Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study.

OBJECTIVE: Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. METHODS: From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). RESULTS: The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3-15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). CONCLUSIONS: Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node.

The surgical margin status after breast-conserving surgery: discussion of an open issue.

Hypothesis The best therapeutic approach to the involved or proximal surgical margins has not been defined yet; surgical margins status can influence the local relapse of disease in breast carcinoma, but the impact on overall survival has not been clearly demonstrated. Purpose of this work is to find in the available literature further evidence to guide the therapeutic behaviour in patients with close margins by invasive carcinoma. Design Review of the currently available literature on the evaluation of surgical margins in breast conserving surgery; influence of margin involvement by invasive component or intraductal component. Patients or other participants Literature research by PubMed on the topics of breast carcinoma, conservative surgery and margin definition and status; therapeutic approach to involved margins. Main outcome measure We reviewed the available literature focusing our attention to the definition of clear surgical margins and to the value of the close proximity of margins in relation to the local control of disease and the best therapeutic management of different situations. Results Further evidence is needed on large numbers of patients to understand how to evaluate surgical margins in invasive breast carcinoma. Conclusions There is no consensus on the definition of "clear surgical margins", and the ideal approach to the close proximity of margins has not been defined. It is not sure whether a new surgical procedure is really needed in every case of close proximity of tumor cells to the margins. Radiation therapy could be a good option in the management of these cases, but further evidence is needed to establish the real impact of clear surgical margins on local control of disease and, furthermore, on survival.

Clinicopathologic characteristics of invasive lobular carcinoma of the breast: results of an analysis of 530 cases from a single institution.

BACKGROUND: Although invasive lobular carcinoma (ILC) is the second most common histotype of breast cancer, the prognostic implications of its clinicopathologic characteristics remain controversial. METHODS: The authors undertook a retrospective analysis of a large series of cases treated and followed at a single institution, with the objective of assessing the prognostic/predictive value of distinct clinicopathologic features of the tumors, after revision of the original histopathologic preparations and statistical analyses. RESULTS: Overall, 530 patients with pure ILC (57% with the classic type; 19% with the alveolar type; 11% with the solid type; and the remaining 13% characterized by pleomorphic, signet ring cell, histiocytoid, or apocrine features) were included in the study. Tumor size, lymph node metastatic involvement, and hormonal status were confirmed to be significant prognostic factors. In addition, statistically significant correlations were demonstrated between the 'classic' histotype of ILC and a lower risk of axillary lymph node metastases (P = .0005), a reduced number of metastatic lymph nodes (P = .04), and lower tumor grade (P < .0001). Patients with ILC of the 'nonclassic' subtype demonstrated significantly increased breast-related events (hazards ratio of 1.80; 95% confidence interval, 1.04-3.10) and a trend toward reduced disease-free survival and overall survival. CONCLUSIONS: The results of the current study confirm the clinical usefulness of several traditional clinicopathologic features of ILC as prognostic parameters but also emphasize the prognostic role of the histopathologic subtyping of these tumors, documenting the more favorable outcome of the classic subtype of ILC.

Preliminary results of electron intraoperative therapy boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal women.

PURPOSE: To report the acute and preliminary data on late toxicity of a pilot study of boost with electron intraoperative therapy followed by hypofractionated external beam radiotherapy (HEBRT) of the whole breast. METHODS AND MATERIALS: Between June 2004 and March 2007, 211 women with a diagnosis of early-stage breast cancer were treated with breast-conserving surgery. During surgery, an electron intraoperative therapy boost of 12 Gy was administered to the tumor bed. Adjuvant local treatment was completed with HEBRT, consisting of a course of 13 daily fractions of 2.85 Gy to the whole breast to a total dose of 37.05 Gy. Acute toxicity of the breast was evaluated at the end of HEBRT and at 1 month of follow-up. Late toxicity was recorded at 6 and 12 months of follow-up. RESULTS: We report the data from 204 patients. The maximal acute skin toxicity was observed at the end of HEBRT (182 patients evaluable) with 7 (3.8%) Grade 3, 52 (28.6%) Grade 2, 123 (67.6%) Grade 1, and no Grade 0 or Grade 4 cases. A total of 108 patients were evaluated for late toxicity. The recorded late skin toxicity was Grade 4 in 1 patient (0.9%), Grade 3 in 1 patient, and Grade 2 or less in 106 patients (98.2%). CONCLUSIONS: The results of this study have shown that electron intraoperative therapy followed by HEBRT allows for the delivery of a high dose to the tumor bed and an adequate dose to the whole breast. This treatment is feasible, compliance is high, and the rate of acute toxicity and the preliminary data on chronic toxicity seem acceptable.

