Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early breast cancer. Currently, no consensus exists on the optimal site of injection of the radioactive tracer or blue dye. METHODS: A systematic review and meta-analysis of studies comparing superficial and deep injections of radioactive tracer or blue dye for lymphatic mapping and SLNB was performed. The axillary and extra-axillary sentinel lymph node (SLN) identification rates obtained by lymphoscintigraphy and intraoperative SLNB were evaluated. Pooled odds ratios (ORs) and 95 per cent c.i. were estimated using fixed-effect analyses, or random-effects analyses if there was statistically significant heterogeneity (P < 0·050). RESULTS: Thirteen studies were included in the meta-analysis. There was no significant difference between superficial and deep injections of radioactive tracer for axillary SLN identification on lymphoscintigraphy (OR 1·59, 95 per cent c.i. 0·79 to 3·17), during surgery (OR 1·27, 0·60 to 2·68) and for SLN identification using blue dye (OR 1·40, 0·83 to 2·35). The rate of extra-axillary SLN identification was significantly greater when deep rather than superficial injection was used (OR 3·00, 1·92 to 4·67). The discordance rate between superficial and deep injections ranged from 4 to 73 per cent for axillary and from 0 to 61 per cent for internal mammary node mapping. CONCLUSION: Both superficial and deep injections of radioactive tracer and blue dye are effective for axillary SLN identification. Clinical consequences of discordance rates between the two injection techniques are unclear. Deep injections are associated with significantly greater extra-axillary SLN identification; however, this may not have a significant impact on clinical management.

Adjuvant taxanes and the development of breast cancer-related arm lymphoedema.

BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.

Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer.

BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2·7(2·5) versus 5·9(4·8) per cent respectively; P = 0·006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com).

Darwin, medicine and cancer.

'Nothing in biology makes sense except in the light of evolution'! So said Theodore Dobzhansky. It is extraordinary how little Darwinism and post-Darwinian evolutionary science has penetrated medicine despite the fact that all biology is built upon its foundations. Randy Nesse, one of the fathers of Darwinian medicine, recently observed that doctors 'know the facts but not the origins'. Clearly, then, in this auspicious year-200 years since Charles Darwin's birth and 150 years since the first edition of the Origin of Species-it is time to reconsider Darwin's legacy to medicine and to invite evolution back into the biomedical fold. Here, we consider the legacy of Darwin and the contribution of the other great evolutionists such as Ernst Mayr to cancer and medicine.

Treatment and survival in breast cancer in the Eastern Region of England.

BACKGROUND: The reasons for variation in survival in breast cancer are multifactorial. METHODS: From 1999 to 2003, the vital status of 9051 cases of invasive breast cancer was identified in the Eastern Region of England. Survival analysis was by Cox proportional hazards regression. Data were analysed separately for patients aged <70 years and those older due to differences in treatment policies. RESULTS: Overall 5-year survival was 78%. In patients aged <70 years, significant differences in survival lost their formal significance after adjustment for detection mode and node status, although this remained close to statistical significance with some residual differences between relative hazards. There was significant negative ecological correlation between proportion with nodes positive or not examined and 9-year survival rates. Patients with estrogen receptor (ER) status unknown were at significantly higher risk of dying than ER-positive patients. There was a clear trend of increasing hazard of dying with increasing deprivation. Survival differences in women aged > or =70 years were related to whether surgery was included as part of treatment. CONCLUSION: This variation in treatment and survival may be attributed to lack of information, in particular nodal and ER status, thereby impacting on staging and prescription of adjuvant therapy.

Sympathetic nerve damage as a potential cause of lymphoedema after axillary dissection for breast cancer.

BACKGROUND: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor. METHODS: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet. RESULTS: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema. CONCLUSION: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery.

Understanding breast cancer-related lymphoedema.

Breast cancer-related lymphoedema (BCRL) is a chronic swelling of the upper limb following surgery to axillary lymph nodes. This clinical literature review considers the risk factors that have been identified for the development of BCRL: the extent of surgery to the breast and the axilla, radiotherapy, nodal status, infection and patient characteristics such as BMI and patient age. The management of BCRL is primarily conservative, but the evidence for pharmacological and surgical approaches is also considered.

