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1.  Nottingham Prognostic Index Plus (NPI+): a modern clinical decision making tool in breast cancer 
British Journal of Cancer  2014;110(7):1688-1697.
Background:
Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. Global gene expression profiling studies have demonstrated that BC comprises distinct molecular classes with clinical relevance. In this study, we hypothesised that molecular features of BC are a key driver of tumour behaviour and when coupled with a novel and bespoke application of established clinicopathologic prognostic variables can predict both clinical outcome and relevant therapeutic options more accurately than existing methods.
Methods:
In the current study, a comprehensive panel of biomarkers with relevance to BC was applied to a large and well-characterised series of BC, using immunohistochemistry and different multivariate clustering techniques, to identify the key molecular classes. Subsequently, each class was further stratified using a set of well-defined prognostic clinicopathologic variables. These variables were combined in formulae to prognostically stratify different molecular classes, collectively known as the Nottingham Prognostic Index Plus (NPI+). The NPI+ was then used to predict outcome in the different molecular classes.
Results:
Seven core molecular classes were identified using a selective panel of 10 biomarkers. Incorporation of clinicopathologic variables in a second-stage analysis resulted in identification of distinct prognostic groups within each molecular class (NPI+). Outcome analysis showed that using the bespoke NPI formulae for each biological BC class provides improved patient outcome stratification superior to the traditional NPI.
Conclusion:
This study provides proof-of-principle evidence for the use of NPI+ in supporting improved individualised clinical decision making.
doi:10.1038/bjc.2014.120
PMCID: PMC3974073  PMID: 24619074
breast cancer; classification; prognostic index; molecular; clinical; outcome
2.  Biology of primary breast cancer in older women treated by surgery: with correlation with long-term clinical outcome and comparison with their younger counterparts 
British Journal of Cancer  2013;108(5):1042-1051.
Background:
As age advances breast cancer appears to change its biological characteristics, however, very limited data are available to define the precise differences between older and younger patients.
Methods:
Over 36 years (1973–2009), 1758 older (⩾70 years) women with early operable primary breast cancer were managed in a dedicated clinic. In all, 813 underwent primary surgery and 575 good quality tumour samples were available for biological analysis. The pattern of biomarkers was analysed using indirect immunohistochemistry on tissue microarrays. Comparison was made with a previously characterised series of younger (<70 years) patients.
Results:
There was high expression of oestrogen receptor (ER), PgR, Bcl2, Muc1, BRCA1 and 2, E-cadherin, luminal cytokeratins, HER3, HER4, MDM2 and 4 and low expression of human epidermal growth factor receptor (HER)-2, Ki67, p53, EGFR and CK17. Oestrogen receptor and axillary stage appeared as independent prognostic factors. Unsupervised partitional clustering showed six biological clusters in older patients, five of which were common in the younger patients, whereas the low ER luminal cluster was distinct in the older series. The luminal phenotype showed better breast cancer-specific survival, whereas basal and HER2-overexpressing tumours were associated with poor outcome.
Conclusion:
Early operable primary breast cancer in older women appears as a distinct biological entity, with existence of a novel cluster. Overall older women showed less aggressive tumour biology and ER appeared as an independent prognostic factor alongside the time-dependent axillary stage. These biological characteristics may explain the differences in clinical outcome and should be considered in making therapeutic decisions.
doi:10.1038/bjc.2012.601
PMCID: PMC3619059  PMID: 23462719
biology; breast cancer; older women; clinical outcome
3.  An overview of assessment of prognostic and predictive factors in breast cancer needle core biopsy specimens 
Journal of Clinical Pathology  2007;60(12):1300-1306.
