the well-recognized high risk of bilateral disease. For invasive carcinoma, molecular studies will allow refinement of therapy and the possibility of novel targeted therapies, for example directed against fibroblast growth factor receptor 1.     

乳腺良恶性病变中CD10表达及意义

目的 探讨CD10免疫标记乳腺肌上皮细胞的可行性。方法 收集50例乳腺良恶性病变的石蜡包埋标本(腺瘤、纤维腺瘤、叶状肿瘤、纤维囊性病、导管内乳头状瘤、乳头腺瘤、导管内癌、小叶内癌、浸润性导管癌、浸润性小叶癌)，采用免疫组化(S-P法)检测CD10在上述病变中的表达。结果 在乳腺良性病变中，CD10阳性的肌上皮细胞连续地环绕在普通型增生的小导管的周围。但在囊性扩张或不典型上皮增生的导管周围，CD10阳性细胞不连续，甚至不见阳性细胞。导管原位癌的癌细胞巢外周的阳性细胞由完整到不完整，甚至完全缺失。在浸润性癌中癌巢周围不见阳性细胞，在早期浸润性癌中可见残存的阳性细胞。除少许癌细胞和肌纤维母细胞表达CD10外，其余癌细胞、肌纤维母细胞、血管平滑肌细胞和上皮细胞均不表达CD10。结论 CD10标记肌上皮细胞具有较高的敏感性和特异性，可以作为肌上皮细胞的有效标记物。     

PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma

Mutations in the PIK3CA gene have recently been reported in different human neoplasms, including breast cancer. This paper reports the results of a systematic analysis of PIK3CA mutations in different histological types of breast carcinoma. One hundred and eighty invasive breast carcinomas, comprising 74 ductal, 56 lobular, 22 mucinous, 20 medullary, and eight papillary, were selected on the basis of their histological type in a consecutive series of 780 breast cancers. Exons 1-20 of the PIK3CA gene were subjected to SSCP analysis followed by direct sequencing. PIK3CA mutations were observed in 46 (26%) of the 180 tumours examined: 23 (50%) mutations were located in exon 9, and 23 (50%) in exon 20. Mutations were frequent in lobular (46%), less frequent in ductal (22%), and uncommon in medullary (10%), mucinous (5%), and papillary tumours (12%) (p = 0.0002). Mutations in exon 9 were more frequent in lobular carcinomas (30% of cases) than in the other histological types (less than 5% of cases) (p = 0.00014). No significant differences were observed in the distribution of mutations in exon 20. There was no significant correlation between PIK3CA mutations and other clinicopathological and biological variables, including age, tumour size, lymph node metastases, oestrogen receptor (ER) status, progesterone receptor (PgR) status, p53 gene mutations, and p53 protein expression. The findings indicate that in invasive breast carcinomas, PIK3CA alterations are mainly present in lobular and ductal tumours, whereas the other histological types, known to be associated with a favourable prognosis, show a very low incidence of PIK3CA mutations.     

Array-based comparative genomic hybridization of ductal carcinoma in situ and synchronous invasive lobular cancer

It has been increasingly recognized that ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and invasive cancer of the breast are often closely associated with one another. However, the genomic relationship between these histologically distinct entities has not been well characterized. Refinements in high-resolution comparative genomic hybridization (CGH) techniques allow for a detailed comparison of genomic alterations in synchronously occurring tumors. The following case illustrates how array CGH may be used to better understand whether synchronous neoplasms share a common origin.     

Epithelial (E-) and placentae (P-) cadherin cell adhesion molecule expression in breast carcinoma

Two members of the cadherin family of intercellular adhesion molecules are found in normal breast tissue: E- (epithelial) cadherin is present in both luminal and myoepithelial cells, whereas P- (placental) cadherin is confined to myoepithelium. There is experimental evidence that loss of E-cadherin is associated with increased invasiveness of malignant cells in vitro, which stimulated us to examine the presence and distribution of E- and P-cadherin in breast carcinomas by means of immunohistochemical staining. E-Cadherin was present in all in situ and invasive ductal carcinomas examined, although it had a patchy distribution and the staining was of variable intensity. However, in 83 per cent of invasive lobular carcinomas and all lobular carcinomas in situ there was complete loss of E-cauherin expression. In the remaining 17 per cent of invasive lobular tumours, E-cadherin appeared to have an abnormal distribution within the cytoplasm with variable expression on the cell membrane. P-Cadherin, by contrast, was absent from all benign breast luminal epithelium and 25 carcinomas of ductal and lobular type. It was found in only one carcinoma of lobular type. We suggest that loss of cell-cell adhesion mediated by E-cadherin plays a part in the characteristic morphology of lobular carcinomas.     

Allelic loss of chromosomal arm 8p in breast cancer progression.

