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Background: Collagen type XI, alpha 1 (COL11A1) is a minor component of extracellular matrix and its overexpression is associated with tumoral progression and poorer outcome in several human cancers; data on breast cancer are promising but scarce. FGD3 expression has been shown to be a strong independent prognostic factor in breast cancer. The aim of our study was to investigate whether COL11A1 expression correlates with other classic pathologic prognostic factors including FGD3 expression, as well as with clinical outcome, to evaluate its potential use as prognostic factor in breast cancer patients. Methods: We evaluated by immunohistochemistry COL11A1 expression and we studied the relationship between this protein expression and traditional breast cancer prognostic factors, FGD3 expression, as well as with patients’ outcome. Results: We found that higher stromal COL11A1 expression was associated with higher tumour grade (G3) (p = 0.001), higher Ki67 proliferation index (p = 0.006), more advanced AJCC stage (p = 0.031) and lower FGD3 expression (p = 0.039). In a case-control analysis, we observed that patients with high-COL11A1 had a higher risk of recurrence (OR = 2.0) and of dying of the disease (OR = 2.0). Patients with high-COL11A1-expressing tumours had shorter disease-free survival and overall survival (difference not significant). There was a linear positive correlation between COL11A1 expression on epithelial tumoral cells and surrounding stromal cells (r = 0.247, p = 0.04). Conclusion: Our findings suggest that COL11A1 may represent a marker of aggressiveness in invasive breast cancer and that its detection warrants further study on larger series to evaluate its possible use in clinical practice.

Invasive ductal carcinoma (IDC) constitutes the most frequent malignant cancer endangering women’s health. In this study, a new spontaneously immortalized breast cancer cell line, DHSF-BR16 cells, was isolated from the primary IDC of a 74-years old female patient, treated with neoadjuvant chemotherapy and disease-free 5-years after adjuvant chemotherapy. Primary breast cancer tissue surgically removed was classified as ER−/PR−/HER2+, and the same phenotype was maintained by DHSF-BR16 cells. We examined DHSF-BR16 cell morphology and relevant biological and molecular markers, as well as their response to anticancer drugs commonly used for breast cancer treatment. MCF-7 cells were used for comparison purposes. The DHSF-BR16 cells showed the ability to form spheroids and migrate. Furthermore, DHSF-BR16 cells showed a mixed stemness phenotype (i.e. CD44+/CD24−/low), high levels of cytokeratin 7, moderate levels of cytokeratin 8 and 18, EpCAM and E-Cadh. Transcriptome analysis showed 2071 differentially expressed genes between DHSF-BR16 and MCF-7 cells (logFC > 2, p-adj

Objective Incidental diagnosis of thyroid nodules, and therefore of thyroid cancer, has definitely increased in recent years, but the mortality rate for thyroid malignancies remains very low. Within this landscape of overdiagnosis, several nodule ultrasound scores (NUS) have been proposed to reduce unnecessary diagnostic procedures. Our aim was to verify the suitability of five main NUS. Methods This single-center, retrospective, observational study analyzed a total number of 6474 valid cytologies. A full clinical and US description of the thyroid gland and nodules was performed. We retrospectively applied five available NUS: KTIRADS, ATA, AACE/ACE-AME, EUTIRADS, and ACRTIRADS. Thereafter, we calculated the sensitivity, specificity, PPV, and NPV, along with the number of possible fine-needle aspiration (FNA) sparing, according to each NUS algorithm and to clustering risk classes within three macro-groups (low, intermediate, and high risk). Results In a real-life setting of thyroid nodule management, available NUS scoring systems show good accuracy at ROC analysis (AUC up to 0.647) and higher NPV (up to 96%). The ability in FNA sparing ranges from 10 to 38% and reaches 44.2% of potential FNA economization in the low-risk macro-group. Considering our cohort, ACRTIRADS and AACE/ACE-AME scores provide the best compromise in terms of accuracy and spared cytology. Conclusions Despite several limitations, available NUS do appear to assist physicians in clinical practice. In the context of a common disease, such as thyroid nodules, higher accuracy and NPV are desirable NUS features. Further improvements in NUS sensitivity and specificity are attainable future goals to optimize nodule management. Key Points • Thyroid nodule ultrasound scores do assist clinicians in real practice. • Ultrasound scores reduce unnecessary diagnostic procedures, containing indolent thyroid microcarcinoma overdiagnosis. • The variable malignancy risk of the “indeterminate” category negatively influences score’s performance in real-life management of thyroid lesions.