Screen-detected vs symptomatic breast cancer: is improved survival due to stage migration alone?

This paper examines whether screen-detected breast cancer confers additional prognostic benefit to the patient, over and above that expected by any shift in stage at presentation. In all, 5604 women (aged 50-70 years) diagnosed with invasive breast cancer between 1998 and 2003 were identified by the Eastern Cancer Registration and Information Centre (ECRIC) and mammographic screening status was determined. Using proportional hazards regression, we estimated the effect of screen detection compared with symptomatic diagnosis on 5-year survival unadjusted, then adjusted for age and Nottingham Prognostic Index (NPI). A total of 72% of the survival benefit associated with screen-detected breast cancer can be accounted for by age and shift in NPI. Survival analysis by continuous NPI showed a small but systematic survival benefit for screen-detected cancers at each NPI value. These data show that although most of the screen-detected survival advantage is due to a shift in NPI, the mode of detection does impact on survival in patients with equivalent NPI scores. This residual survival benefit is small but significant, and is likely to be due to differences in tumour biology. Current prognostication tools may, therefore, overestimate the benefit of systemic treatments in screen-detected cancers and lead to overtreatment of these patients.

A model for predicting non-sentinel lymph node metastatic disease when the sentinel lymph node is positive.

BACKGROUND: Women with axillary sentinel lymph node (SLN)-positive breast cancer usually undergo completion axillary lymph node dissection (ALND). However, not all patients with positive SLNs have further axillary nodal disease. Therefore, in the patients with low risk of further disease, completion ALND could be avoided. The Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram to estimate the risk of non-SLN disease. This study critically appraised the nomogram and refined the model to improve predictive accuracy. METHODS: The MSKCC nomogram was applied to 118 patients with a positive axillary SLN biopsy who subsequently had completion ALND. Predictive accuracy was assessed by calculating the area under the receiver-operator characteristic (ROC) curve. A further predictive model was developed using more detailed pathological information. Backward stepwise multiple logistic regression was used to develop the predictive model for further axillary lymph node disease. This was then converted to a probability score. After k-fold cross-validation within the data, an inverse variance weighted mean ROC curve and area below the ROC curve was calculated. RESULTS: The MSKCC nomogram had an area under the ROC curve of 68 per cent. The revised predictive model showed the weighted mean area under the ROC curve to be 84 per cent. CONCLUSION: The modified predictive model, which incorporated size of SLN metastasis, improved predictive accuracy, although further testing on an independent data set is desirable.

Stem cells and breast cancer.

Proliferation in continuously renewing tissues, including the mammary gland, is hierarchically organized with a small number of slowly dividing stem cells and a greater number of more rapidly proliferating 'transit amplifying' cells. Mammary stem cells have been recently identified and purified based on their surface antigen expression. The recognition of mammary epithelial stem cells had led to the hypothesis that these may be at the root of breast cancer. In support of this, a highly tumorigenic subpopulation of cancer cells - cancer stem cells - has recently been identified in primary and metastatic breast cancer samples and in a number of established breast cancer cell lines. The existence of cancer stem cells would explain why only a small minority of cancer cells is capable of extensive proliferation and transferral of the tumour. In this article we aim to review the evidence in support of the existence of both normal mammary stem cells and breast cancer stem cells, and provide further insight into how taking this subpopulation of cells into account may affect the way we treat epithelial cancers in the future.

"Inflammatory" breast cancer.

BACKGROUND: "Inflammatory" breast cancer is a rare and very aggressive form of the disease characterised by rapid onset and dismal outcome. METHODS: This review describes the clinical and molecular aspects of inflammatory breast cancer. The relevant English language literature on of inflammatory breast cancer was searched via Medline and ISI Web of Knowledge Cross Search (1924-2005), cross-referencing with key articles on the subject. RESULTS AND CONCLUSION: An increasing body of evidence demonstrates that inflammatory breast cancer is a unique form of breast cancer. A prompt diagnosis and multidisciplinary approach (based on neoadjuvant chemotherapy, loco-regional treatment with surgery and/or radiotherapy, followed in some cases by adjuvant systemic therapy) are the two factors most likely to have an impact on survival. As the molecular basis of the disease is becoming increasingly more defined, new potential therapeutic targets may arise in the future.

