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Aims: Treatment strategies for breast cancer continue to evolve. No uniformity exists in the UK for the management of node-positive breast cancer patients. Most centres continue to use conventional histopathology of sampled sentinel lymph nodes (SLNs), which requires delayed axillary clearance in up to 25% of patients. Some use touch imprint cytology or frozen section for intraoperative testing, although both have inherent sensitivity issues. An intraoperative molecular diagnostic approach helps to overcome some of these limitations. The aim of this study was to assess the clinical effectiveness of Metasin, a molecular method for the intraoperative evaluation of SLNs., Methods and Results: RNA from 3296 lymph nodes from 1836 patients undergoing SLN assessment was analysed with Metasin. Alternate slices of tissue were examined in parallel by histology. Cases deemed to be discordant were analysed by protein gel electrophoresis. There was concordance between Metasin and histology in 94.1% of cases, with a sensitivity of 92% [95% confidence interval (CI) 88-94%] and a specificity of 97% (95% CI 95-97%). Positive and negative predictive values were 88% and 98%, respectively. Over half of the discordant cases (4.4%) were ascribed to tissue allocation bias (TAB)., Conclusions: Clinical validation of the Metasin assay suggests that it is sufficiently sensitive and specific to make it fit for purpose in the intraoperative setting., (© 2015 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Introduction: Intra-operative sentinel node analysis (IOA) for breast cancer reduces the need for a second operation by revealing metastasis intra-operatively, allowing immediate axillary clearance. Critics argue that the number of patients deriving benefit is limited, as further surgery is often required for reasons other than nodal status., Aim: To identify the proportion of women avoiding further surgery by using IOA excluding those who require further surgery for reasons other than axillary node metastasis., Patients and Methods: All patients undergoing sentinel node biopsy with IOA over one year were reviewed. Patient demographics, margin positivity, sentinel node metastasis, requirement for further surgery, and cavity shave involvement were analysed., Results: 322 patients were analysed: 253 undergoing breast-conserving surgery [BCS] and 69 undergoing mastectomy). IOA revealed metastasis in 81 (25.2.%) patients [25 undergoing mastectomy and 56 undergoing BCS], who underwent immediate axillary clearance. 43 BCS patients (17%) did not require further surgery other than for sentinel node involvement. 39 patients required further oncological surgery: 16 excision of margins; 13 completion mastectomy; 6 excision of margins followed by mastectomy; 3 completion axillary clearance; and 1 excision of recurrence. 20.6% had involvement of any circumferential histological margin. Cavity shaves were performed in 28.5% patients at initial surgery, the majority of which were clear of malignancy. 20 mastectomy patients had concordant definitive histology, avoiding a second operation. In total, 19.6% of this cohort avoided a second operation through the use of IOA., Discussion: Approximately 15% of patients undergoing breast conservation surgery for breast cancer require further surgery. However, a further 17% were saved subsequent surgery by utilising IOA, since they had immediate axillary clearance. When also considering patients undergoing mastectomy, this proportion is even higher., (Copyright © 2013 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Introduction: Intra-operative specimen radiography (IOSR) is used to screen specimens during breast-conserving surgery and attempt to identify incompletely excised lesions. Universal use of IOSR during surgery for impalpable breast cancer is advocated by current guidelines. This study evaluates the role of IOSR during breast-conserving surgery for palpable breast cancer., Methods: Two cohorts of patients who underwent wide local excision for palpable breast cancer were identified. Retrospective analysis of histological margins, intra-operative cavity shaves, secondary re-excision rates and specimen weight was completed comparing performance prior to the introduction of IOSR (October 2003-April 2005) with that since its introduction (April 2006-October 2007)., Results: 224 Patients were included, 111 in the pre-IOSR cohort (PF) and 113 in the IOSR cohort (F). Patient demographics, tumour size and histology were comparable. No difference in margin involvement prior to intra-operative cavity shaving was noted, PF-26, F-31 (p=0.60). Intra-operative cavity shaves were carried out more frequently in the IOSR group, PF-9, F-32 (p=0.001). When compared with histological findings, IOSR identified margin compromise with sensitivity=58.1%, specificity=80.8%, positive-predictive value=56.25% and negative predictive value=81.9%. Re-operation rate was similar between the 2 groups, PF-26, F-31 (p=0.65). Significantly less tissue was excised following use of IOSR; PF-110g, F-70g (p=0.001)., Conclusion: Introduction of IOSR significantly reduced specimen weights without increasing re-excision rates. As volume of breast tissue removed is the most significant determinant of cosmetic outcome following breast-conserving surgery, the use of IOSR should be advocated in the surgical management of palpable breast cancer., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Accurate intraoperative sentinel lymph node (SLN) assessment enables axillary clearance to be completed immediately in node-positive breast cancer patients. This article reports a study of the introduction of intraoperative molecular SLN analysis in routine clinical practice in the Portsmouth Breast Care Centre., Design: There was prospective analysis of 254 consecutive patients who underwent SLN biopsy in a single centre. Nodes were sectioned at 2 mm intervals and alternate slices were analysed using a CE-marked assay for mammaglobin (MG) and cytokeratin 19 (CK19). Remaining slices of node were sent for histological analysis, which included CK19 immunohistochemistry. While the assay was being carried out, the surgeon performed the breast tumour resection. The cost per patient was estimated retrospectively and the cost effects on the hospital and primary care trust for a typical service were also estimated., Results: A total of 491 SLNs from 254 patients were evaluated. The intraoperative assay showed positivity of SLNs for metastatic cells in 78 patients. There was 100% detection of macrometastases within sentinel nodes analysed by GeneSearch. Overall concordance between histological status, including micrometastases and GeneSearch analysis, was 95% (sensitivity 96%, specificity 95%). The cost per procedure was increased for wide local excision with SLN biopsy and intraoperative assessment compared with other models, but fewer procedures were carried out., Conclusion: Intraoperative assessment of SLNs in breast cancer using a molecular assay is a safe, acceptable and accurate technique that allows a reduction in the frequency of delayed axillary clearance surgery. Take-up of this method may be hampered by perverse incentives operating within healthcare funding.