Context Despite the wide revision of current guidelines, the management of papillary thyroid microcarcinoma (mPTC) still has to be decided case by case. There is conflicting evidence about the role of more frequent histological subtypes, and no data about potential differences at presentation. Objective Our aim was to compare the phenotype of the 2 most frequent mPTC variants, namely, classical papillary thyroid microcarcinoma (mPTCc) and the follicular variant of papillary thyroid microcarcinoma (mFVPTC) . Methods Retrospective observational study, from January 2008 to December 2017 of a consecutive series of patients with mPTCc and mFVPTC. All cases were classified according to the 2015 American Thyroid Association (ATA) risk classification. Clinical and preclinical features of mPTCc and mFVPTC at diagnosis were collected. The comparison was also performed according to the incidental/nonincidental diagnosis and differences were verified by binary logistic analysis. Results In total, 235 patients were eligible for the analysis (125 and 110 mPTCc and mFVPTC, respectively). Compared with mPTCc, mFVPTCs were more often incidental and significantly smaller (4 vs 7 mm) (P < .001 all), possibly influenced by the higher rate of incidental detection. mFVPTC and incidental (P < .001 both) tumors were significantly more often allocated within the low-risk class. A logistic regression model, with ATA risk class as the dependent variable, showed that both mFVPTC (OR 0.465 [0.235-0.922]; P = .028]) and incidental diagnosis (OR 0.074 [0.036-0.163]; P < .001) independently predicted ATA risk stratification. Conclusion mFVPTC shows some differences in diagnostic presentation compared with mPTCc, and seems to retain a significant number of favorable features, including a prevalent onset as incidental diagnosis.

The FGD3 gene works as a cell migration inhibitor and seems to be a promising indicator of outcome in some human cancers including breast. In this study, we analysed for the first time the prognostic role of FGD3 in young breast cancer patients. We studied the relationship between traditional prognostic factors, FGD3 expression and outcome in ≤40 years breast cancer patients. We found that lower FGD3 expression decreased the probability of disease-free survival (p = 0.042) and overall survival (p = 0.007). In a multivariate analysis for overall survival AJCC stage (p = 0.005) and FGD3 expression (p = 0.03) resulted independent prognostic factors. Low FGD3 expression increased the risk of death from disease (HR 5.73, p = 0.03). Moreover, low FGD3 expression was associated with more widespread lymph node involvement (p = 0.04) and a lower FGD3 staining intensity was found in positive-lymph-node patients vs negative (p = 0.003) and in patients with ≥10 involved lymph nodes vs p = 0.05). Our results suggest FGD3 to be a significant independent prognostic factor in young breast cancer patients in terms of disease-free survival and overall survival. A lower expression increased the risk of recurrence and death from disease and was associated with widespread lymph node metastases.

Invasive ductal carcinoma (IDC) constitutes the most frequent malignant cancer endangering women’s health. In this study, a new spontaneously immortalized breast cancer cell line, DHSF-BR16 cells, was isolated from the primary IDC of a 74-years old female patient, treated with neoadjuvant chemotherapy and disease-free 5-years after adjuvant chemotherapy. Primary breast cancer tissue surgically removed was classified as ER−/PR−/HER2+, and the same phenotype was maintained by DHSF-BR16 cells. We examined DHSF-BR16 cell morphology and relevant biological and molecular markers, as well as their response to anticancer drugs commonly used for breast cancer treatment. MCF-7 cells were used for comparison purposes. The DHSF-BR16 cells showed the ability to form spheroids and migrate. Furthermore, DHSF-BR16 cells showed a mixed stemness phenotype (i.e. CD44+/CD24−/low), high levels of cytokeratin 7, moderate levels of cytokeratin 8 and 18, EpCAM and E-Cadh. Transcriptome analysis showed 2071 differentially expressed genes between DHSF-BR16 and MCF-7 cells (logFC > 2, p-adj

