Repeat surgery following breast conservation and intra-operative sentinel lymph node analysis for breast cancer.

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.

The axillary nodal harvest in breast cancer surgery is unchanged by sentinel node biopsy or the timing of surgery.

Introduction. Patients with a positive sentinel lymph node biopsy may undergo delayed completion axillary dissection. Where intraoperative analysis is available, immediate completion axillary dissection can be performed. Alternatively, patients may undergo primary axillary dissection for breast cancer, historically or when preoperative assessment suggests axillary metastases. This study aims to determine if there is a difference in the total number of lymph nodes or the number of metastatic nodes harvested between the 3 possible approaches. Methods. Three consecutive comparable groups of 50 consecutive patients who underwent axillary dissection in each of the above contexts were identified from the Portsmouth Breast Unit Database. Patient demographics, clinicopathological variables, and surgical treatment were recorded. The total pathological nodal count and the number of metastatic nodes were compared between the groups. Results. There were no differences in clinico-pathological features between the three groups for all features studied with the exception of breast surgical procedure (P < 0.001). There were no differences in total nodal harvest (P = 0.822) or in the number of positive nodes harvested (P = 0.157) between the three groups. Conclusion. The three approaches to axillary clearance yield equivalent nodal harvests, suggesting oncological equivalence and robustness of surgical technique.

The effect of introducing an in-theatre intra-operative specimen radiography (IOSR) system on the management of palpable breast cancer within a single unit.

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.

Observational and cost analysis of the implementation of breast cancer sentinel node intraoperative molecular diagnosis.

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.

Breast cancer follow up: a randomised controlled trial comparing point of need access versus routine 6-monthly clinical review.

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.

Thyroid FNAC cytology: can we do it better?

This article reviews recent developments in thyroid fine needle aspiration cytology (FNAC). While thyroid nodules are common, carcinoma is comparatively rare. Although histological assessment is used in most studies as the benchmark, the differential diagnosis on cytology or histology is not always reproducible. The literature shows wide variations in criteria for inadequate thyroid FNAC and study inclusion or exclusion criteria. In-clinic assessment of specimen adequacy and in-clinic reporting of thyroid FNAC has become popular although the costs and resource implications of in-clinic thyroid FNAC assessment and reporting are substantial. Many centres continue to use conventional techniques although liquid-based cytology and ultrasound-guided FNAC are gaining in popularity. Standardized categorical systems for FNAC reporting can make results easier to understand for clinicians and give clear indications for therapeutic action. Multidisciplinary case review is also essential, especially when there is diagnostic uncertainty. While currently of limited use, molecular pathology testing holds out some promise for the future.

A double-blind randomised trial to evaluate the effect of anastrozole for the treatment of non-toxic multinodular goitre.

Multinodular goitre (MNG) is a common clinical finding, particularly in females and is usually asymptomatic. When symptoms occur because of local pressure-related effects the only treatment is surgical involving partial or total thyroidectomy. A number of epidemiological observations and experimental data have suggested that oestrogen aromatase activity may be involved in the pathogenesis of MNG. This study examines the effect of anastrozole, a non-steroidal aromatase inhibitor that inhibits the peripheral conversion of testosterone to oestradiol, in reducing the size of MNG. Thirty-two post-menopausal female patients, median age 63 years (range 42-84) were randomised in a double-blind fashion to receive either anastrozole 1 mg daily or placebo for 3 months. Ultrasonographic measurement of each thyroid lobe and isthmus together with complete biochemical and hormone profiles were performed at the start and end of treatment. There was no significant reduction in the goitre size for patients in the anastrozole group (p = 0.246) or the placebo group (p = 0.418). There were no significant changes in hormone profiles (including throglobulin concentration) within each group between the start and end of the study. We conclude that the use of anastrozole in the treatment of MNG does not appear to have any effect in reducing the size of MNG.

Radiological review of specimen radiographs after breast localisation biopsy is not always necessary.

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.

Galectin-3 is not useful in thyroid FNA.