Aim: To examine a model of care for breast cancer patients based on the concept of point of need access and investigate the effectiveness of this model compared to routine 6-monthly clinical reviews., Design: A parallel randomised controlled trial was used to examine point of need access to specialist care via the nurse specialist, compared to routine hospital based 6-monthly clinical review at year two post breast cancer diagnosis. A total of 237 patients were recruited to the study., Methods: Outcome measures at baseline, 9 and 18 months included psychological morbidity using the GHQ12 questionnaire, quality of life using the FACT-B plus endocrine subscale, fear and isolation. An analysis of covariance was used to detect changes over time. Recurrences and methods of detection were recorded as secondary outcome measures., Results: Two hundred and fourteen patients completed the study. Overall patients were not exposed to risks of increased psychological morbidity (p=0.767) or decline of quality of life (p=0.282) when routine review was discontinued and no significant differences were detected during an 18-month period. Patients not receiving regular review did not feel isolated, and at the end of 18 months did not wish to return to 6-monthly clinical reviews. The presentation of recurrences and short symptom history demonstrate that the recurrences observed were unlikely to have been detected at a routine visit., Conclusions: Point of need access is acceptable to the majority of patients. Although a third of patients may wish to maintain a regular review, patient choice is important. Findings suggest that after 2 years following the diagnosis of breast cancer there is no evidence to support the view that regular clinical review improves psychological morbidity or quality of life. Patients do not appear to be compromised in terms of early detection of recurrence. Point of need access can be provided by suitably trained specialist nurses and provides a fast, responsive management system at a time when patients really need it.

Introduction: The use of specimen radiographs to confirm the presence of the radiological abnormality in a breast specimen after localisation biopsy is standard practice. This study aims to show that a trained surgeon may assess breast specimen radiographs with similar efficacy as a radiologist., Methods: This retrospective study assessed all patients who had localisation breast surgery using wire or ultrasound (US) techniques between January 2002 and March 2003. Histopathological records and mammographic details were recorded from the hospital notes. A consultant radiologist and surgeon reviewed the specimen radiographs, identifying mammographic abnormalities and assessing margins., Results: Localisation surgery was performed on 101 patients with US used to localize 68. The median specimen weight was 64g. A malignant diagnosis was made in 86 patients. In 23, the histological resection margins were considered to be close or involved by tumour and re-excision was performed in eight patients. Sixty-one specimen radiographs were reviewed. The radiologist identified every mammographic abnormality, and the surgeon identified the lesion in 58. The positive predictive value of specimen radiographs to identify histologically involved margins was 75 and 74% by the radiologist and the surgeon, respectively. Where good radiograph margins were reported in 40 and 35 patients by the radiologist and surgeon, respectively, 11 and 7 had histologically involved margins., Conclusions: This study shows that a suitably trained or experienced surgeon can assess specimen radiographs effectively without the need for intraoperative radiological input although complete histological resection is not guaranteed despite specimen radiographs demonstrating clear margins.

Background: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment., Methods: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided., Results: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P < .001), and axillary operative time was reduced (P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P < or = .003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group (P > .05)., Conclusion: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.