Background Invasive triple negative apocrine carcinoma (TNAC) of the breast is a rare type of triple negative breast cancer. Several studies reported significantly distinct prognosis for TNAC when compared with most of the non-apocrine triple negative (NATN) tumors. This is a case-control study reporting onoutcomes from our long-term single-center experience. Patients and Methods We analyzed the clinicopathologic features of a series of 46 TNAC tumors treated in a 15-year period. Tumor characteristics and outcomes have been compared with a homogeneous control series of 43 NATN tumors treated during the same follow-up period. Local relapse-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) have been evaluated. Results LRFS in the TNAC group was 85% and 78% at 5 and 10 years, respectively. LRFS in the NATN group was 90% and 79% at 5 and 10 years, respectively (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.41-3.19; P = .80). DMFS in the TNAC group was 85% and 85% at 5 and 10 years, respectively. DMFS in the NATN group was 85% and 75% at 5 and 10 years, respectively (HR, 0.39; 95% CI, 0.14-1.08; P = .071). OS in the TNAC group was 86% and 83% at 5 and 10 years, respectively. OS in the NATN group was 86% and 63% at 5 and 10 years, respectively. OS was significantly better in the TNAC group (HR, 0.45; 95% CI, 0.20-0.99; P = .049). Conclusions TNAC seems to represent a distinct group of triple negative breast cancer, characterized by a favorable long-term outcome when compared with NATN tumors.

Aim Male breast cancer (MBC) is a rare disease and recommendations for its clinical management are often extrapolated from those for female breast cancer, even if breast cancer (BC) has different characteristics in the two sexes. The purpose of this study was to assess the influence of several individual characteristics including clinico-pathological, lifestyle and genetic factors on overall survival (OS) of a relatively large and well characterized population-based series of 166 MBCs enrolled in Tuscany. Methods We genotyped MBC cases at BRCA1/2 genes and at 9 candidate BC susceptibility SNPs. Kaplan-Meier method and multivariate Cox regression, adjusted for several individual characteristics were used. To reduce a possible selection bias related to the interval between diagnosis and enrolment of MBC cases into the study, we used the date of blood donation as the date of the start of observation for survival analysis. Results Only smoking habits had a significant effect on OS at 10 years (for current smokers, HR: 3.34; 95% CI 1.45–7.68; p = 0.004), while lymph node status fell short of reaching statistical significance (for pN positive, HR: 2.07; 95% CI 0.93–4.55; p = 0.07). In the same multivariate analysis we found a significantly higher OS in cases with FGFR2 rs2981582 variant in the dominant transmission model (HR: 0.29; 95% CI: 0.13–0.62; p = 0.028). A sensitivity analysis with left truncation showed similar results. Conclusions Our results may contribute to shed light on factors influencing MBC survival suggesting an important role for cigarette smoking and FGFR2 rs2981582 variant, and provide clues for better patient management.

Background Breast cancer (BC) is the most frequent malignancy among females worldwide. Despite several efforts and improvements in early diagnosis and treatment, there are still tumors characterized by an aggressive behavior due to unfavorable biology, thus quite difficult to treat. In this view, searching for novel potential biomarkers is mandatory. Among them, in the recent years data have been gathered addressing ion channel as important players in oncology. Methods A retrospective pilot study was performed on 40 BC samples by means of immunohistochemistry in order to evaluate hERG1 potassium channels expression in BC. Results We provide evidence that hERG1 is expressed in all the BC samples analyzed. hERG1 expression was significantly associated with molecular subtype with the highest expression in Luminal A and the lowest in basal-like tumors (p = 0.001), tumor grading (the highest hERG1 expression in well-moderate differentiated tumors, p = 0.020), estrogen receptors (high hERG1 expression in ER-positive samples, p = 0.008) and Ki67 proliferative index (high hERG1 scoring in samples with low proliferative index, p = 0.038). Also, a p value close to significance was noticed for the association between hERG1 and HER2 expression (p = 0.079). At the survival analysis, patients with high hERG1 expression turned out to have a longer progression-free survival, although statistical significance was not reached (p = 0.195). The same trend was observed analyzing local relapse free-survival (LRFS) and metastases-free survival (MFS): patients with higher hERG1 scoring had longer LRFS and MFS (p = 0.124 and p = 0.071, respectively). Conclusions The results of this pilot study provide the first evidence that the hERG1 protein is expressed in primary BC, and its expression associates with molecular subtype. hERG1 apparently behaves as a protective factor, since it contributes to identify a subset of patients with better outcome. Overall, these data suggest that hERG1 might be an additional tool for the management of BC, nevertheless further investigations are warranted to better clarify hERG1 role and clinical usefulness in BC.

