One Step Nucleic Acid Amplification (OSNA) positive micrometastases and additional histopathological NSLN metastases: Results from a single institution over 53 months.

INTRODUCTION: The role of sentinel lymph node micrometastases on histopathological analysis is controversial in axillary staging and management in clinically node negative breast cancer. Long-term studies addressing the clinical relevance of occult breast cancer in sentinel lymph nodes based on molecular analysis are lacking. One Step Nucleic Acid Amplification (OSNA), a highly sensitive assay of cytokeratin 19 mRNA, is used intra-operatively for the detection of lymph node macro- and micrometastases in breast cancer. AIM: The aim of this study is to review the rate of micrometastases and further histopathological NSLN metastases, in our unit following the introduction of OSNA in Guildford. METHODS: Data was collected prospectively from the period of introduction 01/12/2008 to 31/05/2013. All patients eligible for sentinel lymph node biopsy were offered OSNA and operations were performed by the consultant breast surgeons. Presence or absence of micro-metastases depends on the agreed cut-off point on the amplification curve. On detection of micrometastases (+) and positive but inhibited (i+) metastases, a level 1 axillary clearance (ANC) was performed and for a macrometastasis (++), a level 3 ANC was carried out. RESULTS: 66% of the patients had negative SLN (n = 672) and 34% (n = 336) had positive sentinel lymph nodes who had further axillary surgery. Of these, 45% (n = 152/336) had macrometastases, 40% (n = 136/336) had micrometastases and 15% (48/336) had positive but inhibited results. There was no difference in the patient demographics and tumour characteristics in the various positive SLN groups. In patients with micrometastases, 15% (20/136) had further positive NLSNs and a further 6% (8/136) had >4 overall positive nodes (SLN + NSLN) thus requiring adjuvant supraclavicular/chest wall radiotherapy (p < 0.05). 25% of node positive patients had further NLSN metastases (85/336) and in these patients, the ratio of positive SLN/harvested SLN (+SLN/SLN) is constant at 1:1. This shows the likelihood of further positive NSLNs if all the harvested lymph nodes are positive. This linear trend is present in both micro-and macrometastases, thus correlating with the size and number of NSLN metastases. CONCLUSION: Our study reflects the tumour burden of NSLNs based on the molecular analysis of the SLN. OSNA has the potential to accurately identify axillary micrometastases. Micro-metastases are important as some of the patients with micrometastases had overall four positive nodes [SLN + NSLN] (criteria for radiotherapy in the absence of other adverse clinicopathological features). Also, our study highlights certain factors that predict the NSLN metastases, pending validation by further prospective long-term data. This will allow accurate calculation of the axillary tumour burden, particularly in patients with micro-metastases.

A differential intra-operative molecular biological test for the detection of sentinel lymph node metastases in breast carcinoma. An extended experience from the first U.K. centre routinely offering the service in clinical practice.

INTRODUCTION: One-Step Nucleic acid Amplification (OSNA) is a molecular biological assay of cytokeratin-19 (a breast epithelial marker) mRNA. It can be employed intra-operatively for detection of lymph node metastases in breast carcinoma. Patients with positive sentinel nodes may proceed to axillary lymph node dissection (ALND) level I or higher dependent upon the OSNA quantitative result, during the same surgical procedure, avoiding a second operation and eliminating the technical difficulties possibly associated with delayed ALND. AIMS: Our Breast Unit was the first in the UK to implement this novel technique in routine practice. This study reviews our first 44-month data following introduction of OSNA "live" on whole sentinel nodes following an extensive validation study (Snook et al.).(9) METHODS: Data was collected prospectively from the period of introduction 01/12/2008 to 30/08/2012. All patients eligible for sentinel node biopsy were offered OSNA and operations were performed by five consultant breast surgeons. On detection of macro-metastasis a level II/III and for a micro-metastasis a level I ALND was performed. RESULTS: A total of 859 patients (1709 sentinel lymph nodes) were analysed. All except one were females. The majority underwent wide local excision (73.4%, n = 631) or mastectomy 25% (n = 215) and 1.6% (13) underwent SLN biopsy alone. IDC was seen in 79% (n = 680) of the patients and 53.5% (n = 460) had grade II tumours. One-third (30.8%, n = 265) had positive sentinel nodes and had further axillary surgery at the time of SLN biopsy. Of these, 47% (n = 125/265) had macro-metastases, 38% (n = 101/265) had micro-metastases and 14.7% (n = 39/265) had "positive but inhibited" results. Positive non-sentinel lymph nodes (NSLN) were seen in 35% (44/125) of those with macro-metastases; 17.8% (18/101) of the patients with micro-metastases and 10.2% (4/39) of the "positive but inhibited" group. CONCLUSION: In our series over a third of our patients had positive lymph nodes detected with OSNA allowing them to proceed directly to axillary surgery at the same operation. This technique eliminates the need for a second operation in sentinel lymph node positive patients and avoids the anxiety waiting for histological results.