Fluoroscopy and Paget's disease of the breast.

A case report concerning a 36-year-old woman having developed Paget's disease of the breast subsequent to multiple fluoroscopies as a child for the investigation of Fallot's anomaly/pulmonary atresia is presented. This case is discussed with a brief review of the relevant literature regarding current theories as to the pathogenesis of Paget's disease of the breast, ionizing radiation and its role in dysplastic breast disease and their possible interrelation.

Adenomyoepithelioma of the breast; a case report and literature review.

A case of adenomyoepithelioma of the breast is presented in order to illustrate some of the difficulties in achieving a pathological diagnosis of this lesion. Given the emerging evidence for adenomyoepithelioma to develop into malignancy, it is imperative that the histopathological features of this lesion are well described and recognized.

An investigation of lymphovenous communications in the upper limbs of breast cancer patients.

BACKGROUND: Approximately 25% of breast cancer patients who undergo treatment to the axilla develop breast cancer-related lymphoedema (BCRL). The aim of this study was to test the hypothesis that lymphovenous communications (LVCs) open and act as a protective mechanism against the development of BCRL. METHODS: Five patients (Group 1) received intradermal injections of (99m)Technetium-labelled autologous erythrocytes into the 2nd ipsilateral hand webspace before and 6-12 weeks following axillary node clearance surgery (ANC). Ten patients at least three years after ANC were also recruited (Group 2); seven had developed BCRL and three had not. Blood was sampled from ipsilateral and contralateral antecubital veins 5, 15, 30, 60, 120 and 180 min post-injection to assess pre-nodal shunting from lymph to blood (LVCs), since nodes block erythrocyte transit. The proportion of activity remaining in the depot was used to calculate the degree of shunting in those with evidence of LVCs. RESULTS: Significant erythrocyte-bound activity, increasing over time, was detected contralaterally in 3 of the 5 patients from Group 1 (none of whom developed BCRL) and 3 of 7 patients with BCRL from Group 2, which indicated the presence of LVCs. The degree of shunting was more marked in those patients who did not develop BCRL compared with those who did. CONCLUSIONS: The time-course of erythrocyte-bound contralateral activity indicates transit through lymphovenous communications rather than needle-induced trauma. Lymphovenous communications large enough to transmit erythrocytes are probably constitutional rather than induced. A larger study is warranted to assess any resulting protection against BCRL.

A constitutional predisposition to breast cancer-related lymphoedema and effect of axillary lymph node surgery on forearm muscle lymph flow.

AIM: The aims of this prospective study were (a) to examine the relationship between pre-operative muscle lymph flow and the predisposition to BCRL in women treated by axillary nodal surgery for breast cancer; and (b) to test the 'stopcock' hypothesis that axillary lymph node surgery impairs forearm lymph flow in the short term. METHODS: (99m)Tc-nanocoll was injected intramuscularly into both forearms of women undergoing surgery for breast cancer. Lymphatic clearance rate constant, k, representing lymph flow per unit interstitial fluid volume, was measured as the fractional disappearance rate of radioactivity from the depot site by gamma camera imaging. Axillary lymph node activity was calculated as percentage injected activity. BCRL was assessed by clinical examination and upper limb perometry. RESULTS: Of 38 pre-operative women, 33 attended at 8 ± 6 weeks post-operatively and 31 at 58 ± 9 weeks post-operatively. Seven patients (18%) developed BCRL. Prior to surgery the BCRL-destined patients had a higher mean k (0.0962 ± 0.034%/min) than non-BCRL patients (0.0830 ± 0.019%/min) (p = 0.10, unpaired t test). Post-operative k values were not significantly different from pre-operative, in either the ipsilateral (operated) or contralateral limb. Also, post-operative k values did not differ significantly between both upper limbs. Furthermore, there was no significant difference between pre- and post-operative axillary activity. CONCLUSION: Patients who develop BCRL have high lymph flow pre-surgery, which may predispose them to lymphatic overload and failure. Axillary lymph node surgery has no early, measurable effect on forearm muscle lymph flow despite surgical disruption of routes of lymph drainage.

