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1.  Breast cancer histological classification: agreement between the Office for National Statistics and the National Health Service Breast Screening Programme 
Breast Cancer Research  2005;7(6):R1090-R1096.
Introduction
Epidemiological studies rely on data supplied by central cancer registration sources to be timely, accurate and complete. Validation studies of such data at a national level are limited. Data collected for the Million Women Study was used to compare the level of agreement between the Office for National Statistics (ONS) and the National Health Service Breast Screening Programme (NHSBSP) in the recording of incident screen-detected breast cancer histology between 1996 and 2001.
Methods
1.3 million women aged 50 to 64 years were recruited into the Million Women Study cohort via the NHSBSP. Incident screen-detected breast cancer histologies were notified separately by the ONS and NHSBSP. ICD-10 and ICD-02 ONS codes and NHSBSP histology data were similarly coded to allow for comparison in terms of cancer invasiveness and morphology. The statistical outcome measures are percentage agreement and the kappa statistic.
Results
A total of 5,886 incident screen-detected breast cancers were available for analysis. Of the 5,886 screen-detected cancers reported by the ONS and NHSBSP, 5,684 (96.6%, κ = 0.9) agreed in terms of the degree of invasiveness. Of the 5,458 cancers that had been assigned a specific morphology code, there was exact agreement between the ONS and the NHSBSP in 4,922 cases (90.2%, κ = 0.8).
Conclusion
There is an excellent level of agreement between the ONS and NHSBSP in the recording of the histology of screen-detected breast cancer. From these results it is not possible to comment on which source of data is the more or less accurate, although the differences are very small.
doi:10.1186/bcr1352
PMCID: PMC1410775  PMID: 16457689
2.  Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions 
Breast Cancer Research : BCR  2012;14(4):R103.
Introduction
Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype.
Methods
Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003 to 2008. Specimens were widely sampled, and frozen blocks were screened for LCIS and co-existing malignant lesions, and were subject to microdissection. Samples from 65 patients were hybridized to the Affymetrix SNP 6.0 array platform. Cases with both an LCIS sample and an associated ductal carcinoma in situ (DCIS) or invasive tumor sample were evaluated for patterns of somatic copy number changes to assess evidence of clonal relatedness.
Results
LCIS was identified in 44 of the cases, and among these a DCIS and/or invasive lesion was also identified in 21 cases. A total of 17 tumor pairs had adequate DNA/array data for analysis, including nine pairs of LCIS/invasive lobular cancer, four pairs of LCIS/DCIS, and four pairs of LCIS/invasive ductal cancer. Overall, seven pairs (41%) were judged to be clonally related; in five (29%) evidence suggested clonality but was equivocal, and five (29%) were considered independent. Clonal pairs were observed with all matched lesion types and low and high histological grades. We also show anecdotal evidence of clonality between a patient-matched triplet of LCIS, DCIS, and invasive ductal cancer.
Conclusion
Our results support the role of LCIS as a precursor in the development of both high-grade and low-grade ductal and lobular cancers.
doi:10.1186/bcr3222
PMCID: PMC3680923  PMID: 22776144
3.  Impact of a national external quality assessment scheme for breast pathology in the UK 
Journal of Clinical Pathology  2006;59(2):138-145.
Background
This article presents the results and observed effects of the UK National Health Service Breast Screening Programme (NHSBSP) external quality assurance scheme in breast histopathology.
Aims/Methods
The major objectives were to monitor and improve the consistency of diagnoses made by pathologists and the quality of prognostic information in pathology reports. The scheme is based on a twice yearly circulation of 12 cases to over 600 registered participants. The level of agreement was generally measured using κ statistics.
Results
Four main situations were encountered with respect to diagnostic consistency, namely: (1) where consistency is naturally very high—this included diagnosing in situ and invasive carcinomas (and certain distinctive subtypes) and uncomplicated benign lesions; (2) where the level of consistency was low but could be improved by making guidelines more detailed and explicit—this included histological grading; (3) where consistency could be improved but only by changing the system of classification—this included classification of ductal carcinoma in situ; and (4) where no improvement in consistency could be achieved—this included diagnosing atypical hyperplasia and reporting vascular invasion. Size measurements were more consistent for invasive than in situ carcinomas. Even in cases where there is a high level of agreement on tumour size, a few widely outlying measurements were encountered, for which no explanation is readily forthcoming.
Conclusions
These results broadly confirm the robustness of the systems of breast disease diagnosis and classification adopted by the NHSBSP, and also identify areas where improvement or new approaches are required.
doi:10.1136/jcp.2004.025551
PMCID: PMC1860326  PMID: 16443727
breast; external quality assurance; histopathology; pathology; quality assurance
4.  Loss of heterozygosity in lobular carcinoma in situ of the breast 
Clinical Molecular Pathology  1995;48(2):M74-M78.