Multicentre evaluation of intraoperative molecular analysis of sentinel lymph nodes in breast carcinoma.

BACKGROUND: Ideally, intraoperative sentinel lymph node (SLN) analysis in breast cancer should be automated, have high concordance with extensive histopathology, and be applicable in any hospital setting. A prospective multicentre evaluation of the one-step nucleic acid amplification (OSNA) automated molecular diagnostic system of SLN analysis was undertaken. METHODS: Intraoperative examination of SLNs from 204 patients with breast cancer was performed by OSNA at four sites in the UK. Half of each SLN was assessed by OSNA (for cytokeratin 19 mRNA) and the remaining half was paraffin embedded for intensive histological examination at ten levels. Discordant cases were reanalysed by further molecular biological techniques and by additional histological examination of all remaining nodal material to ascertain whether the discordance was due to an uneven distribution of metastases, known as tissue allocation bias (TAB). RESULTS: After exclusion of samples affected by TAB, the overall concordance rate for OSNA versus histopathology was 96.0 per cent, with a sensitivity of 91.7 per cent and a specificity of 96·9 per cent. The median time to process a single SLN was 32 (range 22-97) min, and that for two nodes 42 (30-73) min. CONCLUSION: OSNA enables accurate automated intraoperative diagnosis and can be used successfully in different UK hospitals. When the SLN is shown to be positive, the patient can undergo immediate axillary clearance under the same anaesthetic rather than having a delayed second procedure.

Pregnancy after breast cancer: the importance of active counselling and planning.

AIM: To investigate the effect of breast cancer, its treatment and counselling on future pregnancy and fertility. METHOD: Three hundred and four women 45 years and younger at the time of diagnosis of breast cancer were identified from one breast unit from 1997 to 2006. A questionnaire was sent to all patients asking about pregnancy, counselling and fertility issues. RESULTS: Of 304 women, 248 were still alive and not lost to follow up. The questionnaire response rate was 66% and the average follow up was 60 months. By questionnaire response, 39 women had wanted children before diagnosis, and 24 still wanted them post treatment, giving a successful pregnancy rate of 75%. Eighteen patients have become pregnant, 4 with more than one pregnancy. 107 patients were specifically counselled about fertility prior to breast cancer treatment. The mortality due to breast cancer was 10% in non-pregnant patients and 6% in patients who became pregnant after breast cancer. CONCLUSION: Pregnancy after breast cancer does not confer a poor prognosis. A higher rate of pregnancy than expected was found after treatment, possibly due to newer treatments including fertility preservation and also possibly due to the active counselling programme in this unit. Patients should have active counselling about fertility when planning treatment and fertility conservation can then be incorporated into a treatment plan.

Hepatic resection for breast cancer metastases.