A patient with an accessory breast on the anterior abdominal wall was found to have cancer of this tissue, because of its unusual position it was decided that lymphatic mapping was necessary to identify the lymphatic drainage of this tumour. A metastasis was found in a sentinel node deep to the 'true' ipsilateral breast; however, the sentinel node identified in the axilla of this patient was free of metastases. The use of the sentinel node technique up staged the cancer from I to II and the patient went on to have adjuvant treatment with chemotherapy. The use of lymphatic mapping and sentinel node biopsy in the case of cancer of an accessory breast allows more accurate determination of lymph node status.

This study was aimed at investigating the relationship between serum prolactin levels and the morphology of operable female breast lesions. One hundred fifty-three consecutive patients with operable benign and malignant breast lesions in whom preoperative serum prolactin levels had been determined were stratified into five groups according to their serum prolactin levels. The histologic findings in these groups were analyzed and compared. Most patients (93%) had serum prolactin levels within the normal limits. Of the 54 patients with benign lesions, only 4(7%) had slightly elevated serum prolactin levels. Two of these patients had fibroadenomas, one had a phyllodes tumor and one had fibrocystic change. Of the 99 patients with carcinoma, 7 (7%) had hyperprolactinemia. Five of the seven tumors were invasive and two were in situ. All seven tumors were of low or intermediate grade of malignancy. The two cases with the highest prolactin levels (3057 and 1822 mU/L) were both intermediate-grade ductal carcinoma in situ (DCIS). It is concluded that the great majority of patients presenting with operable breast lesions have normal serum prolactin levels, and that elevated levels, when present, occur with equal frequency in patients with benign and malignant breast lesions. Hyperprolactinemic patients presenting with carcinoma in this study, none of whom had a history of recent pregnancy or lactation, tended to have histologically low- or intermediate-grade tumors, but this needs to be confirmed by investigating more cases.

This paper examines the correlation between axillary lymph node status and primary tumour characteristics in breast cancer and whether this can be used to select patients for axillary lymphadenectomy. The results are based on a retrospective analysis of 909 patients who underwent axillary dissection in our unit. Axillary lymph nodes containing metastases were found in 406 patients (44.7%), all with invasive carcinomas, but in none of the 37 carcinomas-in-situ. Nodal status was negative in all T1a tumours, but lymph node metastases were present in 16.3% and 35.7% of T1b and T1c tumours respectively. When histological grade was taken into account, positivity for grade I T1b and T1c tumours fell to 13.6% and 26.7% respectively. Lymph node metastases were found in 85% of patients with lymphovascular invasion in their tumours as compared to only 15.4% of those without and in 45.5% of oestrogen and progesterone receptor-positive tumours. When one or both hormone receptors were absent this figure was much higher. It appears that for T1a breast cancers axillary dissection is not necessary, whereas for T1b, T1c and grade I T2 tumours other histopathological parameters should be taken into consideration in deciding who should undergo axillary lymphadenectomy.

Acidic fibroblast growth factor (FGF1) and two of its receptors, FGFR1 and FGFR4, were localized in cryostat sections of normal, benign and malignant human breast tissue by immunohistochemistry. Without pretreatment, FGF1 staining was mainly seen in normal epithelial cells. However, polymerase chain reaction (PCR) analysis and immunoblotting of isolated normal epithelial and myoepithelial cells showed FGF1 mRNA and protein to be present in both cell types. Following incubation of frozen sections at 37 degrees C in phosphate-buffered saline, FGF1 staining was also revealed in myoepithelial cells and basement membrane adjacent to carcinoma cells. Treatment with protease inhibitors demonstrated that this effect was due to the activity of an endogenous protease. In contrast, FGF1 staining was found to be associated with the stroma adjacent to malignant cells only in the presence of protease inhibitors. FGFR1 and FGFR4 immunostaining was localized to both normal and malignant epithelial cells and to a lesser extent to myoepithelial cells. There was no difference in the staining intensity for the FGF receptors between normal and cancer samples. The change in location of FGF1 between normal and malignant tissues and the sensitivity of stored FGF1 to the action of endogenous proteases raises the possibility of both autocrine and paracrine roles for FGF1 in the normal and malignant human breast.

The level of expression of keratinocyte growth factor (KGF) mRNA has been measured in human breast cell lines, purified populations of epithelial cells, myoepithelial cells and fibroblasts from reduction mammoplasty tissue and a panel of 42 breast cancers and 30 non-malignant human breast tissues using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) procedure. We found similar levels of KGF mRNA in malignant and non-malignant breast tissues. The study of the amount of KGF mRNA in breast cell lines and purified populations of cells revealed that fibroblasts are the predominant source of KGF with malignant and non-malignant epithelial cells containing very low levels of KGF mRNA. We have examined the distribution of fibroblast growth factor receptor (FGFR)-2-IIIb, which is a high-affinity receptor for KGF and find that it is present on malignant and non-malignant epithelial cells. The level of FGFR-2-IIIb present on breast cancer cell lines was sufficient for KGF stimulation of breast cancer cell proliferation. Other members of the fibroblast growth factor family have been either not expressed in the human breast (FGF3, FGF4) or have been found at much reduced levels in breast cancer (FGF1, FGF2) and this is the first member of the family to potentially influence the progression of breast cancer through stimulation of cell division.