Aims—(1) To investigate whether loss of heterozygosity identified at various loci in invasive breast carcinoma or is present in lobular carcinoma in situ (LCIS). (2) To investigate whether LCIS is a monoclonal (neoplastic) or a polyclonal (hyperplastic) proliferation.
Methods—Forty three cases of LCIS (30 with associated invasive carcinoma or in situ ductal carcinoma (DCIS) and 13 cases of pure LCIS) were investigated for loss of heterozygosity on chromosomes 16q, 17q, 17p, and 13q using a microdissection technique, polymorphic DNA markers, and the polymerase chain reaction (PCR).
Results—Loss of heterozygosity was detected in both subgroups of LCIS at all the loci examined. There was no significant difference in the frequency of the loss between the group associated with invasive carcinoma and the pure LCIS group. The frequency of loss of heterozygosity ranged from 8% on 17p to 50% on 17q.
Conclusions—Because of the nature of the technique employed, our findings show that LCIS is a monoclonal (neoplastic) proliferation rather than a hyperplastic proliferation. The incidence of loss of heterozygosity on 17p (D17S796) is lower than we have observed previously in DCIS, suggesting that LCIS and DCIS are different genetically as well as clinically and morphologically. The similar incidence of loss of heterozygosity on 16q and 17q, however, suggests that DCIS and LCIS may share a common pathway of evolution.
Images
PMCID: PMC407928  PMID: 16695985
Breast cancer; lobular carcinoma in situ; loss of heterozygosity
5.  Histopathological and clonal study of combined lobular and ductal carcinoma of the breast 
Pathology International  2013;63(6):297-304.
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.
doi:10.1111/pin.12065
PMCID: PMC3798103  PMID: 23782331
breast cancer; ductal carcinoma; human androgen receptor (HUMARA) gene; lobular carcinoma; methylation-specific PCR
6.  Serial analysis of gene expression of lobular carcinoma in situ identifies down regulation of claudin 4 and overexpression of matrix metalloproteinase 9 
Introduction
Although lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that LCIS is a low risk, direct precursor of invasive lobular carcinoma. Global gene expression profiling of LCIS has not been performed.
Methods
We analysed the comprehensive gene expression profile of a unique case of mass-forming LCIS using serial analysis of gene expression (SAGE). This SAGE library is publicly available online. By comparing the gene expression profile of LCIS to that of benign breast epithelium and stroma, we identified several genes up and down regulated in LCIS. Differential expression of selected genes not previously studied in LCIS was validated at the protein level by immunohistochemistry and at the RNA level by quantitative reverse transcriptase PCR (RT-PCR).
Results
We identified down regulation of claudin 4 and overexpression of matrix metalloproteinase 9 in LCIS relative to normal breast epithelium and stroma. We validated these findings by immunohistochemistry in a separate series of 11 and 19 LCIS cases, respectively. Overexpression of matrix metalloproteinase 9 was further confirmed by quantitative RT-PCR analysis of the index case.
Conclusions
We have created the first global gene expression profile of LCIS, and demonstrated down regulation of cell junction proteins (an expected result) and overexpression of matrix metalloproteinase 9 (an unexpected result). Additional analysis of this data made available as an online resource should facilitate further molecular characterisation of LCIS.
doi:10.1186/bcr2189
PMCID: PMC2614499  PMID: 18954444
7.  Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast 
Sawyer, Elinor | Roylance, Rebecca | Petridis, Christos | Brook, Mark N. | Nowinski, Salpie | Papouli, Efterpi | Fletcher, Olivia | Pinder, Sarah | Hanby, Andrew | Kohut, Kelly | Gorman, Patricia | Caneppele, Michele | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Swann, Ruth | Dwek, Miriam | Perkins, Katherine-Anne | Gillett, Cheryl | Houlston, Richard | Ross, Gillian | De Ieso, Paolo | Southey, Melissa C. | Hopper, John L. | Provenzano, Elena | Apicella, Carmel | Wesseling, Jelle | Cornelissen, Sten | Keeman, Renske | Fasching, Peter A. | Jud, Sebastian M. | Ekici, Arif B. | Beckmann, Matthias W. | Kerin, Michael J. | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Milne, Roger L. | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Benitez, Javier | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Lochmann, Magdalena | Brauch, Hiltrud | Fischer, Hans-Peter | Ko, Yon-Dschun | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Investigators, kConFab | Lambrechts, Diether | Weltens, Caroline | Van Limbergen, Erik | Hatse, Sigrid | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Bonanni, Bernardo | Volorio, Sara | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Kristensen, Vessela | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Devillee, Peter | Tollenaar, Rob A. E. M. | Seynaeve, Caroline M. | Kriege, Mieke | Figueroa, Jonine | Chanock, Stephen J. | Sherman, Mark E. | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | van Deurzen, Carolien H. M. | Li, Jingmei | Czene, Kamila | Humphreys, Keith | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Shah, Mitul | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Couch, Fergus J. | Hallberg, Emily | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Dunning, Alison M. | Hall, Per | Easton, Doug | Pharoah, Paul | Schmidt, Marjanka K. | Tomlinson, Ian | Garcia-Closas, Montserrat | Gibson, Greg
PLoS Genetics  2014;10(4):e1004285.
Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
Author Summary
Invasive lobular breast cancer (ILC) accounts for 10–15% of invasive breast cancer and is generally ER positive (ER+). To date, none of the genome-wide association studies that have identified loci that predispose to breast cancer in general or to ER+ or ER-negative breast cancer have focused on lobular breast cancer. In this lobular breast cancer study we identified a new variant that appears to be specific to this morphological subtype. We also ascertained which of the known variants predisposes specifically to lobular breast cancer and show for the first time that some of these loci are also associated with lobular carcinoma in situ, a non-obligate precursor of breast cancer and also a risk factor for contralateral breast cancer. Our study shows that the genetic pathways of invasive lobular cancer and ER+ ductal carcinoma mostly overlap, but there are important differences that are likely to provide insights into the biology of lobular breast tumors.
doi:10.1371/journal.pgen.1004285
PMCID: PMC3990493  PMID: 24743323
8.  The Million Women Study: design and characteristics of the study population 
Breast Cancer Research  1999;1(1):73-80.
Objectives:
To describe the design of the Million Women Study and the characteristics of the study population.
Study design:
Population-based cohort study of women aged 50-64 in the UK.
Setting:
Women are asked to join the Million Women Study when they are invited to routine screening for breast cancer at 61 of the screening centres of the UK National Health Service Breast Screening Programme (NHSBSP). An estimated 71% of women screened by the NHSBSP return a completed questionnaire.
Participants:
800 000 women were recruited between May 1996 and June 1999, and it is planned that an additional 200 000 will be recruited by the year 2000.
Results:
The characteristics of the first 121 000 women recruited into the Million Women Study are described here. At recruitment 33% of the study population were currently using hormone replacement therapy and 47% had used it at some time. Over half (54%) had used oral contraceptives, and 18% were current smokers at the time of recruitment. Before they were screened 1.4% of the women had been diagnosed with breast cancer in the past, 6% had a mother with a history of breast cancer and 3.7% had a sister with a history of breast cancer. It is estimated that 1 million women will have been recruited by early in the year 2000, and that by the end of the year 2002 there will be 5000 screen-detected breast cancers and 23 000 deaths in the cohort, the majority of which will be attributed to cancer (12 600 deaths) and circulatory disease (8000 deaths).
Conclusions:
By the end of the year 2002, the Million Women Study will have sufficient statistical power to detect relative risks of 0.8 or less, or of 1.2 or more in current users compared with never users of hormone replacement therapy for mortality from breast cancer, colorectal cancer, lung and ovarian cancer, ischaemic heart disease and stroke.
PMCID: PMC13913  PMID: 11056681
breast cancer; breast screening; cohort study; hormone replacement therapy; lifestyle factors; morbidity; mortality
9.  E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. 
British Journal of Cancer  1997;76(9):1131-1133.
In breast cancer, inactivating point mutations in the E-cadherin gene are frequently found in invasive lobular carcinoma (ILC) but never in invasive ductal carcinoma (IDC). Lobular carcinoma in situ (LCIS) adjacent to ILC has previously been shown to lack E-cadherin expression, but whether LCIS without adjacent invasive carcinoma also lacks E-cadherin expression and whether the gene mutations present in ILC are already present in LCIS is not known. We report here that E-cadherin expression is absent in six cases of LCIS and present in 150 cases of ductal carcinoma in situ (DCIS), both without an adjacent invasive component. Furthermore, using mutation analysis, we could demonstrate the presence of the same truncating mutations and loss of heterozygosity (LOH) of the wild-type E-cadherin in the LCIS component and in the adjacent ILC. Our results indicate that E-cadherin is a very early target gene in lobular breast carcinogenesis and plays a tumour-suppressive role, additional to the previously suggested invasion-suppressive role.
