Precise correlation between MRI and histopathology - exploring treatment margins for MRI-guided localized breast cancer therapy.

BACKGROUND: Magnetic resonance imaging (MRI) is more often considered to guide, evaluate or select patients for partial breast irradiation (PBI) or minimally invasive therapy. Safe treatment margins around the MRI-visible lesion (MRI-GTV) are needed to account for surrounding subclinical occult disease. PURPOSE: To precisely compare MRI findings with histopathology, and to obtain detailed knowledge about type, rate, quantity and distance of occult disease around the MRI-GTV. METHODS AND MATERIALS: Patients undergoing MRI and breast-conserving therapy were prospectively included. The wide local excision specimens were subjected to detailed microscopic examination. The size of the invasive (index) tumor was compared with the MRI-GTV. The gross tumor volume (GTV) was defined as the pre-treatment visible lesion. Subclinical tumor foci were reconstructed at various distances to the MRI-GTV. RESULTS: Sixty-two patients (64 breasts) were included. The mean size difference between MRI-GTV and the index tumor was 1.3mm. Subclinical disease occurred in 52% and 25% of the specimens at distances ≥10mm and ≥20mm, respectively, from the MRI-GTV. CONCLUSIONS: For MRI-guided minimally invasive therapy, typical treatment margins of 10mm around the MRI-GTV may include occult disease in 52% of patients. When surgery achieves a 10mm tumor-free margin around the MRI-GTV, radiotherapy to the tumor bed may require clinical target volume margins >10mm in up to one-fourth of the patients.

Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial.

PURPOSE: To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT). PATIENTS AND METHODS: In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed. RESULTS: The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively. CONCLUSION: Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

Comparison of gene expression profiles predicting progression in breast cancer patients treated with tamoxifen.

BACKGROUND: Molecular signatures that predict outcome in tamoxifen treated breast cancer patients have been identified. For the first time, we compared these response profiles in an independent cohort of (neo)adjuvant systemic treatment naïve breast cancer patients treated with first-line tamoxifen for metastatic disease. METHODS: From a consecutive series of 246 estrogen receptor (ER) positive primary tumors, gene expression profiling was performed on available frozen tumors using 44K oligoarrays (n = 69). A 78-gene tamoxifen response profile (formerly consisting of 81 cDNA-clones), a 21-gene set (microarray-based Recurrence Score), as well as the HOXB13-IL17BR ratio (Two-Gene-Index, RT-PCR) were analyzed. Performance of signatures in relation to time to progression (TTP) was compared with standard immunohistochemical (IHC) markers: ER, progesterone receptor (PgR) and HER2. RESULTS: In univariate analyses, the 78-gene tamoxifen response profile, 21-gene set and HOXB13-IL17BR ratio were all significantly associated with TTP with hazard ratios of 2.2 (95% CI 1.3-3.7, P = 0.005), 2.3 (95% CI 1.3-4.0, P = 0.003) and 4.2 (95% CI 1.4-12.3, P = 0.009), respectively. The concordance among the three classifiers was relatively low, they classified only 45-61% of patients in the same category. In multivariate analyses, the association remained significant for the 78-gene profile and the 21-gene set after adjusting for ER and PgR. CONCLUSION: The 78-gene tamoxifen response profile, the 21-gene set and the HOXB13-IL17BR ratio were all significantly associated with TTP in an independent patient series treated with tamoxifen. The addition of multigene assays to ER (IHC) improves the prediction of outcome in tamoxifen treated patients and deserves incorporation in future clinical studies.

Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH.

BACKGROUND: While new defects in BRCA1 are still being found, it is unclear whether current breast cancer diagnostics misses many BRCA1-associated cases. A reliable test that is able to indicate the involvement of BRCA1 deficiency in cancer genesis could support decision making in genetic counselling and clinical management. To find BRCA1-specific markers and explore the effectiveness of the current diagnostic strategy, we designed a classification method, validated it and examined whether we could find BRCA1-like breast tumours in a group of patients initially diagnosed as non-BRCA1/2 mutation carriers. METHODS: A classifier was built based on array-CGH profiles of 18 BRCA1-related and 32 control breast tumours, and validated on independent sets of 16 BRCA1-related and 16 control breast carcinomas. Subsequently, we applied the classifier to 48 breast tumours of patients from Hereditary Breast and Ovarian Cancer (HBOC) families in whom no germ line BRCA1/BRCA2 mutations were identified. RESULTS: The classifier showed an accuracy of 91% when applied to the validation sets. In 48 non-BRCA1/2 patients, only two breast tumours presented a BRCA1-like CGH profile. Additional evidence for BRCA1 dysfunction was found in one of these tumours. CONCLUSION: We here describe the specific chromosomal aberrations in BRCA1-related breast carcinomas. We developed a predictive genetic test for BRCA1-association and show that BRCA1-related tumours can still be identified in HBOC families after routine DNA diagnostics.