Needle core biopsy (NCB), as part of triple assessment for preoperative evaluation and diagnosis of breast cancer, is now considered as an established, highly accurate method for diagnosing breast cancer that has replaced either fine needle aspiration cytology or excisional biopsy as the initial diagnostic biopsy procedures in many institutions. In addition to its primary role in establishing an accurate histological diagnosis, NCB can potentially provide important additional pathological prognostic information which may be of direct clinical value in certain situations, such as patients being considered for preoperative (neoadjuvant) therapy. With this background in mind we briefly review the current role of NCB in breast cancer diagnosis and then concentrate this review on the usefulness and issues relating to use of this technique in providing accurate, reliable and clinically relevant preoperative prognostic and predictive information in patients with breast cancer.
doi:10.1136/jcp.2006.045377
PMCID: PMC2095575  PMID: 17630399
4.  Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer 
Journal of Clinical Pathology  2007;60(11):1216-1221.
Background
Although in vitro breast cancer models have demonstrated a role for protein kinase C (PKC) α and δ isoforms in endocrine insensitivity and resistance respectively, there is currently little clinical evidence to support these observations.
Aims
To define the pattern of PKC α and δ expression using breast cancer cell lines, with and without endocrine resistance, and also breast cancer samples, where expression can be correlated with clinicopathological and endocrine therapy outcome data.
Methods
PKC isoform expression was examined in tamoxifen responsive, oestrogen receptor positive (ER+), ER+ acquired tamoxifen resistant (TAM‐R) and oestrogen receptor negative (ER−) cell lines by western blotting and immunocytochemical analysis. PKC isoform expression was then examined by immunohistochemistry in archival breast cancer specimens from primary breast cancer patients with known clinical outcome in relation to endocrine response and survival on therapy.
Results
ER+ breast cancer cell lines expressed considerable PKC‐δ but barely detectable levels of PKC‐α, whereas ER− cell lines expressed PKC‐α but little PKC‐δ. ER+ acquired TAM‐R cell lines expressed substantial levels of both PKC‐α and δ. In clinical samples, high PKC‐δ expression correlated to endocrine responsiveness whereas PKC‐α expression correlated to ER negativity. PKC‐δ was an independent predictor of duration of response to therapy. Patients showing a PKC‐δ+/PKC‐α− phenotype had a six times longer endocrine response than patients with the PKC‐δ+/ PKC‐α+ phenotype (equating to tamoxifen resistance in vitro).
Conclusions
Levels of PKC‐α and δ expression appear to be indicative of response to anti‐oestrogen therapy and could be useful in predicting a patient's suitability for endocrine therapy.
doi:10.1136/jcp.2006.041616
PMCID: PMC2095478  PMID: 17965220
5.  Calpain system protein expression in basal-like and triple-negative invasive breast cancer 
Annals of Oncology  2012;23(9):2289-2296.
Background
Basal-like and triple-negative breast tumours encompass an important clinical subgroup and biomarkers that can prognostically stratify these patients are required.
Materials and methods
We investigated two breast cancer tissue microarrays for the expression of calpain-1, calpain-2 and calpastatin using immunohistochemistry. The first microarray was comprised of invasive tumours from 1371 unselected patients, and the verification microarray was comprised of invasive tumours from 387 oestrogen receptor (ER)-negative patients.
Results
The calpain system contains a number of proteases and an endogenous inhibitor, calpastatin. Calpain activity is implicated in important cellular processes including cytoskeletal remodelling, apoptosis and survival. Our results show that the expression of calpastatin and calpain-1 are significantly associated with various clinicopathological criteria including tumour grade and ER expression. High expression of calpain-2 in basal-like or triple-negative disease was associated with adverse breast cancer-specific survival (P = 0.003 and <0.001, respectively) and was verified in an independent cohort of patients. Interestingly, those patients with basal-like or triple-negative disease with a low level of calpain-2 expression had similar breast cancer-specific survival to non-basal- or receptor- (oestrogen, progesterone or human epidermal growth factor receptor 2 (HER2)) positive disease.
Conclusions
Expression of the large catalytic subunit of m-calpain (calpain-2) is significantly associated with clinical outcome of patients with triple-negative and basal-like disease.
doi:10.1093/annonc/mds176
PMCID: PMC3425372  PMID: 22745213
basal; breast cancer; calpain; calpastatin; triple negative
6.  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
7.  Long-term clinical outcome of oestrogen receptor-positive operable primary breast cancer in older women: a large series from a single centre 
British Journal of Cancer  2011;104(9):1393-1400.