INTRODUCTION: Hepatic resection is an established modality of treatment for colorectal cancer metastases. Resection of breast cancer liver metastases remains controversial, but has been shown to be an effective treatment in selected cases. This study reports the outcome of 8 patients with liver metastases from breast cancer. PATIENTS & METHODS: 8 patients with liver metastases from previously treated breast cancer were referred for hepatic resection between September 1996 and December 2002. Six were eligible for liver resection. The mean age was 45.8 years. The resections performed included 1 segmentectomy and 5 hemihepatectomies of which one was an extended hemihepatectomy. One patient had a repeat hepatectomy 44 months after the first resection. RESULTS: There were no postoperative deaths or major morbidity. The resectability rate was 75%. Follow-up periods range from 6 to 70 months with a median survival of 31 months following resection. There have been 2 deaths, one died of recurrence in the residual liver at 6 months and one died disease-free from a stroke. Of the remaining 4 patients, 1 has had a further liver resection at 44 months following which she is alive and 'disease-free' at 70 months. The one patient with peritoneal recurrence is alive 49 months after her liver resection with 2 patients remaining disease-free. CONCLUSION: Hepatic resection for breast cancer liver metastases is a safe procedure with low morbidity and mortality.

T1 G1 NO ER positive breast cancer--adjuvant therapy is needed.

AIMS: To assess the outcome of treating patients with excellent prognosis (T1 G1 N0 ER +ve) breast cancers with breast conserving surgery alone. METHODS: One hundred and twenty-one women with grade 1, node negative, ER+ tumours, smaller than 20 mm who were treated by breast conserving surgery alone between 1991 and 2000. Margin width was always at least 5 mm. The following were recorded: local recurrence (LR), distant recurrence, new contra-lateral primaries and death. Recurrence rates were then compared to those in the largest series. RESULTS: One hundred and twenty-one women were followed up for a median of 68 months. Fourteen developed further breast cancer in the same side and eight new cancers in the contra-lateral breast. There was one case of distant metastasis and no deaths. Local recurrence rate was significantly higher than other studies (p=0.006). CONCLUSIONS: Although there is no detrimental effect on survival after this length of follow-up, the omission of radiotherapy and tamoxifen appears to increase the probability of LR. Patients with T1 G1 N0 ER+ breast cancer treated by breast conserving surgery should be offered both radiotherapy and tamoxifen.

Quantitative assessment of the radiation hazards and risks in sentinel node procedures.

Sentinel node localization using an injected radiopharmaceutical and a gamma probe is performed in many hospitals. Employers have a duty to give appropriate training to staff who may not have been previously formally trained to work with unsealed radioactive sources. A study was performed to assess hazards and risks at all stages of the localization procedure. Whole body doses and finger doses of imaging, surgery and pathology staff were determined. The activity remaining in the tumour specimen, excised nodes and disposable waste from the operating theatre was measured. Any radioactive contamination of the operating theatre and equipment was also ascertained. All results were then assessed in light of current UK radiation protection legislation for the protection of staff and members of the public. Results showed that radiation doses are low and no additional procedures are required for protection of staff, provided the usual procedures for biohazards are in place. However, an information sheet has been prepared for the reassurance of staff, and theatre swabs may need to be stored temporarily before disposal. Injecting and imaging on the day before surgery is preferred, compared with injecting and imaging before surgery on the same day, since this gives lower radiation doses to staff, lower activity in excised specimens and waste, and provides a higher count rate giving better image quality.

Randomized clinical trial of the effect of needle gauge and local anaesthetic on the pain of breast fine-needle aspiration cytology.

BACKGROUND: Breast fine-needle aspiration cytology (FNAC) is an invasive investigation which can be uncomfortable or distressing. This randomized study investigated the discomfort of breast FNAC and the effect of different techniques. METHODS: Some 116 FNAC samples were taken from 98 women with a palpable breast mass. Each patient was randomized to one of four study groups; aspiration was performed using a green-hub (21 G) or blue-hub (23 G) needle, either with or without local anaesthetic. Each patient scored the pain of the whole procedure using a visual analogue scale. RESULTS: A green-hub needle caused significantly more discomfort (mean(s.e.m.) pain score 5.1(0. 4) cm) than a blue-hub needle (2.9(0.4) cm), or either a blue- or green-hub needle with local anaesthetic (3.0(0.4) and 2.1(0.4) cm respectively) (F = 10.28, 3112 d.f., P < 0.01, analysis of variance). CONCLUSION: The discomfort of breast FNAC is dependent upon the gauge of the needle and the use of local anaesthetic. A blue-hub needle without local anaesthetic should be first choice for breast FNAC.