Loss of heterozygosity (LOH) of chromosomal arm 8p has been reported to occur at high frequency for a number of common forms of human cancer, including breast cancer. The objectives of this study were to define the regions on this chromosomal arm that are likely to contain breast cancer tumor suppressor genes and to determine when loss of chromosomal arm 8p occurs during breast cancer progression. For mapping the tumor suppressor gene loci, we evaluated 60 cases of infiltrating ductal cancer for allelic loss using 14 microsatellite markers mapped to this chromosomal arm and found LOH of 8p in 36 (60%) of the tumors. Whereas most of these tumors had allelic loss at all informative markers, five tumors had partial loss of 8p affecting two nonoverlapping regions. LOH for all but one of the tumors with 8p loss involved the region between markers D8S560 and D8S518 at 8p21.3-p23.3, suggesting that this is the locus of a breast cancer tumor suppressor gene. We then studied LOH of 8p in 38 cases of ductal carcinoma in situ (DCIS) with multiple individually microdissected tumor foci evaluated for each case. LOH of 8p was found in 14 of the DCIS cases (36%), including 6 of 16 cases of low histological grade and 8 of 22 cases of intermediate or high histological grade. In four of these DCIS cases, 8p LOH was seen in some but not all of the multiple tumor foci examined. These data suggest that during the evolution of these tumors, LOH of 8p occurred after loss of other chromosomal arms that were lost in all tumor foci. Thus, LOH of 8p, particularly 8p21.3-p23, is a common genetic alteration in infiltrating and in situ breast cancer. Although 8p LOH is common even in low histological grade DCIS, this allelic loss often appears to be preceded by loss of other alleles in the evolution of breast cancer.     

BigH3 protein expression as a marker for breast cancer

The current hypothesis of tumorigenesis in humans suggests that cancer cells acquire their hallmarks of malignancy through the accumulation of advantageous gene activation and inactivation events over long periods of time. For breast cancer development, this multistep process may manifest itself as a sequence of pathologically defined stages. It is widely held that breast cancer originates at the premalignant stage of atypical ductal hyperplasia, progresses to the preinvasive stage of ductal carcinoma in situ, and culminates in the potentially lethal stage of invasive ductal carcinoma. Tumor grade has been a highly valuable prognostic factor for breast cancer, and high-grade ductal carcinoma in situ lesions are associated with poor clinical outcome. The aim of this work was to investigate the BigH3 protein expression changes associated with various stages of breast cancer progression in comparison to benign specimens using tissue microarray technology. Pathological characteristics of breast tissues ranged from benign lesions to breast cancers either of lobular or ductal carcinomas in origin, and included in situ ductal carcinomas, lobular carcinomas, infiltrating ductal carcinomas, carcinomas, scirrhous carcinomas, adenocarcinomas and infiltrating colloid carcinomas. BigH3 protein expression was analyzed by immunohistochemistry in 192 cases of breast tumors. Results indicated a decrease in BigH3 protein expression from benign tissues to in situ ductal carcinoma, lobular carcinoma, infiltrating ductal carcinomas, carcinomas, scirrhous carcinoma, adenocarcinomas to infiltrating colloid carcinomas. We observed that the benign tissue had a 23-fold increase in BigH3 protein expression compared to the infiltrating colloid carcinoma which was the most malignant tissue analyzed. In summary, these studies confirmed the suppressor effect of the BigH3 gene expressed as protein expression in those processes related to the progression of breast tumorigenesis. We conclude that this protein can be used as a marker for breast cancer progression.     

对乳腺浸润性导管癌和浸润性小叶癌鉴别诊断的探讨

目的 探讨组织形态上易混淆的浸润性导管癌(IDC)与浸润性小叶癌(ILC)的鉴别诊断方法 .方法 收集北京大学第一医院1998年1月至2001年12月4年间普通外科诊治并有完整随访资料的IDC Ⅰ级24例、ILC 12例和具有混合性导管-小叶特征的浸润性癌(简称混合癌)14例共50例原发性乳腺癌患者资料和标本.采用EnVision法免疫组织化学染色检测E-钙黏蛋白(E-cad)、p120连环蛋白(p120ctn)、上皮膜蛋白(EMP)1和DVL1.结果 E-cad在IDC Ⅰ级和ILC中的阳性率分别为83.3%(20/24)和0,其差异有统计学意义(P<0.01);p120ctn在IDC Ⅰ级中阳性率为100.0%,且均为胞膜着色,在ILC中亦为12例均阳性,但均为细胞质着色;EMP1和DVL1在IDC Ⅰ级和ILC中的阳性分别为95.8%(23/24)和12例,54.2%(13/24)和5例,其差异无统计学意义(P>0.05).E-cad和p120ctn联合使用将14例混合痛确诊为IDC 12例和ILC 2例.结论 E-cad和p120ctn联合使用可以鉴别易混淆的IDC和ILC,使组织分型更准确.EMP1、DVL1不能作为鉴别IDC和ILC的指标.     