ATBF1 and NQO1 as candidate targets for allelic loss at chromosome arm 16q in breast cancer: absence of somatic ATBF1 mutations and no role for the C609T NQO1 polymorphism.

BACKGROUND: Loss of heterozygosity (LOH) at chromosome arm 16q is frequently observed in human breast cancer, suggesting that one or more target tumor suppressor genes (TSGs) are located there. However, detailed mapping of the smallest region of LOH has not yet resulted in the identification of a TSG at 16q. Therefore, the present study attempted to identify TSGs using an approach based on mRNA expression. METHODS: A cDNA microarray for the 16q region was constructed and analyzed using RNA samples from 39 breast tumors with known LOH status at 16q. RESULTS: Five genes were identified to show lower expression in tumors with LOH at 16q compared to tumors without LOH. The genes for NAD(P)H dehydrogenase quinone (NQO1) and AT-binding transcription factor 1 (ATBF1) were further investigated given their functions as potential TSGs. NQO1 has been implicated in carcinogenesis due to its role in quinone detoxification and in stabilization of p53. One inactive polymorphic variant of NQO1 encodes a product showing reduced enzymatic activity. However, we did not find preferential targeting of the active NQO1 allele in tumors with LOH at 16q. Immunohistochemical analysis of 354 invasive breast tumors revealed that NQO1 protein expression in a subset of breast tumors is higher than in normal epithelium, which contradicts its proposed role as a tumor suppressor gene.ATBF1 has been suggested as a target for LOH at 16q in prostate cancer. We analyzed the entire coding sequence in 48 breast tumors, but did not identify somatic sequence changes. We did find several in-frame insertions and deletions, two variants of which were reported to be somatic pathogenic mutations in prostate cancer. Here, we show that these variants are also present in the germline in 2.5% of 550 breast cancer patients and 2.9% of 175 healthy controls. This indicates that the frequency of these variants is not increased in breast cancer patients. Moreover, there is no preferential LOH of the wildtype allele in breast tumors. CONCLUSION: Two likely candidate TSGs at 16q in breast cancer, NQO1 and ATBF1, were identified here as showing reduced expression in tumors with 16q LOH, but further analysis indicated that they are not target genes of LOH. Furthermore, our results call into question the validity of the previously reported pathogenic variants of the ATBF1 gene.

Prognostic significance of macrophage infiltration in leiomyosarcomas.

PURPOSE: Macrophages are migratory cells that are frequently recruited to the site of tumors. Their presence is associated with poor clinical outcome in a variety of epithelial malignancies. The aim of this study is to examine the prognostic significance of tumor-associated macrophages in sarcomas. EXPERIMENTAL DESIGN: Global gene expression profiling data of a series of soft tissue tumors were analyzed for macrophage-associated gene expression. Immunohistochemistry on tissue microarrays containing leiomyosarcoma cases with known clinical outcome was used to verify the presence of macrophages and to examine the relationship between tumor-associated macrophages and clinical outcome. RESULTS: Gene expression profiling revealed high-level expression of several macrophage-associated genes such as CD163 and CD68 in a subset of leiomyosarcomas, indicating the presence of variable numbers of tumor-infiltrating macrophages. This was confirmed by CD68 and CD163 immunostaining of a tissue microarray containing 149 primary leiomyosarcomas. Kaplan-Meier survival analysis showed that high density of tumor-infiltrating macrophages as identified by CD163 or CD68 staining is associated with a significantly worse disease-specific survival in nongynecologic leiomyosarcomas, whereas leiomyosarcomas arising from the gynecologic tract showed no significant association between macrophage infiltration and survival. The presence of tumor necrosis did not correlate significantly with outcome. CONCLUSIONS: An increased density of CD163- or CD68-positive tumor-infiltrating macrophages is associated with poor outcome in nongynecologic leiomyosarcomas. This may help the clinical management of patients with leiomyosarcomas.

Clinical outcome after selective treatment of patients diagnosed with ductal carcinoma in situ of the breast.