Introduction:
A Cochrane review of seven randomised trials (N=1571) comparing surgery and primary endocrine therapy (PET) (oestrogen receptor (ER) unselected) shows no difference in overall survival (OS). We report outcome of a large series with ER-positive (ER+) early invasive primary breast cancer.
Methods:
Between 1973 and 2009, 1065 older (⩾70 years) women (median age 78 years (70–99)) had either surgery (N=449) or PET (N=616) as initial treatment.
Results:
At 49-month median follow-up (longest 230 months), the 5-year breast cancer-specific survival (BCSS) and OS were 90 and 62%, respectively. Majority (74.2%) died from causes other than breast cancer. The rates (per annum) of local/regional recurrence (<1%) (following surgery), contralateral tumour (<1%) and metastases (<3%) were low. For patients on PET, 97.9% achieved clinical benefit (CB) at 6 months, with median time to progression of 49 months (longest 132 months) and significantly longer BCSS when compared with those who progressed (P<0.001). All patients with strongly ER+ (H-score >250) tumours achieved CB and had better BCSS (P<0.01). Patients with tumours having an H-score >250 were found to have equivalent BCSS regardless of treatment (surgery or PET; P=0.175), whereas for those with H-score ⩽250, surgery produced better outcome (P<0.001).
Conclusion:
Older women with ER+ breast cancer appear to have excellent long-term outcome regardless of initial treatment. Majority also die from non-breast cancer causes. Although surgery remains the treatment of choice, patients with ER-rich (H-score >250) tumours tend to do equally well when treated by PET. This should be taken into account when therapies are considered.
doi:10.1038/bjc.2011.105
PMCID: PMC3101924  PMID: 21448163
elderly; ER; primary breast cancer; endocrine therapy; surgery
8.  Comparison of methods for handling missing data on immunohistochemical markers in survival analysis of breast cancer 
British Journal of Cancer  2011;104(4):693-699.
Background:
Tissue micro-arrays (TMAs) are increasingly used to generate data of the molecular phenotype of tumours in clinical epidemiology studies, such as studies of disease prognosis. However, TMA data are particularly prone to missingness. A variety of methods to deal with missing data are available. However, the validity of the various approaches is dependent on the structure of the missing data and there are few empirical studies dealing with missing data from molecular pathology. The purpose of this study was to investigate the results of four commonly used approaches to handling missing data from a large, multi-centre study of the molecular pathological determinants of prognosis in breast cancer.
Patients and methods:
We pooled data from over 11 000 cases of invasive breast cancer from five studies that collected information on seven prognostic indicators together with survival time data. We compared the results of a multi-variate Cox regression using four approaches to handling missing data – complete case analysis (CCA), mean substitution (MS) and multiple imputation without inclusion of the outcome (MI−) and multiple imputation with inclusion of the outcome (MI+). We also performed an analysis in which missing data were simulated under different assumptions and the results of the four methods were compared.
Results:
Over half the cases had missing data on at least one of the seven variables and 11 percent had missing data on 4 or more. The multi-variate hazard ratio estimates based on multiple imputation models were very similar to those derived after using MS, with similar standard errors. Hazard ratio estimates based on the CCA were only slightly different, but the estimates were less precise as the standard errors were large. However, in data simulated to be missing completely at random (MCAR) or missing at random (MAR), estimates for MI+ were least biased and most accurate, whereas estimates for CCA were most biased and least accurate.
Conclusion:
In this study, empirical results from analyses using CCA, MS, MI− and MI+ were similar, although results from CCA were less precise. The results from simulations suggest that in general MI+ is likely to be the best. Given the ease of implementing MI in standard statistical software, the results of MI+ and CCA should be compared in any multi-variate analysis where missing data are a problem.
doi:10.1038/sj.bjc.6606078
PMCID: PMC3049587  PMID: 21266980
missing data; multiple imputation; complete case analysis; missing covariates; tissue micro-arrays
9.  A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR/ANZ DCIS trial 
British Journal of Cancer  2010;103(1):94-100.