Lobular intraepithelial neoplasia: previously unexplored aspects assessed in 775 cases and their clinical implications

Lobular intraepithelial neoplasia (LIN) is currently considered a risk factor for the development of invasive breast cancer of varying morphologies (ductal or lobular) and prognoses in either breast. The reason for the high frequency (50%) of subsequent development of invasive ductal cancers remains unclear and the issue unexplored. A total of 775 LIN cases were retrieved from the Armed Forces Institute of Pathology files and separated into three groups using our three-tiered grading system. The presence or absence of simultaneous invasive cancer (ductal or lobular type) and various grades of ductal intraepithelial neoplasia (DIN) were noted for each case and correlated with the grade of LIN. Of the 775 cases, 80% qualified as LIN 2, with the other 20% being relatively evenly split between LIN 1 and LIN 3. Of the 775 cases, 163 cases were pure LIN, while invasive carcinoma was present in 140 cases. The remaining 472 cases were associated with various grades of DIN. The frequency of associated invasive carcinomas (ductal and lobular) increased from 14% in LIN 1 to 23% in LIN 3. Remarkably, while the frequency of invasive lobular carcinoma increased dramatically from 11% in LIN 1 to 86% in LIN 3, the frequency of invasive ductal carcinoma markedly decreased with advancing grade of LIN from 89% in LIN 1 to 14% in LIN 3. Among the cases of LIN unassociated with invasive carcinoma, DIN was present in 75% of LIN 1, 75% of LIN 2, and 66% of LIN 3 cases. The grade of DIN was directly proportional to the grade of LIN. Based on the higher frequency of invasive lobular carcinoma associated with LIN 3, biopsies with LIN 3 should be evaluated diligently for the presence of an associated invasive lobular carcinoma. Furthermore, an excisional biopsy should be performed when LIN 3 is observed in a core biopsy. The high frequency of DIN associated with LIN might suggest that the subsequent invasive ductal carcinomas originate from the associated DIN and that some of this may represent a different phenotype of the same cells that form the LIN lesion. It is also possible that the neoplastic cells may reflect or retain stem cell characteristics with plasticity and the capacity to attain or progress into either a ductal or lobular invasive phenotype.     

Paucity of fibronectin in invasive lobular carcinoma of breast

Fifty-four cases of invasive carcinoma of breast were immunostained for fibronectin and laminin. They included 36 cases of invasive ductal carcinoma and 18 cases of invasive lobular carcinoma. Although there was some heterogeneity within tumours, it was found that whilst the majority of ductal carcinomas (31/36) had abundant fibronectin at cell/stroma boundaries or diffusely throughout stroma, a substantial proportion of lobular carcinomas (12/18) had very little (P less than 0.001). This difference could not be related to differences in laminin immunoreactivity, which was most commonly scanty or absent in both tumour types. It is postulated that the characteristic infiltration pattern of lobular carcinoma may be attributed in part to paucity of stromal fibronectin.     

Loss of laminin-5 in the epithelium-stroma interface: an immunohistochemical marker of malignancy in epithelial lesions of the breast

AIMS: To demonstrate immunohistochemically the alpha3 and gamma2 chain of laminin-5 in benign epithelial and malignant lesions of the human breast. METHODS AND RESULTS: The alpha3 chain was identified by the monoclonal antibody BM165 and the gamma2 chain by GB3 in shock frozen samples using APAAP (alkaline phosphatase monoclonal anti-alkaline phosphatase) technique. The pre-existing breast epithelium, the 12 benign ductal and lobular proliferations and the three fibroadenomas showed a continuous immunostaining in the basement membrane region. In contrast to benign epithelial lesions, the 44 cases of invasive breast carcinoma showed a loss of the laminin-5 chains in more than 50% of the carcinoma stroma interface. Twenty-four out of the 44 invasive carcinomas revealed a complete loss of laminin-5 immunostaining. Focal defects of the laminin-5 immunostaining were also found in ductal carcinoma in situ in its pure form. CONCLUSIONS: As recently described, the malignant transformation of breast epithelium with expression of an invasive phenotype is associated with a decrease of hemidesmosomes. The reduced immunostaining of laminin-5 is in line with this finding because laminin-5 represents the major component of the anchoring filaments attaching hemidesmosomes to the basement membrane. We feel that immunohistochemical demonstration of laminin-5 may serve as a marker of benignity in epithelial breast lesions. While other carcinoma types exhibit an increased laminin-5 deposition, which has been suggested as an invasion promoting factor, the loss of laminin-5 in breast cancer supports the view that breast carcinomas do not utilize laminin-5 for invasion.     