The effect of needle gauge and local anaesthetic on the diagnostic accuracy of breast fine-needle aspiration cytology.

AIMS: The value of breast fine needle aspiration cytology (FNAC) is well established. This prospective study evaluates the effects of local anaesthetic (LA) and different gauge needles on the diagnostic accuracy of breast FNAC. METHODS: Aspirates were obtained from 59 consecutive excised breast tumours (51 malignant, eight benign) using green (21-G) and blue-hub (23-G) needles, both before and after infiltration of LA at the aspiration site. RESULTS: There was good agreement for the cytological diagnosis of each tumour when compared by needle size (kappa = 0.85) and the presence of LA (kappa = 0.77). Diagnostic sensitivity ranged from 88 to 92%. None of the differences were statistically significant. In addition LA appeared to have no effect upon the cytological grading of breast carcinomas (chi2 = 1.98, (df 3, P = 0.58). DISCUSSION: The use of the smaller gauge blue-hub needle or LA does not appear to affect adversely the diagnostic accuracy of breast FNAC. Whether using LA or the blue needle routinely in the breast clinic will have an effect upon the discomfort experienced during FNAC remains to be proven.

Differential cytologic features of fibroepithelial lesions of the breast.

The surgical treatment of phyllodes tumors differs from that for fibroadenomas, with the former necessitating complete excision with no remaining neoplastic tissue to produce local recurrence. To determine whether we could predict the type of breast lesion on cytology we reviewed the cytological features of 39 fibroepithelial lesions, including ordinary fibroadenomas, fibroadenoma variants (intermediate group), benign phyllodes tumors, and malignant phyllodes tumors, which had a biopsy diagnosis and adequate cytology. We found no differences in the glandular elements, the myoepithelial and single stromal cells, and the type of stromal fragments seen in the three benign groups. The stromal nuclei, the number of leaf-shaped fragments, and the numbers of spindle-cell groups present showed a spectrum of changes varying from those of fibroadenomas at one end to those of benign phyllodes tumors at the other. Malignant phyllodes tumors had characteristic features which were quite different from those of the benign lesions.

Staging of symptomatic primary breast cancer with MR imaging.

OBJECTIVE: This study was designed to investigate the accuracy of contrast-enhanced MR imaging in the locoregional staging of symptomatic primary breast cancer and to determine the impact of contrast-enhanced MR imaging in planning surgical management. MATERIALS AND METHODS: Ninety patients with primary breast cancer (including two bilateral cancers) diagnosed and treated on the basis of conventional triple assessment (clinical, cytologic, and mammographic examination) underwent MR imaging at 1.0 T using a three-dimensional fast low-angle shot T1-weighted pulse sequence before and after contrast enhancement. A short inversion time inversion recovery sequence was also obtained to evaluate the axilla of each patient. After resection, tumors were histopathologically mapped in detail and correlated with the extent of contrast enhancement on MR imaging. RESULTS: On the basis of triple assessment, 53 cancers were treated by wide local excision, of which 17 (32%) had positive margins at excision. Residual disease at reexcision was detected in eight of these 17 patients, a finding that correlated accurately with the extent of contrast enhancement on MR imaging. MR imaging was more accurate than mammography in determining invasive tumor size (r2 = .93 versus r2 = .59), in depicting multifocality and extensive intraductal component (sensitivity, 81% versus 62%), and in assessing nipple-retroareolar complex. MR imaging-histopathologic correlation was possible in 75 axillae. Sensitivity and specificity for axillary node metastases were 90% and 82%, respectively. CONCLUSION: MR imaging of the breast has value in the preoperative locoregional staging of symptomatic primary breast cancer and is useful in planning a single definitive surgical resection in patients with breast cancer.