Background:
There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR/ANZ DCIS trial have been histologically reviewed to determine the features of prognostic importance.
Method:
A total of 72% of 1694 cases entered into the UKCCCR/ANZ DCIS trial had full pathological review. A large number of histological features were assessed, blinded to outcome and compared regarding ability to predict ipsilateral recurrence, as either DCIS or progression to invasive carcinoma.
Results:
Pathological features associated with ipsilateral recurrence in univariate analysis included high cytonuclear grade, larger lesion size, growth pattern, presence of necrosis or chronic inflammation, incompleteness (or uncertainty of completeness) of excision and smaller margin width. Receipt of post-operative radiotherapy was also a strong prognostic factor.
We report a novel sub-division of the large group of high-grade lesions, which enables identification of a very poor prognosis sub-group; namely, DCIS that is of high cytonuclear grade, predominantly (>50%) solid architecture, bearing extensive comedo-type necrosis (>50% of ducts). In addition, we found little difference in ipsilateral recurrence rates between low- and intermediate-grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence.
Conclusion:
We present a novel pathological classification for DCIS with substantially better prognostic discrimination for ipsilateral recurrence than the classical categorisation based on cytonuclear grade alone.
doi:10.1038/sj.bjc.6605718
PMCID: PMC2905282  PMID: 20517310
ductal carcinoma in situ; prognosis; histopathology
10.  Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype 
British Journal of Cancer  2008;99(2):327-334.
Caveolin-1 (CAV1) and caveolin 2 (CAV2) are the principal structural proteins of caveolae, sphingolipid and cholesterol-rich invaginations of the plasma membrane involved in vesicular trafficking and signal transduction. Over the recent years there has been controversy about their role in breast cancer and their suitability as markers of basal-like phenotype. Caveolin-1 and CAV2 protein expression was assessed on a tissue microarray containing 880 unselected invasive breast cancer cases, by means of immunohistochemistry. Caveolin-1 and CAV2 expression was observed in 13.4 and 5.9% of all breast cancer, respectively. Their expression was strongly associated with high histological grade, lack of steroid hormone receptor positivity (ER and PR), and expression of basal markers (basal cytokeratins, P63, P-cadherin). Furthermore, there was a significant association between CAV1 and CAV2 expression and basal-like phenotype. On univariate analysis only CAV2 had a prognostic impact on breast cancer-specific survival; however, this was not independent from other traditional markers on multivariate analysis. Our results demonstrate that both CAV1 and CAV2 are associated with basal-like phenotype. Further studies are warranted to determine whether they play an oncogenic role in basal-like/triple-negative breast cancer development or are just surrogate markers for this subgroup.
doi:10.1038/sj.bjc.6604463
PMCID: PMC2480981  PMID: 18612310
caveolin 1; caveolin 2; immunohistochemistry; breast; basal-like
11.  The NHS breast screening programme (pathology) EQA: experience in recent years relating to issues involved in individual performance appraisal 
Journal of Clinical Pathology  2006;59(2):130-137.
Background
The original role of the National Health Service breast screening programme (pathology) external quality assessment (EQA) scheme was educational; it aimed to raise standards, reinforce use of common terminology, and assess the consistency of pathology reporting of breast disease in the UK.
Aims/Methods
To examine the performance (scores) of pathologists participating in the scheme in recent years. The scheme has evolved to help identify poor performers, reliant upon setting an acceptable cutpoint. Therefore, the effects of different cutpoint strategies were evaluated and implications discussed.
Results/Conclusions
Pathologists who joined the scheme improved over time, particularly those who did less well initially. There was no obvious association between performance and the number of breast cancer cases reported each year. This is not unexpected because the EQA does not measure expertise, but was established to demonstrate a common level of performance (conformity to consensus) for routine cases, rather than the ability to diagnose unusual/difficult cases. A new method of establishing cutpoints using interquartile ranges is proposed. The findings also suggest that EQA can alter a pathologist's practice: those who leave the scheme (for whatever reason) have, on average, marginally lower scores. Consequently, with the cutpoint methodology currently used (which is common to several EQA schemes) there is the potential for the cutpoint to drift upwards. In future, individuals previously deemed competent could subsequently be erroneously labelled as poor performers. Due consideration should be given to this issue with future development of schemes.
doi:10.1136/jcp.2004.025619
PMCID: PMC1860311  PMID: 16443726
breast; cancer; pathology; screening; external quality assessment
12.  Three dimensional reconstruction of a human breast carcinoma using routine laboratory equipment and immunohistochemistry 
Journal of Clinical Pathology  2005;58(9):968-972.