BACKGROUND: The effect of treatment of patients diagnosed with ductal carcinoma in situ (DCIS) of the breast was evaluated, and factors associated with local recurrence were assessed. METHODS: The study involved 504 patients treated by means of wide local excision alone (WLE) (n = 91), wide local excision and radiotherapy (WLE+RT) (n = 119), or mastectomy (n = 294) at the Netherlands Cancer Institute between 1986 and 2005. Clinical, pathological, and follow-up data were evaluated. RESULTS: The median time to follow-up was 6.7 years. The 8-year overall local recurrence rate was 12% after breast-conserving treatment (BCT) [15.6% after WLE and 8.8% after WLE+RT (P = 0.161)] and 0.9% after mastectomy (P < 0.0001). In total, 18 (66.7%) invasive local recurrences and 9 (33.3%) DCIS local recurrences occurred. The 8-year distant metastasis rate was 4% after BCT [4.3% after WLE and 4.2% after WLE+RT (P = 0.983)] and 0.9% after mastectomy (P = 0.048). Median tumor extent was 10, 15, and 35 mm for patients treated with WLE, WLE+RT, and mastectomy, respectively. Margins were involved in 6.4% of all patients. Factors associated with local recurrence were age younger than 40 years (HR 8.66), surgical margin involvement (HR 5.75), WLE (HR 26.77), and WLE+RT (HR 7.42). CONCLUSION: BCT of DCIS bears the risk of residual disease progressing into invasive local recurrence and distant metastasis. A re-excision or mastectomy is therefore desired in all patients with unclear margins. Mastectomy treatment is associated with optimal local control and might be considered for patients younger than 40 years who are at high risk of local recurrence.

Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER).

BACKGROUND: A microarray-based 70-gene prognosis signature might improve the selection of patients with node-negative breast cancer for adjuvant systemic treatment. The main aims of this MicroarRAy PrognoSTics in Breast CancER (RASTER) study were to assess prospectively the feasibility of implementation of the 70-gene prognosis signature in community-based settings and its effect on adjuvant systemic treatment decisions when considered with treatment advice formulated from the Dutch Institute for Healthcare Improvement (CBO) and other guidelines. METHODS: Between January, 2004 and December, 2006, 812 women aged under 61 years with primary breast carcinoma (clinical T1-4N0M0) were enrolled. Fresh tumour samples were collected in 16 hospitals in the Netherlands within 1 h after surgery. Clinicopathological factors were collected and microarray analysis was done with a custom-designed array chip that assessed the mRNA expression index of the 70 genes previously identified for the prognostic signature. Patients with a "good" signature were deemed to have a good prognosis and, therefore, could be spared adjuvant systemic treatment with its associated adverse effects, whereas patients with a "poor" signature were judged to have a poor prognosis and should be considered for adjuvant systemic treatment. Concordance between risk predicted by the prognosis signature and risk predicted by commonly used clinicopathological guidelines (ie, St Gallen guidelines, Nottingham Prognostic Index, and Adjuvant! Online) was assessed. FINDINGS: Of 585 eligible patients, 158 patients were excluded because of sampling failure (n=128) and incorrect procedure (n=30). Prognosis signatures were assessed in 427 patients. The 70-gene prognosis signature identified 219 (51%) patients with good prognosis and 208 (49%) patients with poor prognosis. The Dutch CBO guidelines identified 184 patients (43%) with poor prognosis, which was discordant with those findings obtained with the prognosis signature in 128 (30%) patients. Oncologists recommended adjuvant treatment in 203 (48%) patients based on Dutch CBO guidelines, in 265 (62%) patients if the guidelines were used with the prognosis signature, and in 259 (61%) patients if Dutch CBO guidelines, prognosis signature, and patients' preferences for treatment were all taken into account. Adjuvant! Online guidelines identified more patients with poor prognosis than did the signature alone (294 [69%]), and discordance with the signature occurred in 160 (37%) patients. St Gallen guidelines identified 353 (83%) patients with poor prognosis with the signature and discordance in 168 (39%) patients. Nottingham Prognostic Index recorded 179 (42%) patients with poor prognosis with the signature and discordance in 117 (27%) patients. INTERPRETATION: Use of the prognosis signature is feasible in Dutch community hospitals. Adjuvant systemic treatment was advised less often when the more restrictive Dutch CBO guidelines were used compared with that finally given after use of the prognosis signature. For the other guidelines assessed, less adjuvant chemotherapy would be given when the data based on prognosis signature alone are used, which might spare patients from adverse effects and confirms previous findings. Future studies should assess whether use of the prognosis signature could improve survival or equal survival while avoiding unnecessary adjuvant systemic treatment without affecting patients' survival, and further assess the factors that physicians use to recommend adjuvant systemic treatment.