Images
PMCID: PMC2228132  PMID: 9365159
10.  Diagnostic utility of E-cadherin and P120 catenin cocktail immunostain in distinguishing DCIS from LCIS 
Background: Breast carcinoma in situ (CIS) is classified into ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). DCIS is treated with surgical excision while LCIS can be clinically followed with or without hormonal treatment. Thus, it is critical to distinguish DCIS from LCIS. Immunohistochemical (IHC) staining for E-cadherin is routinely used to differentiate DCIS from LCIS in diagnostically challenging cases. Circumferential diffuse membranous staining of E-cadherin is the typical pattern in DCIS, whereas LCIS lacks or shows decreased E-cadherin expression. Recent studies have shown that DCIS has membranous staining of P120 catenin and LCIS has diffuse cytoplasmic staining of P120 catenin. We developed a cocktail composed of E-cadherin and P120 catenin primary antibodies so that only one slide is needed for the double immunostains. Designs: Twenty-seven blocks of formalin-fixed paraffin-embedded tissue from 26 cases of DCIS or LCIS were retrieved from the archives of Houston Methodist Hospital. Four consecutive sections from the same blocks were used for H&E and immunohistochemical (IHC) stains. The E-cadherin antibody was a rabbit polyclonal antibody and the P120 catenin antibody was a mouse monoclonal antibody. The E-cadherin primary antibody was detected using a secondary antibody raised against rabbit antibody and was visualized with a brown color. The P120 catenin primary antibody was detected using a secondary antibody raised against mouse antibody and was visualized with a red color. Results: Using individual antibodies, 15 of 15 DCIS lesions had diffuse circumferential membranous E-cadherin staining (brown stain) or P120 catenin staining (red stain). All 12 LCIS cases showed cytoplasmic P120 red staining or loss of E-cadherin staining when the single P120 catenin or E-cadherin antibody was used. When stained with the antibody cocktail, all 15 DCIS samples showed diffuse red and brown membranous staining without cytoplasmic stain; all 12 LCIS samples showed diffuse cytoplasmic red staining for P120 catenin but no membranous staining for E-cadherin. Conclusions: 1. This antibody cocktail can be applied in daily practice on paraffin-embedded tissue and is especially useful in small biopsies with small foci of CIS lesions. 2. Immunohistochemical staining with the antibody cocktail showed 100% concordance with the traditional single antibody immunostaining using either E-cadherin or P120 catenin antibody. 3. Our antibody cocktail includes E-cadherin as a positive membranous stain for DCIS and P120 catenin as a positive cytoplasmic stain for LCIS, which may enhance accuracy and confidence in the differential diagnoses.
PMCID: PMC4069889  PMID: 24966968
DCIS; LCIS; E-cadherin; p120 catenin
11.  The clinical effectiveness of fine needle aspiration biopsy in patients with palpable breast lesions seen at the University College Hospital, Ibadan, Nigeria: A 10-year retrospective study 
Background:
Although open surgical biopsy is the ‘gold standard’ for diagnosis of palpable breast lesions, in recent years two types of minimally invasive breast biopsy techniques, core needle biopsy and fine needle aspiration biopsy (FNAB), have become established for the diagnostic evaluation of palpable breast lesions.
Aims:
This study was undertaken to evaluate the clinical effectiveness of FNAB as a first line diagnostic procedure in the management of patients with breast lumps in University College Hospital (UCH), Ibadan, using the suggested thresholds for cytology performance as recommended by the United Kingdom National Health Services Breast Screening Programme (NHSBSP).
Settings and Design:
A 10-year retrospective cohort study carried out in the Pathology Department of UCH.
Materials and Methods:
All FNAB and histologically diagnosed cases of breast lesions in the pathology department between January 1996 and December 2005 were reviewed. The cytological diagnoses were then categorized into one of five diagnostic categories in accordance with the recommendations of the NHSBSP.
Results:
The positive predictive value for malignancy was 99.3% with a complete sensitivity of 97.7% and specificity (full) of 94.2%.
Conclusions:
The high quality assurance measures obtained in this study affirms FNAB as a clinically effective diagnostic procedure for breast lesions.
doi:10.4103/0970-9371.83467
PMCID: PMC3159286  PMID: 21897544
Clinical effectiveness; fine needle aspiration biopsy; Nigeria; palpable breast lesions
12.  Disparate E-cadherin mutations in LCIS and associated invasive breast carcinomas 
Molecular Pathology  2001;54(2):91-97.
Aims—The relation between lobular carcinoma in situ (LCIS) and invasive breast cancer is unresolved. In an attempt to establish whether LCIS is a precursor of invasive cancer the mutational status and the expression of E-cadherin was analysed in LCIS and associated invasive breast carcinoma in 23 patients.
Methods—Foci of LCIS and associated invasive carcinoma were individually microdissected from tissue from 23 patients. Exons 4–16 of the E-cadherin gene were analysed using single strand conformation polymorphism (SSCP); protein expression and the localisation of E-cadherin and β-catenin were assessed with the use of immunohistochemistry.
Results—Immunohistochemistry revealed a lack of expression of E-cadherin and β-catenin in most LCIS samples and invasive foci. In all but four cases, the staining pattern was identical in the LCIS and associated invasive areas. When E-cadherin was absent, β-catenin was also undetected, suggesting a lack of expression of alternative classic cadherin members in these lesions. Coincident E-cadherin mutations in LCIS and associated invasive carcinoma were not identified in this series of patients. However, mutational analysis of E-cadherin in multiple foci of carcinoma in situ surrounding an invasive lesion provided evidence to support ductal carcinoma in situ as a precursor of invasive ductal carcinoma.
Conclusion—These data support the hypothesis that LCIS is not a precursor of invasive breast carcinoma but a marker of increased risk of developing invasive disease.
PMCID: PMC1187009  PMID: 11322170
lobular carcinoma in situ; breast; E-cadherin; infiltrating lobular carcinoma
13.  Genetic relation of lobular carcinoma in situ, ductal carcinoma in situ, and associated invasive carcinoma of the breast 
Molecular Pathology  2000;53(3):118-121.