Aims: To establish a three dimensional reconstruction of an invasive breast carcinoma using basic laboratory equipment to evaluate and characterise the spatial arrangement of the parenchymal cells of the breast.
Methods: One hundred and twenty eight sequential 4 μm sections (20 μm apart) of the tumour were stained immunohistochemically with an epithelial specific marker (AE1/AE3) or tumour specific marker (c-erbB-2) to reconstruct two different three dimensional images of the normal and malignant parenchymal cells. Sections were digitally imaged using a microscope, scanner, and digital camera linked to a conventional personal computer. Accurate alignment of the digitalised images was carried out using a semiautomatic graphical method of manual interaction, using the cross correlation coefficient as a goodness of fit measure, and an automatic search algorithm using the Fibonacci search algorithm for automatic alignment. The volume was reconstructed using maximum, minimum point projection and “back to front” opacity blending.
Results: The quality of the reconstructed images was distinct and perfect, providing a comprehensive and explicit view of the normal and malignant parenchymal tissues of the breast that is not possible by viewing two dimensional histological sections. Specifically, this approach showed the spatial arrangement of the tumour cells and their relation to the surrounding tissues at a high resolution.
Conclusion: This simple and reproducible approach enables the spread and infiltration of invasive carcinoma to be understood and could also be used to analyse the spatial relation between atypical hyperplastic and malignant in situ lesions of the breast.
doi:10.1136/jcp.2004.024794
PMCID: PMC1770828  PMID: 16126880
breast cancer; computer assisted three dimensional reconstruction; invasion; immunohistochemistry
13.  Sections of the nipple and quadrants in mastectomy specimens for carcinoma are of limited value 
Journal of Clinical Pathology  2005;58(5):543-545.
Aim: To assess the value of nipple and quadrant sections in mastectomy specimens for carcinoma in detecting Paget’s disease and multifocal carcinoma.
Methods: Two hundred and forty eight consecutive mastectomies performed for carcinoma were reviewed. The presence of Paget’s disease of the nipple and mode of identification of any multifocal carcinoma was recorded.
Results: Nipple sections showed Paget’s disease in eight specimens: in five the diagnosis had been made on previous biopsy and in three (1%) this was a new diagnosis. In the 220 specimens in which all four quadrants were sampled, multifocal disease was identified more often in specimens with invasive carcinoma (39 of 186; 21%) than in those with only ductal carcinoma in situ (0 of 34). In specimens with invasive carcinoma, multifocality was identified macroscopically in 20: on microscopy of tumour sections in four, on microscopic examination of quadrant sections in 11, in the nipple in three, and in both quadrant and nipple sections in one. Overall, multifocality was found on microscopic examination of quadrant or nipple sections in 15 of 220 specimens (7%).
Conclusions: The low frequency of detection of multifocality or Paget’s disease in nipple and quadrant sections from mastectomy specimens, combined with the fact that such findings do not affect patient management, suggest that nipple and quadrant sections should only be taken if resources permit.
doi:10.1136/jcp.2004.022665
PMCID: PMC1770662  PMID: 15858129
quadrant; nipple; mastectomy
14.  The significance of lobular neoplasia on needle core biopsy of the breast 
Virchows Archiv  2008;452(5):473-479.