Monoclonal antibodies against two epitopes of FGFR-1 have been used to investigate FGFR-1 expression in the normal and neoplastic human breast. Different forms are detected in the different cell types constituting the normal breast. Moreover, breast cancer cells lack one form of FGFR-1. Western blot analysis showed 115-kDa and 106-kDa forms of FGFR-1 within the human breast. The 115-kDa band corresponds to the beta form of FGFR-1, whereas the 106-kDa band is truncated at the carboxyl terminus. The 106-kDa form of FGFR-1 is the major form present in breast fibroblasts and myoepithelial cells, whereas epithelial cells contain equal amounts of the 115-kDa and 106-kDa forms. Breast cancer cells, however, appear to contain only the 115-kDa form of FGFR-1. This expression pattern is reflected in malignant and non-malignant tissue samples. Using reverse transcription polymerase chain reaction (RT-PCR) analysis, we have shown that the 106-kDa FGFR-1 isoform is not the previously described alpha 2 receptor that arises from a 25-base pair insertion in the second kinase domain. It is probable that the 106-kDa FGFR-1 has different signalling properties to the full-length receptor, having lost at least one tyrosine at amino acid 766, which is required for phospholipase C activation. This form of FGFR-1 appears to be lost in all breast cancer cells analysed and its absence may have a bearing on malignancy.

This paper examines the expression of fibroblast growth factor 2 (FGF-2) in the malignant human breast. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assess the level of expression of FGF-2 in a series of 51 patients clinically followed up for a median of 84 months (Luqmani et al, 1992). Immunohistochemistry and Western blotting were used to show that the level of FGF-2 in breast tissues correlated with the amount of FGF-2 mRNA. FGF-2 was present in both malignant and non-malignant breast, although less was expressed in malignant tissues as determined by all three methods. Immunohistochemistry on frozen sections of breast tissue showed expression of FGF-2 in myoepithelial and epithelial cells in non-malignant samples and generally lower or undetectable levels of staining in malignant epithelial cells. The results obtained by immunohistochemistry correlated well with RT-PCR data showing similar levels of FGF-2 and FGF-2 mRNA expression in samples. No correlation was found between FGF-2 mRNA expression and T stage, nodal status or oestrogen receptor status. However, Kaplan-Meier survival plots show that higher levels of FGF-2 are associated with improved overall and disease-free survival. We suggest that FGF-2 expression may have value as a prognostic indicator in breast cancer.

Fine-needle aspiration cytology (FNAC) of the breast was performed in 491 patients over a 3-year period. Some 365 examinations (74.3 percent) were performed by palpation and the remaining 126 (25.7 percent) by stereotaxis. Ninety-six patients were excluded because of inadequate follow-up. Using a standard method of reporting the results 247 smears were classified as C1 and C2, but based on clinical and radiological criteria excision biopsy was recommended and performed in 122 patients with these lesions. Twenty-two per cent of C2 lesions were found to be malignant after histological examination. Forty-two patients with C3 or C4 cytology were advised to have excision biopsy and 41 had surgery. In all but one case the lesion was found to be malignant histologically. Definitive surgery was performed on 106 patients with C5 cytology and the diagnosis of malignancy was confirmed histologically in 105 of them. FNAC is a useful diagnostic tool in breast screening but in view of the number of false-negative results, cytology alone is unreliable and, therefore, full triple assessment is recommended.

We have measured the amount of fibroblast growth factor 1 (FGF-1) mRNA and protein in primary breast cancers and non-malignant breast tissue and have found greatly reduced levels in breast cancer compared with non-malignant tissue. A total of 116 breast cancers and 37 biopsies taken from non-malignant breast were compared for FGF-1 mRNA expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and significantly lower levels were found in the cancer tissues (P < 0.001). These findings were confirmed at the protein level where four out of five breast cancers contained no detectable FGF-1 and a fifth cancer had a low level of FGF-1 compared with three samples from reduction mammoplasties. Similar results were obtained from breast cell lines in which 80% of cancer cell lines had very low levels of FGF-1, whereas all non-malignant breast cell lines contained higher levels of FGF-1. Immunohistochemical analysis indicated that FGF-1 was present in the luminal epithelial cells of the non-malignant breast but was absent from cancer cells. The decreased levels of FGF-1 in breast cancer may indicate that stimulation of cancer cells is resulting in down-regulation of FGF-1 expression or may implicate FGF-1 as a differentiation factor rather than a growth factor at its physiological concentration in the breast.