Pregnancy after breast cancer.

The issue of pregnancy in patients previously treated for breast cancer is controversial. This paper reviews the literature using Medline and Embase databases over the last 50 years to address the issue. Overall survival in patients treated for breast cancer who subsequently become pregnant compares favourably with controls. This paper also addresses the effects of adjuvant therapy (loco-regional and systemic) on subsequent pregnancy. Introduction of a national registry of these patients may help inform such patients in the future.

Is physical function a more appropriate measure than volume excess in the assessment of breast cancer-related lymphoedema (BCRL)?

The aim of this study was to objectively measure impairment of arm function in women with breast cancer-related lymphoedema (BCRL), and investigate possible associations between this, arm volume excess, and psychological morbidity as measured by the Medical Outcomes Study 36-item short form (SF-36) questionnaire. A total of 48 patients were recruited. Manual dexterity was significantly impaired in the affected arm, independent of dominant or non-dominant arm involvement, but was not associated with arm volume excess. Psychological morbidity was significantly impaired in the domains of 'physical function' and 'bodily pain' when compared with population controls. Degree of impairment in the 'physical function' domain correlated with the absolute level of objectively tested manual dexterity. Impairment of manual dexterity appears to have a greater impact than arm volume excess on the overall psychological morbidity associated with BCRL, suggesting that greater emphasis should be placed upon arm function in the assessment, treatment targeting, and monitoring of patients with this condition.

Hormone receptor status in primary breast cancer--time for a consensus?

In a previous study, we demonstrated wide variability in the access to oestrogen receptor (ER) measurement, patient selection, choice of technique and the cut-off point for positivity. The aim of this study was to update information on the current use of ER and progesterone receptor (PR) measurement in the United Kingdom (UK). Questionnaires, asking about availability, use and technique of ER and PR measurement, were returned from 170 (74%) units in the UK. Where ER positivity was determined using the percentage of cells staining positive (33%), the absolute cut-off point for positivity varied widely from 5 to 80% of cells. Of the 170 responding units, 107 (63%) felt that PR measurement was important. This study confirms considerable variability in both the technique of ER measurement and the absolute cut-off point for positivity (5-80%). It is essential that a consensus be reached regarding the choice of technique, as well as the threshold for positivity.

Detection of intraoperative tumor cell dissemination in patients with breast cancer by use of reverse transcription and polymerase chain reaction.

BACKGROUND: Animal studies have shown that malignant cells are shed into the blood stream during surgical resection of a primary tumor and that this may enhance the development of metastases. The evidence for tumor cell dissemination during surgical manipulation of human cancer is unclear. We have applied the technique of reverse transcription and polymerase chain reaction to detect circulating tumor cells in peripheral venous blood of patients with breast cancer perioperatively. METHODS: To target breast-specific gene transcription complementary DNA was prepared by reverse transcription of blood messenger RNA with oligonucleotide primers unique to CK18 and DF3 antigens. Preliminary assessment of specificity showed that the DF3 antigen was more suitable than CK18 for the purpose of this study. Assessment of sensitivity showed that as few as 10 tumor cells per 5 ml blood could be identified by this method. Peripheral blood samples were obtained by venepuncture from patients before, during, and 24 hours after breast surgery (nine malignant and three benign). RESULTS: In the group of patients with malignant disease, tumor cells were detected in one patient before operation and four patients during operation. No tumor cells were detected in the postoperative samples nor in any of the samples of patients with benign disease. CONCLUSIONS: These findings suggest that tumor manipulation during operation encourages tumor cell dissemination.