Aims—The mutual relation of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) of the breast, as accepted precursor lesions of invasive breast cancer, is controversial. Because they display genetic heterogeneity, it is not clear how genetically advanced these entities are and what causes the transition to an invasive carcinoma.
Methods—Six cases of LCIS, four of them with associated lobular invasive carcinoma, four cases of intermediately differentiated DCIS with an associated invasive lobular carcinoma, and nine cases of intermediately and poorly differentiated DCIS with associated ductal invasive carcinoma were investigated by means of comparative genomic hybridisation (CGH) after microdissection and immunohistochemical staining of E-cadherin.
Results—LCIS was characterised by a low average rate of copy number changes, no evidence of amplifications, and a high rate of gains and losses of chromosomal material at 1q and 16q, respectively. A high degree of genetic homology with well differentiated DCIS was obvious, as reported previously. The cases of intermediately differentiated DCIS with associated lobular invasive components and lobular differentiation revealed striking homologies, and a significant difference of E-cadherin expression. The comparison of preinvasive and invasive breast lesions, irrespective of differentiation within the same patient, revealed no specific alteration that might be associated with invasion. Genetic alterations seen in invasive carcinoma were not necessarily seen in the adjacent precursor lesions.
Conclusions—These results provide strong evidence that invasive breast cancer is a disease with multiple cytogenetic subclones already present in preinvasive lesions. Moreover, specific CGH alterations associated with invasion were not observed. Furthermore, the close genetic association between well differentiated and a subgroup of intermediately differentiated DCIS and LCIS led to the hypothesis that LCIS and a subgroup of DCIS are different phenotypic forms of a common genotype.
PMCID: PMC1186916  PMID: 10897329
lobular carcinoma in situ; ductal carcinoma in situ; invasion
14.  Lobular carcinoma in situ of the breast is not caused by constitutional mutations in the E-cadherin gene 
British Journal of Cancer  2000;82(3):568-570.
Lobular carcinoma in situ (LCIS) is an unusual histological pattern of non-invasive neoplastic disease of the breast occurring predominantly in women aged between 40 and 50 years. LCIS is frequently multicentric and bilateral, and there is evidence that it is associated with an elevated familial risk of breast cancer. Although women with LCIS suffer an increased risk of invasive breast disease, this risk is moderate suggesting that LCIS may result from mutation of a gene or genes conferring a high risk of LCIS, but a lower risk of invasive breast cancer. The high frequency of somatic mutations in E-cadherin in LCIS, coupled with recent reports that germline mutations in this gene can predispose to diffuse gastric cancer, raised the possibility that constitutional E-cadherin mutations may confer susceptibility to LCIS. In order to explore this possibility we have examined a series of 65 LCIS patients for germline E-cadherin mutations. Four polymorphisms were detected but no pathogenic mutations were identified. The results indicate that E-cadherin is unlikely to act as a susceptibility gene for LCIS. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.0965
PMCID: PMC2363330  PMID: 10682667
LCIS; germline; E-cadherin mutations
15.  A case of lobular carcinoma in situ presenting as a solid mass 
The British Journal of Radiology  2011;84(999):e048-e050.
A patient presented with a 2 cm lump in the lower outer quadrant of the left breast. Mammogram and ultrasonography showed a solid mass with a microlobulated contour, partially irregular border and microcalcifications. MRI showed an irregular mass with early enhancement and high signal intensity, and the late-phase image demonstrated a partial washout pattern. These findings suggest that the tumour was a malignant invasive carcinoma. Non-invasive ductal carcinoma was diagnosed after a fine needle aspiration and core needle biopsy followed by a partial breast excision and sentinel lymph node (SLN) biopsy. A pathological examination of the lesion displayed characteristic small monomorphic cells, solid proliferation and massive distension within the lobular unit. The tumour was immunohistochemically negative for E-cadherin and pure lobular carcinoma in situ (LCIS) was diagnosed. Pure LCIS is very rare and there have been no previous reports of pure LCIS forming a solid mass.
doi:10.1259/bjr/32795948
PMCID: PMC3473884  PMID: 21325356
16.  Topographical and histological presentation of mammographic pathology in breast cancer. 
Journal of Clinical Pathology  1988;41(1):3-11.
Between 1979 and 1985 surgical resections from 680 cases of primary breast cancer were examined histologically. The patients were divided into four groups: (i) patients aged between 45 and 69 years who had been screened (n = 316); (ii) those younger than 45 who had not been screened (n = 55); (iii) those aged between 45 and 69 who had not been screened (n = 104); and (iv) those older than 69 who had not been screened (n = 205). The material was compared in terms of the association between in situ and invasive carcinoma. There was a low incidence of lobular carcinoma in situ (LCIS) in all groups and a high incidence of ductal carcinoma in situ (DCIS) which declined with age. Ninety nine group i patients had in situ carcinoma or early invasive carcinoma (less than 1 cm in diameter) compared with 19 of group iii cases. Screened patients had fewer multicentric cancers and a lower incidence of large invasive cancer compared with unscreened patients. Group ii patients had a higher incidence of whole quadrant in situ carcinoma, multiple cancer, and lymph node metastases. Group iv patients had a lower incidence of in situ cancer, and more low grade cancer than the other groups. Cases were divided into four types on the basis of this analysis.