Background and Objectives. Breast-conserving surgery represents the standard of care for the treatment of small breast cancers. However, there is a population of patients who cannot undergo the standard surgical procedures due to several reasons such as age, performance status, or comorbidity. Our aim was to investigate the feasibility and safety of percutaneous US-guided laser ablation for unresectable unifocal breast cancer (BC). Methods. Between December 2012 and March 2017, 12 consecutive patients underwent percutaneous US-guided laser ablation as radical treatment of primary inoperable unifocal BC. Results. At median follow-up of 28.5 months (range 6-51), no residual disease or progression occurred; the overall success rate for complete tumor ablation was therefore 100%. No significant operative side effects were observed, with only 2 (13.3%) experiencing slight to mild pain during the procedure, and all patients complained of a mild dull aching pain in the first week after procedure. Conclusions. Laser ablation promises to be a safe and feasible approach in those patients who are not eligible to the standard surgical approach. However, longer follow-up results and larger studies are strongly needed.

Microinvasive breast cancer is a rare entity in which an invasive component not exceeding 1 mm is found, mostly in a ductal carcinoma in situ setting. Its diagnosis can be difficult and must rely upon immunohistochemistry markers. Many studies have analyzed pathological characteristics of this cancer to delineate its biological profile and possibly identify risk factors of axillary lymph nodes infiltration, which might be present and therefore clinically relevant. Starting from a relative large number of cases we aimed to analyze pathological data, cancer subtypes distribution, and their correlation to nodal metastasis, comparing our results to the existing recent literature. All cases of microinvasive breast cancer were retrieved from institutional database from 1992 to 2014. Pathological parameters were analyzed for entire cohort. Moreover, cases submitted to standardized sentinel node biopsy in a restricted period, 2000–2014, were selected to correlate pathology and cancer subtype to axillary lymph nodes status. 174 cases (1.4 % of operated breast cancers) were evaluated in the larger period, 1992–2014. Neither specific pathological parameters were expressed nor a peculiar cancer subtype was represented. 126 cases were selected for axillary staging analysis. Eighteen cases (14.3 %) had lymph nodes metastasis, 10 ITCs (7.9 %), 3 micrometastases (2.4 %), and 5 macrometastases (4 %). An associated intraductal component of carcinoma over 20 mm in maximum dimension resulted significant at multivariate analysis, but only if including ITCs, while this risk factor was not reproduced for micro- and macrometastases only. Microinvasive breast cancer does not seem to have specific pathological and biological traits. An associated intraductal component of carcinoma >20 mm in size is a specific risk factor for ITCs nodal metastasis. Its clinical significance is anyway limited and therefore sentinel node biopsy should be performed case by case and not routinely.

Epithelioid angiosarcoma of the thyroid is a rare mesenchymal neoplasm, mainly described in the Alpine area. This lesion was initially considered an anaplastic carcinoma, but immunohistochemical and ultrastructural features have proven the endothelial differentiation of tumor cells. In fact, the peculiarity of this tumor concerns the expression of low-molecular weight cytokeratins by neoplastic cells of endothelial origin. We describe a case of epithelioid angiosarcoma of the thyroid occurred in a 73-year-old woman from an Italian non-Alpine area, and a review of non-Alpine primary thyroid epitheliod angiosarcoma is presented.

The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.

Aims Image-guided 14-gauge (G) core biopsy (CB) has been shown to be an accurate method providing histological diagnosis of breast lesions. The purpose of this study was to evaluate the reliability of image-guided 14-G CB in the diagnosis of phyllodes tumours (PT) reported as B3 category and its accuracy in distinguishing this lesion from fibroadenomas (FA). Materials and methods The records of 10 000 image-guided 14-G CB of the breast performed from January 2001 to August 2011 at the Diagnostic Senology Unit of Careggi University Hospital were reviewed; 2554 (25.5%) were fibroepithelial lesions: 56 of them (2%) were diagnosed as PT and reported as B3 category. The database of the Pathological Anatomy Unit of Careggi University Hospital was then searched to verify the histological diagnosis after surgical excision. Fifty-one cases of PT diagnosed as B3 category in 51 women were included in the present study. Results Of the 51 cases of PT diagnosed as B3 category on 14-G CB, 39 (76.5%) lesions were confirmed as PT on SE (30, 4 and 5 as benign, borderline and malignant PT respectively) with a PPV of 76.5%. Twelve lesions (23.5%) were diagnosed as FA after surgical excision. Conclusions Our study shows that 14-G CB is a valuable tool, in a preoperative setting, in diagnosing PT.