The management of a core biopsy diagnosis of lobular neoplasia is controversial. Detailed radiological–pathological review of 47 patients with cores showing classical lobular neoplasia was performed (patients with pleomorphic lobular carcinoma in situ (LCIS) or associated risk lesions were considered separately). Immediate surgical excision in 25 patients showed invasive carcinoma in 7, ductal carcinoma in situ (DCIS) in 1 and pleomorphic LCIS in 1; radiological–pathological review showed that the core biopsy missed a mass in 5, missed calcification in 2 and that calcification appeared adequately sampled in 2. Nineteen patients had follow-up of at least 2 years. Four patients developed malignancy at the site of the core biopsy (invasive carcinoma in three, DCIS in one); one carcinoma was mammographically occult, one patient had dense original mammograms and two had calcifications apparently adequately sampled by the core. In conclusion, most carcinomas identified at the site of core biopsy showing lobular neoplasia were the result of the core missing the radiological lesion, emphasising the importance of multidisciplinary review and investigation of any discordance. Some carcinomas were found after apparently adequate core biopsy, raising the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia.
doi:10.1007/s00428-008-0607-8
PMCID: PMC2329729  PMID: 18389278
Lobular neoplasia; Atypical lobular neoplasia; Lobular carcinoma in situ; Pleomorphic lobular carcinoma in situ; Needle biopsy; Breast
15.  Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis 
British Journal of Cancer  2007;96(7):1092-1100.
Vascular endothelial cell growth factors (VEGF)-A, -C and -D have potent angio and lymphangiogenic functions in experimental models, although their role in the progression of human breast cancer is unclear. The aims of the current study were to examine the relationship between the expression of the aforementioned growth factors with the angio and lymphangiogenic characteristics of breast cancer, and to assess their suitability as potential prognostic factors. Paraffin-embedded sections of 177 primary invasive breast cancer, with complete clinical follow-up information for 10 years, were stained for VEGF-A, -C, -D, podoplanin and CD34 using standard immunohistochemical approaches. The expression of the growth factors was correlated with clinicopathological criteria and patients' survival. Lymph vessel density (LVD) and microvessel density (MVD) were assessed and correlated with expression of the growth factors. Vascular endothelial cell growth factor-A, -C and -D were highly expressed in 40, 37 and 42% of specimens, respectively. High expression of VEGF-A and - C, but not of -D, was associated with a higher LVD (P=0.013 and P=0.014, respectively), a higher MVD (P<0.001 and P=0.002, respectively), the presence of lymph node metastasis (P<0.001 and P<0.001, respectively), distant metastasis (P=0.010 and P=0.008, respectively) and a shorter Overall Survival (P=0.029 and 0.028, respectively). In conclusion, breast cancers that express high levels of VEGF-A and -C are characterised by a poor prognosis, likely through the induction of angio and lymphangiogenesis. Examination of expression of VEGF-A and -C in breast cancer may be beneficial in the identification of a subset of tumours that have a higher probability of recurrence and metastatic spread.
doi:10.1038/sj.bjc.6603678
PMCID: PMC2360132  PMID: 17353919
breast cancer; vascular endothelial cell growth factors; VEGF-A; VEGF-C; VEGF-D; lymphangiogenesis; angiogenesis
16.  EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer 
British Journal of Cancer  2006;95(6):735-743.
Endothelial-monocyte-activating polypeptide-II (EMAP-II) is a novel multifunctional polypeptide with proinflammatory activity. We have previously shown that the recombinant and native forms of EMAP-II can induce apoptosis in mitogen-stimulated lymphocytes, and that the release of this protein into the extracellular milieu is enhanced by hypoxia. We hypothesised that hypoxia may lead to death of tumour-infiltrating lymphocytes (TILs) via an EMAP-II-dependent mechanism, thereby assisting tumours to evade the immune system. In this study, we used immunohistochemistry to detect EMAP-II, active caspase-3 and cleaved Poly (ADP-ribose) Polymerase (PARP) as indicators of apoptosis in TILs, and carbonic anhydrase IX (CA IX) as a surrogate marker of hypoxia. EMAP-II expression is associated with regions of hypoxia, and furthermore there is a significant association between TILs apoptosis and the presence of hypoxia. Using a coculture model of colorectal cancer cell/lymphocyte interactions, we were also able to demonstrate lymphocyte apoptosis induced by tumour cells, with concomitant caspase-3 activity. Lymphocyte killing was enhanced by direct cell–cell contact, particularly by tumour cells exposed to hypoxic conditions. Our data support the hypothesis that hypoxia plays a role in immune evasion by tumour cells, through EMAP-II-dependent lymphocyte killing.
doi:10.1038/sj.bjc.6603299
PMCID: PMC2360520  PMID: 16929248
EMAP-II; hypoxia; lymphocytes apoptosis; colorectal cancer
17.  Best Practice No 179 
Journal of Clinical Pathology  2004;57(9):897-902.