Laser therapy for breast cancer: MR imaging and histopathologic correlation.

PURPOSE: To investigate magnetic resonance (MR) imaging guidance of interstitial laser photocoagulation to treat primary breast cancer. MATERIALS AND METHODS: Twenty female patients with symptomatic breast cancers diagnosed at cytologic examination underwent interstitial laser photocoagulation by means of a single fiber prior to surgical excision. Gadolinium-enhanced T1-weighted three-dimensional fast low-angle shot (FLASH) MR imaging was performed before and after laser therapy (median, 48 hours; range, 24-96 hours). Following resection, tumors were mapped in detail histopathologically. The extent of disease, size of laser burn, and extent of residual tumor were correlated with MR findings. RESULTS: Twenty-seven tumors were detected at histopathologic examination in the 20 patients. Five patients had more than one invasive mass. Twenty-five of the 27 tumors were identified as discrete enhancing masses at MR. The two missed invasive foci were obscured on MR images by diffuse patchy enhancement that correlated with the presence of an associated extensive intraductal component. Early (4-hour) follow-up images failed to depict the laser effect. Later (24-96 hours) follow-up images depicted the laser-induced necrosis as a zone of nonenhancement within the residual enhancing tumor. The correlation coefficients (MR vs histopathologic analysis) for the laser-burn diameter and residual tumor were 0.80 and 0.86, respectively. CONCLUSION: Delayed gadolinium-enhanced MR images can help define the extent of laser-induced necrosis and residual tumor after interstitial laser photocoagulation therapy in breast cancer.

A survey of the management of breast cancer in England and Wales.

The management of breast cancer is controversial. In order to obtain an overview of the way that surgeons manage breast cancer in England and Wales and to assess trends in management by comparisons with the results of previous surveys a postal questionnaire was sent to all consultant general surgeons in England and Wales (n = 985). The response rate was 61%. Fine-needle aspiration is now the preferred technique to obtain a tissue diagnosis by 85% of surgeons. The majority of surgeons now treat early breast cancer either by breast-conserving surgery or offer the patient the choice of conservation or mastectomy. Comparisons with previous surveys carried out in the last 10 years suggest that fewer surgeons now recommend mastectomy. In all, 83% of surgeons indicated that they would biopsy the ipsilateral axilla routinely. Opinion is divided with regard to treatment of breast cancer in the elderly and treatment of an incompletely excised tumour, although the majority perform a mastectomy for a local recurrence after conservative surgery. Follow-up was regarded as worthwhile by 90%, but the majority do not routinely do follow-up investigations on asymptomatic patients apart from mammography. This study has shown very little consensus regarding the management of breast cancer in England and Wales. We suggest that the management of breast cancer should be in the hands of those with a special interest in the subject, as these surgeons will be more aware of ongoing clinical trials and current literature, more patients will then be entered into clinical trials and further trials instigated.

Lobular carcinoma of the breast: cytological features supporting the diagnosis of lobular cancer.

Lobular carcinomas have a distinct natural history with a better response to endocrine therapy and a higher incidence of local recurrence and are more often bilateral. The cytological diagnosis of lobular carcinoma permits a discriminating therapeutic approach with pre-operative Tamoxifen, more generous resection margins, and assessment of the contralateral breast. The cytological features of lobular cancer however are not well defined and the low cell yield from such neoplasms can result in a high false negative rate. To determine whether we could improve the pre-operative diagnosis, we reviewed the cytological features of 112 lobular carcinomas. They had small uniform sized nuclei with irregular outlines and inconspicuous nucleoli. The degree of dissociation was similar to duct carcinomas and the incidence of inadequate aspirates was no higher. We found no features that confidently diagnosed lobular cancer or its sub-types. However, using a combination of features, typing of lobular cancer on aspirated material is possible and should be attempted.