Images
PMCID: PMC1141326  PMID: 2830318
17.  Molecular Classification of Breast Carcinoma In Situ 
Current Genomics  2006;7(8):523-532.
Pleomorphic variant of invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular carcinoma (ILC). Its in situ counterpart, pleomorphic lobular carcinoma in situ (PLCIS) is a recently described entity. Morphologically it has the typical architectural pattern of LCIS, but the neoplastic cells resemble intermediate grade DCIS. Molecular signatures that distinguish PLCIS from DCIS and LCIS would provide additional tools to aid in the histopathologic classification of PLCIS as a lesion distinct from LCIS and DCIS. CIS lesions, obtained from a study cohort of 38 breast cancer patients, were divided into 18 DCIS, 14 PLCIS and 6 LCIS. DNA from microdissected archival tissue was interrogated for loss or gain of 112 breast-cancer-specific genes using the Multiplex Ligation-dependent Probe Amplification Assay (MLPA). Classification Regression Tree (CART) analysis was employed to develop a gene-based molecular classification to distinguish or separate out PLCIS from DCIS and LCIS. Molecular classification via CART, based on gene copy number, agreed with histopathology in 34/38 CIS cases. Loss of CASP1 was predictive of LCIS (n=4) with one misclassified PLCIS. Gain of RELA predicted only the LCIS classification (n=2 cases). STK15 and TNFRSF1B were predictive only for DCIS with no misclassifications. Gain of EHF and TNFRSF1B and loss of NCOA3 were predictive of PLCIS, but not without misclassification. Molecular reclassification by CART was accomplished in 4 CIS cases: 1 PLCIS was reclassified as LCIS, 1 LCIS reclassified as PLCIS, and 2 DCIS cases as PLCIS. This study provides additional rationale for molecular modeling strategies in the evaluation of CIS lesions. This diagnostic aid may serve to minimize misclassification between PLCIS and DCIS, and PLCIS and LCIS, aiding to increase accuracy in the differential diagnosis of CIS lesions.
PMCID: PMC1828915  PMID: 17375183
Carcinoma in situ (CIS); Ductal carcinoma in situ (DCIS); Pleomorphic lobular carcinoma in situ (PLCIS); Lobular carcinoma in situ (LCIS); Classification Regression Tree (CART); molecular classification; Multiplex Ligation-dependent Probe Amplification Assay (MLPA); differential diagnosis
18.  MOLECULAR CLASSIFICATION OF BREAST CARCINOMA IN SITU 
Current genomics  2006;7(8):523-532.
Pleomorphic variant of invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular carcinoma (ILC). Its in situ counterpart, pleomorphic lobular carcinoma in situ (PLCIS) is a recently described entity. Morphologically it has the typical architectural pattern of LCIS, but the neoplastic cells resemble intermediate grade DCIS. Molecular signatures that distinguish PLCIS from DCIS and LCIS would provide additional tools to aid in the histopathologic classification of PLCIS as a lesion distinct from LCIS and DCIS. CIS lesions, obtained from a study cohort of 38 breast cancer patients, were divided into 18 DCIS, 14 PLCIS and 6 LCIS. DNA from microdissected archival tissue was interrogated for loss or gain of 112 breast-cancer-specific genes using the Multiplex Ligation-dependent Probe Amplification Assay (MLPA). Classification Regression Tree (CART) analysis was employed to develop a gene-based molecular classification to distinguish or separate out PLCIS from DCIS and LCIS. Molecular classification via CART, based on gene copy number, agreed with histopathology in 34/38 CIS cases. Loss of CASP1 was predictive of LCIS (n=4) with one misclassified PLCIS. Gain of RELA predicted only the LCIS classification (n=2 cases). STK15 and TNFRSF1B were predictive only for DCIS with no misclassifications. Gain of EHF and TNFRSF1B and loss of NCOA3 were predictive of PLCIS, but not without misclassification. Molecular reclassification by CART was accomplished in 4 CIS cases: 1 PLCIS was reclassified as LCIS, 1 LCIS reclassified as PLCIS, and 2 DCIS cases as PLCIS. This study provides additional rationale for molecular modeling strategies in the evaluation of CIS lesions. This diagnostic aid may serve to minimize misclassification between PLCIS and DCIS, and PLCIS and LCIS, aiding to increase accuracy in the differential diagnosis of CIS lesions.