D2-40 expression by breast myoepithelium: potential pitfalls in distinguishing intralymphatic carcinoma from in situ carcinoma

Lymphovascular invasion is an adverse prognostic factor in breast cancer. The lymphatic endothelial marker D2-40 has been shown to improve accuracy in detecting lymphovascular invasion. In addition to marking lymphatic endothelium, D2-40 has been cursorily noted to react with breast myoepithelium. The extent of this expression and the potential for misinterpreting in situ carcinoma as lymphovascular invasion because of D2-40-positive myoepithelium have not been formally addressed. The aim of this study was to determine the scope of breast myoepithelial expression of D2-40 and to identify problematic patterns of expression by in situ carcinoma that could be confused with lymphovascular invasion. We evaluated the distribution and intensity of D2-40 immunohistochemical expression in breast myoepithelium in normal breast (n = 50), proliferative fibrocystic changes (n = 10), ductal carcinoma in situ (n = 35), and lobular carcinoma in situ (n = 5). All cases of normal breast exhibited a variable degree of D2-40 expression by myoepithelium. The distribution was patchy and the intensity was less than that of the adjacent lymphatic endothelium. Larger ducts were more often positive than terminal ducts and lobules. D2-40 marked 77% of ductal carcinoma in situ cases and all lobular carcinoma in situ cases to a variable degree. Only a minority of involved ducts were reactive in each positive case; the intensity was weak to moderate. Although the tumor growth pattern generally enabled distinction of ductal carcinoma in situ from lymphovascular invasion, D2-40 myoepithelial expression in small ducts completely filled by solid-pattern ductal carcinoma in situ mimicked the pattern expected for lymphovascular invasion. Morphology of these myoepithelial cells was not diagnostically helpful as their compressed, stretched-out shape mimicked that of endothelium. Myoepithelial markers (p63 and smooth muscle myosin) confirmed each diagnosis of ductal carcinoma in situ. Lobular carcinoma in situ posed similar problems. The interpretation of D2-40 in the breast requires awareness that myoepithelium may also be immunoreactive. Solid-pattern ductal carcinoma in situ and lobular carcinoma in situ may be misinterpreted as lymphovascular invasion. We recommend that myoepithelial markers be used in conjunction with D2-40 to distinguish solid intralymphatic tumor emboli from solid pattern in situ carcinoma.     

E‐cadherin immunohistochemistry in breast pathology: uses and pitfalls

E‐cadherin immunohistochemistry is used commonly in surgical pathology practice to help distinguish lobular carcinoma in situ from ductal carcinoma in situ and invasive lobular carcinoma from invasive ductal carcinoma in histologically problematic or indeterminate cases. However, the interpretation of E‐cadherin immunostains is not always straightforward. Failure to recognize the pitfalls and limitations of E‐cadherin immunostains can lead to an erroneous diagnosis which may result in inappropriate patient management, particularly for patients with in‐situ lesions. In this paper we review the uses and, particularly, the pitfalls in the interpretation of E‐cadherin immunostains in distinguishing lobular from ductal lesions of the breast.     

Invasive mammary carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges

Tang F, Wei B, Tian Z, Gilcrease M Z, Huo L, Albarracin C T, Resetkova E, Zhang H, Sahin A, Chen J, Bu H, Abraham S & Wu Y
(2011) Histopathology 59 , 106–115 Invasive mammary carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges Aims: The aim of this study was to review the histomorphological features of primary neuroendocrine carcinomas (NEC) of the breast, in order to identify features useful in recognition of this entity for appropriate classification. Methods and results: 2003 World Health Organization (WHO) classification of tumors of the breast and female genital organs defined NEC of the breast as a subtype of invasive mammary carcinoma in which >50% of the tumor cells express neuroendocrine markers. Seventy‐four cases that fulfilled the WHO diagnostic criteria for NEC of the breast, excluding small cell carcinoma and low‐grade solid papillary carcinoma with a predominant in‐situ component, were identified between 1984 and 2008 from MD Anderson Cancer Center, and were included in the study. NECs of the breast had variable histomorphological features. The most common histologic patterns were papillary (80%) and nested (64%). Mixed growth patterns were common (59%), including admixed ductal component. The tumor cells could be polygonal, round, plasmacytoid, spindled, or with signet ring cell features. The cytoplasm could be granular, eosinophilic, clear, or finely vacuolated. These tumors frequently mimicked invasive or in situ ductal carcinoma, or invasive lobular carcinoma. Conclusions: NEC of the breast is underrecognized. Careful attention to cytologic and architectural features can help to identify cases that require further immunophenotypic confirmation for correct tumor classification.     

Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer

The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.