Paget's disease of the breast: the experience of the European Institute of Oncology and review of the literature.

BACKGROUND: Paget's disease of the breast is an uncommon presentation of breast malignancy, accounting for 1-3% of all the breast tumors and presents in different histopathologic patterns: in association with an underlying invasive or non invasive carcinoma, or without any underlying neoplasia. In the literature, different methods are used for the treatment. Mastectomy with or without axillary dissection has been considered as the standard treatment procedure for many years. Several studies have already shown that breast conservation with radiation therapy is an oncologically safe option. Regarding the axillary approach, several studies have documented the presence of positive sentinel lymph node even in Paget's disease alone. The objective of this study was to retrospectively analyze outcome of patients affected by Paget's breast disease and to define our institutional experience. PATIENTS AND METHODS: Between May 1996 and February 2003, 114 patients with confirmed Paget's disease of the breast were retrieved and underwent surgery at the European Institute of Oncology of Milan, Italy. The median age of the patients was 54 years at the time of the diagnosis. In our study, the histopathological examination of the operated specimen revealed one hundred seven patients with Paget's disease associated with an underlying invasive or non invasive carcinoma, and seven patients without underlying carcinoma. Patients underwent either conservative breast surgery or mastectomy, with or without sentinel lymph node biopsy and/or axillary surgery. Each patient was evaluated after surgery at a multidisciplinary meeting to selecting systemic therapy. RESULTS: Seven patients had "pure" Paget's disease of the breast and one hundred seven had the disease associated with an underlying carcinoma. As surgical techniques 71 mastectomies and 43 breast conserving surgeries have been performed. Complete axillary dissection was done in patients with clinically positive lymph node and/or sentinel lymph node biopsy positive. Sentinel lymph node biopsy was performed in nineteen patients with invasive component and five were positive and underwent axillary dissection. Eleven sentinel lymph node biopsies were done in patients with non invasive component and none of them was positive. Adjuvant systemic therapies were based on the final tumor, node and metastasis stage: thirty patients received adjuvant chemotherapy alone, fourteen received endocrine treatment alone, twenty-six patients were evaluated to receive both chemo and endocrine therapy. The median duration of follow up was 73 months and was updated in the last 6 months. Five patients developed local recurrence, one had regional recurrence, another two had loco-regional recurrences and fourteen had distant metastasis as a first event. Malignancy-related deaths were censored in the statistical analyses cancer for and due to another tumor in eleven patients. Additionally, deaths were not related to malignancy totally in thirteen patients. CONCLUSIONS: Screening examination and imaging techniques are fundamental. Breast conserving surgery combined with breast irradiation for patients with invasive and non invasive breast carcinoma has become the treatment of first choice. All surgical conservative approaches should include the complete nipple-areolar complex and margins of resected specimen free of tumor. Thanks to the evolution of the conservative approach, good cosmetic result can be obtained. To be informed about the axillary lymph node status and to avoid the patient to have a second surgical approach, sentinel lymph node biopsy should be performed.

When sentinel lymph node is intramammary.