PMCID: PMC1828915  PMID: 17375183
Carcinoma in situ (CIS); Ductal carcinoma in situ (DCIS); Pleomorphic lobular carcinoma in situ (PLCIS); Lobular carcinoma in situ (LCIS); Classification Regression Tree (CART); molecular classification; Multiplex Ligation-dependent Probe Amplification Assay (MLPA); differential diagnosis
19.  An ongoing case-control study to evaluate the NHS breast screening programme 
BMC Cancer  2013;13:596.
Background
In England, a national breast screening programme (NHSBSP) has been in place since 1988, and assessment of its impact on breast cancer incidence and mortality is essential to ensure that the programme is indeed doing more good than harm. This article describes large observation studies designed to estimate the effects of the current programme in terms of the benefits on breast cancer incidence and mortality and detrimental effect in terms of overdiagnosis. The case-control design of the cervical screening programme evaluation was highly effective in informing policy on screening intervals and age ranges. We propose innovative selection of cases and controls and gathering of additional variables to address new outcomes of interest and develop new methodologies to control for potential sources of bias.
Methods/Design
Traditional case-control evaluation of breast screening uses women who have died from breast cancer as cases, and women known to be alive at the time of case death as controls. Breast screening histories prior to the cases’ date of first diagnosis are compared. If breast screening is preventing mortality from breast cancer, cases will be characterised by a lesser screening history than controls. All deaths and incident cases of primary breast cancer in England within each 2-year study period will be included in this ongoing evaluation. Cases will be age- and area-matched to controls and variables related to cancer treatment and breast tumour pathology will be obtained to investigate the interplay between screening and treatment, and the effect of screening on incidence of advanced stage disease. Screening attendance at other national screening programmes will also be collected to derive superior adjustment for self-selection bias.
The study is registered and has received full ethics approval.
doi:10.1186/1471-2407-13-596
PMCID: PMC3866937  PMID: 24330588
Breast cancer; Case–control; Incidence; Mortality; Overdiagnosis; Advanced stage; Bias
20.  Increased levels of active c-Src distinguish invasive from in situ lobular lesions 
Introduction
Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC.
Methods
Immunochemistry for c-Src and other cancer-related molecules was performed on archived tissue specimens from 57 LBC patients. Relative c-Src activity was estimated by comparing fluorescence intensity of ILC with that of adjacent ALH/LCIS and nonneoplastic epithelia after staining with an antibody against active c-Src. Expression of active c-Src was correlated with markers of invasion and malignancy and with relapse among LBC patients.
Results
Levels of activated c-Src were increased in ILC relative to ALH/LCIS (1.63-fold ± 0.24 SD) and nonneoplastic epithelia (1.47 ± 0.18 SD). Increased c-Src levels correlated with the activation of c-Src downstream targets (Fak, Stat-3) and the expression of mesenchymal markers. ILC cells with activated c-Src co-expressed metastatic markers (Opn, Cxcr4) and included cells positive for the cancer stem cell marker Aldh1. A tendency for high c-Src levels (P = 0.072) was observed among the seven LBC patients with relapsed disease.
Conclusions
Our data indicate elevated c-Src activity in ILC relative to noninvasive neoplastic tissue. The associated molecular changes suggest that c-Src promotes LBC invasiveness by inducing an epithelial-mesenchymal transition. Therefore, c-Src antagonists might counteract the acquisition of invasiveness during LBC progression. Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth. Together with the possible association between high c-Src levels and disease recurrence, our findings encourage the evaluation of c-Src antagonists for the treatment of LBC.
doi:10.1186/bcr2332
PMCID: PMC2750104  PMID: 19583841
21.  The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions 
British Journal of Cancer  2006;96(1):110-117.
Immunohistochemical staining for FHIT and PCNA proteins was carried out in 451 breast lesions showing nonproliferative benign breast disease (BBD) (n=263), proliferative BBD without atypia (n=128), proliferative BBD with atypia (n=11), carcinoma in situ (n=15) or invasive carcinoma (n=34) and for EGFR protein in a subset of 71 of these cases. FHIT underexpression was not detected in nonproliferative lesions, but occurred in 2% of proliferative BBD without atypia, 10% proliferative BBD with atypia, 27% of carcinoma in situ and 41% of invasive carcinoma, which suggests that it could be useful in assessing those carcinoma in situ lesions (ductal, DCIS and lobular, LCIS) that are more likely to progress to malignancy. Preliminary microarray comparisons on DCIS and invasive carcinoma samples dissected from formalin-fixed paraffin sections showed a consistent downregulation of two previously identified FHIT-related genes, caspase 1 and BRCA1 in lesions underexpressing FHIT.
doi:10.1038/sj.bjc.6603512
PMCID: PMC2360209  PMID: 17164758
FHIT; PCNA; EGFR; BBD; CIS; Ca
22.  A Case Report: Lobular Carcinoma In Situ in a Male Patient with Subsequent Invasive Ductal Carcinoma Identified on Screening Breast MRI 
Journal of Cancer  2012;3:226-230.