The purpose of this study is to describe a case of concurrent medullary and papillary thyroid carcinoma (MTC and PTC) and cutaneous melanoma and to analyze BRAF(V600E) mutation in plasma and tissues. We report the clinical history and the laboratory, imaging, and histopathological findings of a 47-year-old man affected by multinodular goiter. BRAF(V600E)-mutated DNA was quantified in plasma samples and in cancer sections by quantitative real-time polymerase chain reaction (qPCR). At ultrasound examination, the dominant right nodule of the thyroid was weakly hyperechoic and hypervascularized, while the left one was hypoechoic without internal vascularization. Regional lymphadenomegalia was not detected. Basal plasma calcitonin was elevated, and the patient underwent total thyroidectomy and resection of central cervical lymph nodes. Histopathological examination identified two distinct foci of MTC and PTC and micrometastasis of well-differentiated carcinoma in one of the six resected lymph nodes. RET proto-oncogene germline mutations were not detected. Cutaneous melanoma of the thorax was subsequently diagnosed. BRAF(V600E) tissue DNA was detected in PTC and melanoma but not in MTC. The cell-free plasma percentage of BRAF(V600E) DNA was detected in pre-thyroidectomy peripheral blood and was drastically reduced after cancer treatments. This study confirms the occurrence of synchronous MTC and PTC and is the first evidence of the co-existence of melanoma and distinct thyroid cancers of different origin. BRAF(V600E) allele was detected in PTC and melanoma but not in MTC tissues. BRAF(V600E) molecular quantification in pre- and post-treatment blood supports our previous data, suggesting its possible role in diagnosis and follow-up of BRAF-positive tumors.

Cell-free nucleic acids circulating in plasma are considered a promising noninvasive tool for cancer monitoring. BRAF(V600E) mutation in cell-free DNA (cfDNA) could represent an appropriate marker for papillary thyroid carcinoma (PTC).Our aim is to investigate the role of BRAF(V600E)-mutated allele in cfDNA as a marker for the diagnosis and follow-up of PTC.BRAF(V600E) allele was detected and quantified by an allele-specific real-time quantitative PCR assay in plasma from 103 patients affected by nodular goiter. As control populations, we enrolled 49 healthy subjects and 16 patients with non-nodular thyroid diseases.The percentage of circulating BRAF(V600E) was significantly different between patients and controls and throughout different cytological categories of ultrasound-assisted fine-needle aspiration. Patients with a histopathological diagnosis of PTC showed a higher percentage of circulating BRAF(V600E) (P = .035) compared to those with benign histology. In 19 patients, a second blood draw, taken 3-6 months after surgery, showed a lower percentage of BRAF(V600E) in cfDNA than the presurgical sample (P.001). The diagnostic performance of circulating BRAF(V600E) was assessed by receiver operating characteristic curve analysis resulting in an area under the curve of 0.797. A cutoff value was chosen corresponding to maximum specificity (65%) and sensitivity (80%). On this basis, we evaluated the predictive value of BRAF(V600E) in Thy 3 patients with a resulting positive predictive value of 33% and a negative predictive value of 80%.The results of the present study provide encouraging data supporting the possibility to take advantage of circulating BRAF(V600E) in the management of PTC.

The 11-gauge (11G) stereotactic vacuum-assisted breast biopsy (VABB) showed a better profile than 14G-VABB in terms of feasibility, safety, microcalcification sampling, and accuracy. Underestimation rates were significantly lower with 11G-VABB than with 14G-VABB. Thus, the introduction of an even larger needle at the VABB procedure could reduce this rate further. The purpose of this study was to compare the overall performance of stereotactic VABB with 8G and 11G needles.Four hundred and three VABBs performed between July 2012 and February 2015 at the Breast Diagnostic Unit of Careggi Hospital in Florence were retrospectively analyzed; 197 were performed with 11G-VABB and 206 with 8G-VABB. Lesions were classified according to mammographical patterns in microcalcifications, architectural distortions, or opacities, and all biopsy targets were classified according to BIRADS classification as BIRADS III, IV or V. Data were collected on radiological classification of targets, imaging presentation, procedure time, number of specimens per procedure, and microcalcification retrieval on histological findings. Surgery was always performed when high-risk or malignant lesions (B3 or B5) were detected; the final diagnosis was made on surgical pathology.Compared to VABB with an 11G needle, 8G-VABB allows a reduction in the time needed to complete the procedure (20.6 versus 27.4, P 0.00001) and the number of specimens collected per lesion (21.6 versus 12.2, P 0.00001). Moreover, 8G-VABB resulted in the same diagnostic accuracy, and the underestimation rates were comparable between the two groups for both B3 and DCIS lesions.The 8G needle should be considered as a valid alternative option in VABB for breast lesions.