Non-operative diagnosis has become the norm in breast disease assessment and, until relatively recently, fine needle aspiration cytology has been the sampling method of choice. The introduction of automated core biopsy guns in the mid 1990s led to the additional introduction of core biopsy in assessment units. This paper presents a summary of the guidance on handling and routine reporting of breast needle core biopsy specimens in the context of breast disease multidisciplinary assessment. This guidance has been produced by the UK National Coordinating Committee for Breast Screening Pathology and is endorsed by the European Commission working group on breast screening pathology.
doi:10.1136/jcp.2003.010983
PMCID: PMC1770422  PMID: 15333647
breast cancer; guidelines; needle biopsy; pathology reporting
18.  Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology 
Journal of Clinical Pathology  2004;57(7):695-701.
Aims: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision.
Methods: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further.
Results: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines.
Conclusions: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.
doi:10.1136/jcp.2003.013599
PMCID: PMC1770358  PMID: 15220360
breast cancer; guidelines; questionnaire; sentinel lymph nodes
19.  Best Practice No 176 
Journal of Clinical Pathology  2004;57(3):233-237.
This paper serves to update previously published guidance on rationale and methodology for HER2 laboratory testing following the recommendation for the use of HER2 targeted treatment in the management of advanced breast cancer in the UK. Emphasis is placed on the standardisation of methodology and assessment and strategies to achieve high quality performance. A two phase testing algorithm based on first line immunocytochemistry evaluation and second line fluorescence in situ hybridisation assessment of borderline cases is recommended. To ensure maintenance of expertise, an annual caseload volume of at least 250 cases is recommended for laboratories providing a testing service.
doi:10.1136/jcp.2003.007724
PMCID: PMC1770242  PMID: 14990588
breast cancer; HER2; UK; guidelines; laboratory testing
20.  Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1 
British Journal of Cancer  2004;91(8):1591-1596.
doi:10.1038/sj.bjc.6602144
PMCID: PMC2409935  PMID: 15354217
breast cancer; chromosome 16; CTCF; immunohistochemistry
21.  Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma 
British Journal of Cancer  2004;91(8):1532-1542.
doi:10.1038/sj.bjc.6602184
PMCID: PMC2410019  PMID: 15480434
EGFR family; breast cancer; immunohistochemistry; tissue microarray
22.  Diagnosis of axillary nodal metastases by ultrasound-guided core biopsy in primary operable breast cancer 
British Journal of Cancer  2003;89(7):1310-1313.
doi:10.1038/sj.bjc.6601290
PMCID: PMC2394321  PMID: 14520465
ultrasound; core biopsy; breast tumour; axilla
23.  Growth pattern of ductal carcinoma in situ (DCIS): a retrospective analysis based on mammographic findings 
British Journal of Cancer  2001;85(2):225-227.