Validation of clinical prediction rules for a low probability of nonsentinel and extensive lymph node involvement in breast cancer patients.

BACKGROUND: Two recently developed clinical prediction rules aim to anticipate the lack of nonsentinel lymph node metastases and the involvement of less than 4 lymph nodes in breast cancer patients with positive sentinel lymph nodes (SLNs). METHODS: The University of Louisville Breast SLN Study clinical prediction rules were validated on an independent set of SLN-positive patients with tumors < or = 15 mm. RESULTS: The data on 475 and 473 patients, respectively, were used for the validation. The areas under the receiver operating characteristic curves were similar to the originals for both predictive tools (.70 and .76). The lowest score of 1 identified 5 of 7 patients with disease limited to the SLNs and 161 of 165 as having less than 4 involved lymph nodes. CONCLUSIONS: A subset of patients with SLN-only involvement and less than 4 metastatic lymph nodes can probably be identified by means of the Louisville clinical prediction rules, but prediction of the lack of non-SLN metastasis seems less reliable.

Squamous cell carcinoma in situ of the breast: a light microscopic and immunohistochemical study of a previously undescribed lesion.

Three cases of squamous carcinoma in situ of the breast, one with an invasive component are described in women aged 35, 51, and 59 years. Two cases were detected by screening mammography. In 1 case, the squamous ductal carcinoma in situ was extensive. All cases showed obvious squamous features on standard hematoxylin and eosin sections. The in situ component of the lesions and the squamous differentiation were supported by immunohistochemistry. In 2 cases, the neoplastic cells showed actin positivity indicating myoepithelial cell differentiation. One case showed trilineage differentiation into luminal, squamous, and myoepithelial cells. These cases illustrate a variant of duct carcinoma in situ that has not been described in the current literature and provide insights into the dual epithelial-myoepithelial differentiation of some breast neoplasms.

Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer.

Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1- and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.

Sentinel lymph node biopsy and non-sentinel node involvement in special type breast carcinomas with a good prognosis.

This study aimed at identifying factors related to sentinel lymph node (SLN) involvement in patients with tubular, cribriform, mucinous or papillary breast carcinoma and those related to non-SLN metastases if an SLN was positive. Multivariate analyses involved logistic and stepwise regressions. The SLNs harboured metastases in 85 of 572 cases, 78 of whom underwent axillary dissection; 19 presented non-SLN positive disease. Lack of lymphovascular invasion, a tumour size < or = 10 mm and a single SLN removed were the factors predicting an SLN metastasis rate <10%, and patients with these features could be candidates for no surgical axillary staging. A positive SLN proportion of < or = 50% and no lymphovascular invasion were associated with a <10% rate of non-SLN invasion; patients with a positive SLN and these features could be candidates for the omission of completion axillary dissection. The opposite presentation of these factors would mandate SLN biopsy and axillary dissection, respectively.

Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study.

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.

Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation.

PURPOSE: Women carrying a CHEK2*1100delC germline mutation have an increased risk of developing breast cancer. This study aims to determine the proportion of CHEK2*1100delC carriers in a premenopausal breast cancer population, unselected for family history of breast cancer, and to investigate tumor characteristics and disease outcome with sufficient follow-up. PATIENTS AND METHODS: We identified a retrospective cohort of 1,479 patients, who received surgery for invasive breast cancer between 1970 and 1994. All patients were diagnosed before age 50. Paraffin-embedded tissue blocks were collected for DNA isolation (normal tissue), subsequent CHEK2*1100delC analysis, and tumor revision. Median follow-up was 10.1 years. RESULTS: We detected a CHEK2*1100delC germline mutation in 54 patients (3.7%). Tumor characteristics of CHEK2*1100delC carriers did not differ significantly from those of noncarriers. CHEK2*1100delC carriers had a two-fold increased risk (hazard ratio [HR], 2.1; 95% CI, 1.0 to 4.3; P = .049) of developing a second breast cancer and they had worse recurrence-free survival (HR, 1.7; 95% CI, 1.2 to 2.4; P = .006) and worse breast cancer-specific survival (HR, 1.4; 95% CI, 1.0 to 2.1; P = .072) compared with noncarriers. The poorer disease outcome of CHEK2*1100delC carriers could not be explained by the increased risk of second breast cancer. CONCLUSION: Our study, which is representative for the premenopausal breast cancer population, reveals approximately 4% CHEK2*1100delC carriers have an increased risk of second breast cancer and a worse long-term recurrence-free survival rate. Their identification at time of diagnosis and prolonged intensive follow-up should be considered to optimize clinical management.

Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.

Metastatic disease is the primary cause of death in breast cancer, the most common malignancy in Western women. Loss of E-cadherin is associated with tumor metastasis, as well as with invasive lobular carcinoma (ILC), which accounts for 10%-15% of all breast cancers. To study the role of E-cadherin in breast oncogenesis, we have introduced conditional E-cadherin mutations into a mouse tumor model based on epithelium-specific knockout of p53. Combined loss of E-cadherin and p53 resulted in accelerated development of invasive and metastatic mammary carcinomas, which show strong resemblance to human ILC. Moreover, loss of E-cadherin induced anoikis resistance and facilitated angiogenesis, thus promoting metastatic disease. Our results suggest that loss of E-cadherin contributes to both mammary tumor initiation and metastasis.

Classification of ductal carcinoma in situ by gene expression profiling.

INTRODUCTION: Ductal carcinoma in situ (DCIS) is characterised by the intraductal proliferation of malignant epithelial cells. Several histological classification systems have been developed, but assessing the histological type/grade of DCIS lesions is still challenging, making treatment decisions based on these features difficult. To obtain insight in the molecular basis of the development of different types of DCIS and its progression to invasive breast cancer, we have studied differences in gene expression between different types of DCIS and between DCIS and invasive breast carcinomas. METHODS: Gene expression profiling using microarray analysis has been performed on 40 in situ and 40 invasive breast cancer cases. RESULTS: DCIS cases were classified as well- (n = 6), intermediately (n = 18), and poorly (n = 14) differentiated type. Of the 40 invasive breast cancer samples, five samples were grade I, 11 samples were grade II, and 24 samples were grade III. Using two-dimensional hierarchical clustering, the basal-like type, ERB-B2 type, and the luminal-type tumours originally described for invasive breast cancer could also be identified in DCIS. CONCLUSION: Using supervised classification, we identified a gene expression classifier of 35 genes, which differed between DCIS and invasive breast cancer; a classifier of 43 genes could be identified separating between well- and poorly differentiated DCIS samples.

Ultrasonography and fine-needle aspiration cytology in the preoperative evaluation of melanoma patients eligible for sentinel node biopsy.

BACKGROUND: Ultrasonography with fine-needle aspiration cytology (FNAC) has proven to be a valuable diagnostic tool in the preoperative workup of patients with breast cancer or penile cancer eligible for sentinel lymph node biopsy. The aim of this study was to evaluate the use of this technique in the initial assessment of patients with primary cutaneous melanoma. METHODS: A total of 107 patients with cutaneous melanoma eligible for sentinel node biopsy with clinically negative nodes were studied prospectively. Patients underwent ultrasonography of potentially involved basins and FNAC in case of a suspicious lymph node. The sentinel node procedure was omitted in patients with tumour-positive lymph nodes in lieu of lymph node dissection. RESULTS: Ultrasonography with FNAC correctly identified disease preoperatively in two of the 107 patients (2%). Thirteen of the 22 patients (59%) with a suspicious node on ultrasonographic imaging but a tumour-negative fine-needle aspirate were shown to have involved nodes. Of the 85 patients with ultrasonographically normal nodes, 25 (29%) were shown to have metastases. Of the total of 43 involved basins, 16 contained metastases > 2 mm and 25 < or = 2 mm. CONCLUSIONS: In our hands, the sensitivity and specificity of preoperative ultrasonography to detect lymph node involvement in patients with melanoma are 34% and 87%, respectively. In combination with FNAC, this is 4.7% and 100%, respectively. This yield is insufficient for this technique to be used as a routine diagnostic tool in the selection of patients eligible for sentinel node biopsy.

Additional axillary metastases and stage migration in breast cancer patients with micrometastases or submicrometastases in sentinel lymph nodes.