INTRODUCTION: Sentinel lymph node biopsy is an accepted standard of care for staging the axilla in patients with early-stage breast cancer. Little attention has been placed to the presence of intramammary sentinel lymph nodes (intraMSLNs) on preoperative lymphoscintigraphy. METHODS: Between December 2001 and September 2006, in 9632 breast cancer patients with clinically uninvolved axillary nodes, lymphoscintigraphy was performed at the European Institute of Oncology (EIO). An axillary SLN (axSLN) was identified in 99.4% of cases. An intraMSLN was identified in association with the axillary sentinel lymph node in 22 patients (0.2%). In 15 cases both the axSLN and the intraMSLN were excised. RESULTS: The intraMSLN was positive in six patients (micrometastatic in three cases). The axSLNs were negative in all 15 cases. Two patients with positive intraMSLNs and one patient with a negative intraMSLN underwent axillary dissection; all three cases had negative axillary nodes. At a median follow-up of 24 months, no locoregional or systemic recurrences were observed. CONCLUSIONS: Positive intraMSLNs can improve disease staging but do not necessarily portend axillary lymph node metastasis. When intraMSLNs and axSLNs are present, we advocate biopsy of both sites and that management of the axilla should rely on axSLN status. In cases with intraMSLNs as the only draining site on lymphoscintigraphy, decisions on axillary management should be made on individualized basis.

Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2.

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56(+) T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16(+) lymphocytes was influenced by 158 V/F polymorphism of Fc gamma RIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16(+) lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism.

The sentinel node biopsy under local anesthesia in breast cancer: advantages and problems, how the technique influenced the activity of a breast surgery department; update from the European Institute of Oncology with more than 1000 cases.

Sentinel lymph node biopsy (SLNB) is a staging technique with a significant impact on patients' quality of life: the oncological effectiveness in a large number of patients affected by breast carcinoma has been already demonstrated, and the clinical research is now focusing on new indication for the biopsy and widespread adoption of the technique. At the European Institute of Oncology we are applying SLNB under local anesthesia: our aim is to improve the management of the disease with low costs for the structure and patients, and to improve patients' acceptance of breast cancer treatments. We are now discussing the impact of the SLNB under local anesthesia on the activity of a breast surgery department. We also present an update of our experience.

Accuracy of computed tomography perfusion in assessing metastatic involvement of enlarged axillary lymph nodes in patients with breast cancer.

INTRODUCTION: The purpose of this study was to evaluate the diagnostic accuracy of computed tomography (CT) perfusion in differentiating metastatic from inflammatory enlarged axillary lymph nodes in patients with breast cancer. METHODS: Twenty-five patients with 26 locally advanced breast tumors and clinically palpable axillary lymph nodes underwent dynamic multi-detector CT (LightSpeed 16; General Electric Company) at one scan per second for 150 seconds at the same table position after 40 ml intravenous contrast injection at 4.0 ml/second. Semi-automatic calculation of values of perfusion parameters - blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface (PS) - was performed. Results were compared with pathology and with Her-2/neu and Ki-67 levels in a surgical specimen of the primary tumor. RESULTS: Examined lymph nodes were inflammatory in 8 cases and metastatic in 18. Mean values of perfusion parameters in inflammatory and metastatic nodes, respectively, were BF of 76.18 (confidence interval [CI], 31.53) and 161.60 (CI, 40.94) ml/100 mg per minute (p < 0.05), BV of 5.81 (CI, 2.50) and 9.15 (CI, 3.02) ml/100 mg (not significant [n.s.]), MTT of 6.80 (CI, 1.55) and 5.50 (CI, 1.84) seconds (p = 0.07), and PS of 25.82 (CI, 4.62) and 25.96 (CI, 7.47) ml/100 mg per minute (n.s.). Size of nodes, stage of breast cancer, Ki-67 and Her-2/neu levels in breast cancer, and expression of primary tumor activity were not correlated to any perfusion parameter in metastatic nodes. CONCLUSION: CT perfusion might be an effective tool for studying enlarged axillary lymph nodes in patients with breast cancer. It gives information on vascularization of lymph nodes, helping to understand the changes occurring when neoplastic cells implant in lymph nodes.

Synchronous bilateral breast cancer in men: a case report and review of the literature.

Breast carcinoma is a rare disease in men, and bilateral cases are extremely uncommon. The rarity of male breast carcinoma and the small number of large studies on this topic have made it necessary to extrapolate treatment standards and outcomes from those established for women. Between 1997 and 2007, 75 men with breast cancer were referred to our institute, and the bilateral case we present here was the only one we have observed since 1994. The goal of our work was to contribute to the available literature with this extremely unusual presentation of the disease.