INTRODUCTION: Previous studies have suggested that galectin-3 immunohistochemistry may be useful in the fine needle aspiration (FNA) diagnosis of thyroid carcinoma as it has been reported to selectively stain carcinomas and not adenomas or goitres. METHODS: Fifty-one patients were included in a prospective study of galectin-3 in thyroid FNA; 88.2% were female and 11.8% male, mean age 53 years, range 25-87 years. Cell blocks were prepared and stained for galectin-3 if any cells were present in needle washings from the respective FNAs. RESULTS: Twelve of 51 (23.5%) of cell blocks contained epithelial cells. One benign and one inadequate FNA were negative for galectin-3 staining. One of five non-diagnostic FNA cases, a papillary carcinoma on final histology showed positive staining. Four follicular neoplasm/suspicious of carcinoma cases showed negative staining. One malignant FNA case, a papillary carcinoma showed positive staining with galectin-3 but three further carcinomas, two papillary and one follicular were galectin-3 negative. CONCLUSION: Galectin-3 immunohistochemistry does not appear to be a useful adjunct to diagnosis in thyroid FNA as it does not reliably distinguish malignant and benign lesions. Many thyroid aspirates are of low cellularity and are not suitable for cell block immunohistochemistry.

Sentinel lymph node biopsy in male breast cancer patients.

The concept of sentinel node biopsy has been validated for female breast cancer patients whereas, ALND remains the standard of care for male breast cancer patients with similar tumours. We evaluated the results of SLN biopsy in male breast cancer patients with clinically negative axillae. This study included all male breast cancer patients who underwent SLN biopsy between February 1998 and October 2003. All patients had negative axillae on clinical examination. All patients underwent pre-operative lymphoscintigraphy. SLN biopsy was performed using a combination of Patent blue V and 99mTc-radiolabelled colloidal albumin injected peritumourally. Nine patients, 26-79 years of age, were included in the study. Pre-operative lymphoscinitgraphy identified SLNs in all patients. Intraoperatively, SLNs were successfully localised in all patients. The mean number of SLNs encountered was 2.4. Five patients had a positive SLN, four a negative SLN. Five patients (one with a negative SLN, four with a positive SLN) had been elected pre-operatively to undergo ALND regardless of findings on SLN biopsy. ALND confirmed the SLN to be negative in one patient (false-negative rate: 0%) and three of the four patients with positive SLN(s) had additional positive nodes in the axilla. SLN biopsy accurately predicted axillary lymph node status in these five patients. These findings compare favourably with findings reported in the literature regarding SLN biopsy in female breast cancer patients. SLN biopsy accurately staged the axilla in male breast cancer patients and should be considered for axillary staging in male breast cancer patients with clinically negative axillae.

The use of sentinel node biopsy in the treatment of cancer of an accessory breast.

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.

Primary tumour characteristics and axillary lymph node status in breast cancer.

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.

A paracrine role for myoepithelial cell-derived FGF2 in the normal human breast.

We have studied separated normal human breast epithelial and myoepithelial cells for the presence of basic fibroblast growth factor (FGF2) and its receptors, both low (heparan sulfate proteoglycans) and high affinity (FGFR1), and for the effects of FGF2 on the proliferation of both cell types. Our results indicate that these cells differ markedly in their synthesis and response to FGF2. We found, using PCR of purified cell populations, mRNA for FGF2 only in the myoepithelial cells, whereas immunostaining and Western blotting results demonstrated the presence of FGF2 protein in both epithelial and myoepithelial cells. FGF2 had no effect on the proliferation of myoepithelial cells, but it did maintain the survival of the separated epithelial cells in low serum and stimulate their growth in 5% and 10% FCS. Immunostainable FGFR1 was present in epithelial cells and, to a lesser extent, in myoepithelial cells. Low-affinity binding sites for FGF2 were synthesized by epithelial and myoepithelial cells, but myoepithelial cells possessed a greater proportion of higher-affinity heparan sulfate proteoglycans. These results indicate that myoepithelial cell-derived FGF2 may be an important paracrine factor controlling epithelial cell survival and growth in the normal human breast.

Expression of keratinocyte growth factor and its receptor in human breast cancer.

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.

The location of acidic fibroblast growth factor in the breast is dependent on the activity of proteases present in breast cancer tissue.

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.