BACKGROUND: In patients with breast cancer, micrometastases and submicrometastases are increasingly found in sentinel nodes when step sectioning and/or immunohistochemical staining are applied. The aims of the current study were to investigate the incidence of micro- and submicrometastases in the sentinel node, to estimate the risk of additional metastases in the remaining axillary lymph nodes, and to consider implications for staging and treatment. METHODS: A total of 2150 breast cancer patients who had undergone axillary sentinel node biopsy between 1999 and 2004 were retrospectively evaluated. RESULTS: In all, 649 patients (30%) had a tumor-positive axillary sentinel node. Of these 649 patients, 148 had (23%) micrometastases and 105 (16%) submicrometastases. Of the 148 patients with micrometastases, 106 underwent axillary lymph node dissection (ALND) and additional metastases were found in 20 patients (19%). Sixteen (15%) had macrometastases and were upstaged. The other 4 patients had additional micrometastases. Seven of the 106 patients (7%) received additional systemic treatment based on the findings in the axillary lymph nodes. Fifty-four of the 105 patients with submicrometastases underwent ALND. Two (4%) of them had additional macrometastases and were upstaged and 2 had additional micrometastases. None received additional treatment based on the ALND findings. CONCLUSIONS: Of the involved sentinel nodes, 23% contained micrometastases and 16% submicrometastases. Additional macrometastases were found in 15% and 4%, respectively, and treatment was altered in 7%. Based on these findings, offering additional treatment of the axilla is suggested in patients with micrometastases, but refraining from ALND in patients with submicrometastases in their sentinel node.

Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group.

PURPOSE: The European Organisation for Research and Treatment of Cancer conducted a randomized trial investigating the role of radiotherapy (RT) after local excision (LE) of ductal carcinoma-in-situ (DCIS) of the breast. We analyzed the efficacy of RT with 10 years follow-up on both the overall risk of local recurrence (LR) and related to clinical, histologic, and treatment factors. PATIENTS AND METHODS: After complete LE, women with DCIS were randomly assigned to no further treatment or RT (50 Gy). One thousand ten women with mostly (71%) mammographically detected DCIS were included. The median follow-up was 10.5 years. RESULTS: The 10-year LR-free rate was 74% in the group treated with LE alone compared with 85% in the women treated by LE plus RT (log-rank P < .0001; hazard ratio [HR] = 0.53). The risk of DCIS and invasive LR was reduced by 48% (P = .0011) and 42% (P = .0065) respectively. Both groups had similar low risks of metastases and death. At multivariate analysis, factors significantly associated with an increased LR risk were young age (< or = 40 years; HR = 1.89), symptomatic detection (HR = 1.55), intermediately or poorly differentiated DCIS (as opposed to well-differentiated DCIS; HR = 1.85 and HR = 1.61 respectively), cribriform or solid growth pattern (as opposed to clinging/micropapillary subtypes; HR = 2.39 and HR = 2.25 respectively), doubtful margins (HR = 1.84), and treatment by LE alone (HR = 1.82). The effect of RT was homogeneous across all assessed risk factors. CONCLUSION: With long-term follow-up, RT after LE for DCIS continued to reduce the risk of LR, with a 47% reduction at 10 years. All patient subgroups benefited from RT.

Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy.

BACKGROUND: Some 30% to 40% of the breast cancer patients scheduled for sentinel node biopsy have axillary metastasis. Pilot studies suggest that ultrasonography is useful in the preoperative detection of such nodes. The aims of this study were to evaluate the sensitivity of preoperative ultrasonography and fine-needle aspiration cytology for detecting axillary metastases and to assess how often sentinel node biopsy could be avoided. METHODS: Between October 1999 and December 2003, 726 patients with clinically negative lymph nodes were eligible for sentinel node biopsy. A total of 732 axillae were examined. Preoperative ultrasonography with subsequent fine-needle aspiration cytology in case of suspicious lymph nodes was performed in all patients. The sentinel node procedure was omitted in patients with tumor-positive axillary lymph nodes in lieu of axillary lymph node dissection. RESULTS: Ultrasound and fine-needle aspiration cytology established axillary metastases in 58 (8%) of the 726 patients. These 58 were 21% of the total of 271 patients who were proven to have axillary metastasis in the end. Of the patients with ultrasonographically suspicious lymph nodes and negative cytology, 31% had tumor-positive sentinel nodes. Patients with preoperatively established metastases by ultrasonography and fine-needle aspiration cytology had more tumor-positive lymph nodes (P < .001) than patients with metastases established later on. CONCLUSIONS: The sensitivity of ultrasonography and fine-needle aspiration cytology is 21%, and unnecessary sentinel node biopsy is avoided in 8% of the patients. This approach improves the selection of patients eligible for sentinel node biopsy.