Lobular carcinoma in situ is a form of in situ neoplasia that develops within the terminal lobules of the breast. It is an extremely rare finding in males due to the lack of lobular development in the male breast. The authors herein report an unusual case of incidentally discovered lobular carcinoma in situ in a male patient with recurrent bilateral gynecomastia who was subsequently diagnosed with invasive ductal carcinoma of the left breast. The pathology of lobular carcinoma in situ in a male as well as screening MRI surveillance of male patients at high risk for breast cancer are discussed, emphasizing the importance of screening and imaging follow up in men who are at high risk for breast cancer.
doi:10.7150/jca.4091
PMCID: PMC3366477  PMID: 22670156
Lobular carcinoma in situ; male; breast cancer; MRI; screening and imaging
23.  Evolving concepts in breast lobular neoplasia and invasive lobular carcinoma, and their impact on imaging methods 
Insights into Imaging  2014;5(2):183-194.
Invasive lobular carcinoma (ILC) and lobular neoplasia (LN) are two distinct conditions that still pose challenges regarding to their classification, diagnosis and management. Although they share similar cellular characteristics, such as discohesive neoplastic cells and absence of e-cadherin staining, they represent completely different conditions. LN encompasses atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), which are currently considered risk factors and non-obligatory precursors of breast neoplasia. These lesions are diagnosed as incidental findings in percutaneous biopsies or appear as non-specific clusters of punctate calcifications in mammograms. ILC is the second most common breast malignancy and has typical histological features, such as infiltrative growth and low desmoplasia. These histological features are reflected in imaging findings and constitute the reasons for typical subtle mammographic features of ILC, as architectural distortion or focal asymmetries. Ultrasonography (US) may detect almost 75 % of the ILCs missed by mammography and represents the modality of choice for guiding biopsies. Magnetic resonance imaging (MRI) exhibits a high sensitivity for the diagnosis of ILC and for detecting synchronous lesions.
Teaching Points
• LN includes ALH and LCIS, risk factors and non-obligatory precursors of breast cancer.
• Absence of e-cadherin staining is crucial for differentiation among ductal and lobular lesions.
• ILC has typical histological features, such as infiltrative growth and low desmoplasia.
• Mammographic features of ILC are often subtle and reflect the histological features.
• MRI exhibits a high sensitivity for the diagnosis of ILC and for detecting synchronous lesions.
doi:10.1007/s13244-014-0324-6
PMCID: PMC3999371  PMID: 24633840
Breast cancer; Lobular neoplasm; Invasive lobular carcinoma; Breast imaging; Resonance magnetic
24.  Mixed apocrine/endocrine ductal carcinoma in situ of the breast coexistent with lobular carcinoma in situ 
Journal of Clinical Pathology  2001;54(1):70-73.
An unusual mixed form of ductal carcinoma in situ (DCIS) of the breast is described, which exhibits a biphenotypic morphology encompassing a range of differential diagnostic DCIS subtypes. In adddition, immunophenotypic and ultrastructural studies demonstrate neuroendocrine and apocrine differentiation, raising questions regarding appropriate classification and biological behaviour. In two cases, coexistence of this mixed form of DCIS with lobular carcinoma in situ (LCIS) in the same duct lobular units is an additional unusual feature that might, at least in some cases, indicate a closer relation between them.
Key Words: lobular carcinoma in situ • ductal carcinoma in situ • apocrine differentiation
doi:10.1136/jcp.54.1.70
PMCID: PMC1731276  PMID: 11271793
25.  Effect of margins of excision on recurrence after local excision of ductal carcinoma in situ of the breast 
Journal of Clinical Pathology  2002;55(8):581-586.
Aims: To determine important factors influencing recurrence after local excision of duct carcinoma in situ (DCIS) of the breast.
Materials and methods: The extent (size) in millimetres, classification (by cytonuclear grade (NHSBSP system), by extent of necrosis, and by the Van Nuys system), and excision margins of 115 cases of screen detected DCIS treated by local excision were measured. A prognostic index was calculated by the addition of the Van Nuys classification (low grade, 1; moderate grade, 2; high grade, 3), margin score (≥ 10 mm, 1; 1–9 mm, 2; < 1 mm, 3), and size score (≤ 15 mm, 1; 16–40 mm, 2; and ≥ 41 mm, 3), giving a total score of 3–9.
Results: Classification using cytonuclear grade, extent of necrosis, or the Van Nuys system did not correlate significantly with recurrence. The excision margin (in millimetres) was associated with recurrence (p = 0.027) and if excision margin status was simplified using the scoring system (≥ 10 mm, 1; 1–9 mm, 2; < 1 mm, 3), the margin score was significantly associated with recurrence (p = 0.03). A prognostic index based on the Van Nuys score, margin status, and size was significantly associated with recurrence (p = 0.003).
Conclusion: The results support the hypothesis that the margin of excision is the most important factor predicting the recurrence of DCIS after local excision.
PMCID: PMC1769717  PMID: 12147650
duct carcinoma of breast; duct carcinoma in situ; breast

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