The aim of this study was to obtain information concerning the direction and rates of growth of ductal carcinoma in situ (DCIS). The previous mammograms of 124 women diagnosed with DCIS were examined. If in retrospect calcifications were present on the previous examination, the exact size and position were recorded on both diagnostic and previous imaging. The rates of change and direction of change in extent of calcifications were calculated. 39 women with a diagnosis of DCIS in retrospect had calcifications visible on both their current and prior examinations; these formed the study group. For individual clusters of calcification, change occurred along an axis to the nipple at a mean of 5.5 mm y−1and along an axis at 90° to the nipple at 2.6 mm y−1. Increase in calcifications along the axis to the nipple occurred at 2.6 mm y−1toward and 2.8 mm y−1away from the nipple. Increase in the axis to the nipple occurred at 1.8 mm y−1for low grade, 4.2 mm y−1for intermediate grade and 7.1 mm y−1for high grade. DCIS growth along an axis to the nipple occurs at over twice the rate of growth in the other direction(s) and growth toward and away from the nipple occurred equally. Growth rates increased with increasing nuclear grade of DCIS. These results validate nuclear grading of DCIS. Additionally, the results suggest that increased importance should be placed on identifying the ‘nipple’ and ‘anti-nipple’ margins of DCIS represented by calcifications for both surgical excision and pathological scrutiny. © 2001 Cancer Research Compaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1877
PMCID: PMC2364049  PMID: 11461081
breast; mammography; ductal carcinoma in situ; diagnosis
24.  c-erbB-4 protein expression in human breast cancer 
British Journal of Cancer  2000;82(6):1163-1170.
The Type 1 family of growth factor receptors includes epidermal growth factor receptor (EGFR), c- erb B-2, c- erb B-3 and c- erb B-4. Overexpression of the first two members is associated with poorer prognosis in patients with breast carcinoma. In this study we examined the expression of c- erb B-4 protein using the monoclonal antibody HFR-1. A total of 127 consecutive cases of primary operable invasive breast carcinoma presenting between 1975 and 1977 were studied. All patients were managed by simple mastectomy or conservation surgery with radiotherapy and no adjuvant therapy given. Long-term follow-up was maintained. Routine, formalin-fixed, paraffin-embedded tumour samples were used and sections were stained immunohistochemically using the Duet StreptABC method. Immunoreactivity was classified using a simple semi-quantitative scoring method. Protein expression was generally low but definite positive cytoplasmic, membranous and nuclear reactivity was identified in 58%, 41% and 25% of cases respectively. Expression at all three sites demonstrated significant inverse associations were histological grade. In addition, membrane accentuation correlated inversely with the Nottingham Prognostic Index (NPI), while cytoplasmic reactivity showed a positive association with c- erb B-3 expression. No significant associations were found with disease-free interval or survival. The results of this study demonstrate that higher levels of c- erb B-4 protein expression are associated with a more differentiated histological phenotype in contrast to the other members of the Type 1 family. Larger series with extended follow-up will be required to ascertain definitively the prognostic value of c- erb B-4 expression in breast carcinoma. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.1057
PMCID: PMC2363344  PMID: 10735500
breast cancer; c-erbB-4; growth factor receptor; prognostic factors
25.  Oestrogen receptor expression in ductal carcinoma in situ of the breast: relationship to flow cytometric analysis of DNA and expression of the c-erbB-2 oncoprotein. 
British Journal of Cancer  1993;68(1):156-161.
The expression of oestrogen receptor protein (ER) was examined in 151 cases of symptomatic or screening detected pure ductal carcinoma in situ (DCIS) of the breast by immunocytochemical assay (ERICA), in formalin-fixed paraffin-embedded tissue, with the monoclonal antibody H 222 (Abbott). Forty-eight tumours (31.8%) of cases were ER positive. Twenty-seven (17.9%) of cases showed high level ER expression and 21 (13.9%) of cases showed low level ER immunoreactivity. Significant associations of positive tumour ER immunoreactivity and non-comedo architecture chi 2 = 6.76; (d.f. = 1): P < 0.001, small cell size chi 2 = 4.49; (d.f. = 1): P = 0.034, higher S-phase fraction chi 2 = 4.71; (d.f. = 1): P = 0.03 and lack of c-erbB-2 protein overexpression chi 2 = 7.96; (d.f. = 1): P < 0.01 were identified. No significant associations of ER expression and patient age, histological grade of necrosis in DCIS, or DNA ploidy were found. ER expression is detectable in less than one third of symptomatic and screening detected cases of DCIS, implying that endocrine therapy of DCIS may be a more appropriate form of management for morphological subtypes of DCIS which show higher rates of oestrogen receptor expression, particularly those of non-comedo and small cell type.
Images
PMCID: PMC1968326  PMID: 8100443

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