Sentinel lymph node biopsy in male patients with early breast cancer.

Mastectomy with axillary dissection is still the most commonly recommended procedure for male breast cancer. The aim of this study was to retrospectively evaluate our experience in 32 male patients with early breast cancer who underwent sentinel lymph node biopsy (SLNB) and axillary dissection only in cases of metastases in the sentinel lymph node (SLN). The median age was 58 years (range, 33-80). Lymphoscintigraphy was successful in all patients, with a mean number of visualized SLNs per patient of 1.3 (range, 1-2). At surgery, the identification rate of the SLN was 100%, with a mean number of removed SLNs per patient of 1.5 (range, 1-3). Twenty-six patients had negative SLNs, six patients had positive SLNs. Two patients with metastatic SLNs had additional positive nodes. After a median follow-up of 30 months (range, 1-63) no axillary reappearance of the disease occurred. As with women, we recommend SLNB in male patients with breast cancer and clinically negative axilla.

The evolution of the conservative approach to breast cancer.

The profound revolution that surgical treatment of breast cancer has undergone during the past 30 years has led to the progressive reduction of the extent of surgery, with less mutilation. As a consequence, quality of life has improved and women are now more motivated to follow screening programs for early diagnosis of the disease. Since conservative surgery is as effective as radical surgery, research is now focused on reducing radiotherapy. Overall, survival after breast cancer is not affected by reducing the extent of surgery, which, together with less invasive diagnostic procedures, has a good effect on patients' quality of life. For this reason in our Institute we are now evaluating the feasibility of a reduction of the radiation field and the sensibility and sensitivity of new diagnostic approaches for axillary staging.

Male breast cancer in a young patient treated with nipple-sparing mastectomy: case report and review of the literature.

Male breast carcinoma is an uncommon phenomenon, accounting for less than 1% of all malignancies of the breast. The approximate annual incidence in Europe is 1 in 100,000 cases. The highest incidence occurs 5-10 years later in men than in women, with a peak at 60 to 67 years of age. We here describe a case of male breast carcinoma in a young patient (44 years of age), which is quite unusual in the pattern of breast carcinoma presentation.

Metaplastic carcinoma of the breast, an unusual disease with worse prognosis: the experience of the European Institute of Oncology and review of the literature.

BACKGROUND: Metaplastic carcinoma of the breast is a rare form of breast cancer and has an uncertain prognostic significance. The purpose of the present study was to compare the clinical course, and prognosis, between this type of tumor and poorly differentiated ductal carcinoma. PATIENTS AND METHODS: We analyzed 37 cases of metaplastic carcinoma of the breast treated at our institution (European Institute of Oncology in Milan, Italy) between 1997 and 2004, comparing them with 72 cases (control group) of poorly differentiated ductal carcinoma. All 109 patients had negative receptors and were G3 at final histology. The control cases were matched according to year of surgery, pT (pT1 vs. pT2/3/4), and pN (absent vs. present). RESULTS: Of the 37 patients, eleven died from disease progression, eight developed metastatic disease and two experienced local recurrence. In the control group (72 patients) we observed three deaths due to disease progression, 13 distant metastases, and two local recurrences. CONCLUSION: The overall survival in the metaplastic carcinoma group was significantly worse than in the control group. As regards to disease-free survival, there was no statistically significant difference between the two groups.

Angiosarcoma of the breast: the experience of the European Institute of Oncology and a review of the literature.

Angiosarcoma of the breast (AB) is a rare entity: its overall incidence is estimated at between 0.002% and 0.005% per year. Some potential risk factors have been described, mainly previous irradiation of the breast. We report the experience of the European Institute of Oncology with this unusual disease from January 1996 to January 2006: sixteen patients with angiosarcoma, 9 (56%) of whom had primary AB and 7 (44%), secondary AB, are discussed.

Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study.

BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS: Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1). INTERPRETATION: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.