Background Core needle biopsy (CNB) plays a crucial role as diagnostic tool for breast cancer (BC). The characterization of biomarkers status before surgical treatment is crucial when primary systemic therapy is a therapeutic option. The aim of this analysis was to report concordance between preoperative CNB and surgical specimen (SS) in evaluating biomarkers and molecular subtypes. Methods Data have been collected from a cohort of 101 patients affected by early BC treated at Careggi Florence University Hospital, between January 2014 and March 2015. The conformity between molecular subtype classification was tested using kappa (κ) test. Results Mean age was 57.5 years (range 29–86). There was concordance between the estrogen receptor (ER) assessment on CNB and SS in 95 cases (94.1%). Concordance of the progesterone receptor (PgR) assessment was observed in 89 cases (88.1%). Concordance for detecting immunohistochemistry-assessed BC molecular subtypes was 87.1% (κ = 0.78). Concerning Ki-67 evaluation, we report a concordance rate of 88.1% (κ = 0.68). The evaluation of luminal A plus luminal B/HER negative subgroup showed a κ-value of 0.65. Conclusions CNB showed good accuracy in evaluating hormonal receptors status, HER2, and BC molecular subtypes. Evaluation of Ki67 status was less accurate than other biomarkers; therefore, we recommend that it should be detected both on CNB and SS samples, especially in hormonal positive HER2 negative tumors, in order to avoid a misclassification of tumor subtypes that could lead to an omission of potential effective systemic therapy.

The purpose of this study was to evaluate the reliability of image-guided 14-gauge needle core biopsy in the diagnosis of radial scar without associated atypical epithelial proliferation, by comparison with definitive histological diagnosis on surgical excision. The records of 8792 consecutive image-guided 14-gauge needle core biopsy of the breast performed from January 1996 to December 2009 were reviewed. Forty-nine cases of radial scar without associated atypical epithelial proliferation were identified and compared with definitive histological diagnosis on surgical excision. The definitive histological diagnosis on surgical excision confirmed the results of image-guided 14-gauge needle core biopsy in 36 of 49 cases (73.5%), in 9 cases (18.3%) radial scar was associated with atypical epithelial proliferation, while 4 cases out of 49 cases were upgraded to carcinoma (3 cases of ductal carcinoma in situ and one case of invasive lobular carcinoma), with an underestimation rate of 8.2%. A diagnosis of radial scar without associated atypical epithelial proliferation on image-guided 14-gauge needle core biopsy does not exclude a malignancy on surgical excision; consequently during the multidisciplinary discussion further assessment by surgical excision or vacuum-assisted excision, as recently reported, needs to be considered to obtain a definitive histological diagnosis.

Introduction. Human epidermal growth factor receptor 2 (HER2) amplification has become the prototype biomarker to develop tailored biological treatment. Many studies suggested that HER2 positivity is an independent predictor of disease recurrence and breast cancer mortality. Trastuzumab has been introduced into clinical practice for high-risk HER2−positive patients who have completed the standard adjuvant treatment. However, small ( The aim of our analysis was to evaluate the prognostic factors of local and distant recurrence in patients diagnosed with T1a-b, node-negative, HER-2 positive breast cancer. Materials and methods. A total of 704 patients were diagnosed at Florence University between November 1999 and December 2008 with node-negative, invasive BC that were 1 cm or smaller. Patients with ductal carcinoma in situ, with recurrent BC at presentation and patients that received adjuvant chemotherapy were excluded from analysis. Results. Mean follow-up was 4.9 years (0.5−10.8 years); we recorded a total of 19 recurrences, including 10 distant recurrences. Mean time to local relapse occurrence was 3.8 years (0.4−7.3 years); mean time to distant metastases diagnosis was 4.4 years (1.4−7.6 years). Among all patients, the recurrence-free survival (RFS) was 93.7%. The only parameter that emerged as significant predictor of events is the age (p=0.02). The distant recurrence-free survival (DRFS) rate was 96.5%. Patients who had HER2−positive BC had worse DRFS than patients who had HER2−negative BC (92.0% v 96.9%; p=0.045). In addition to HER2, also HR status was significantly associated with DRFS (p=0.026). Patients who had HR negative status had worse DRFS than patients who had HR positive status (91.4% v 97.4%; p=0.045). Conclusions. Patients with T1a-b, node-negative, breast cancer have a low risk of distant and local recurrence. Women with HER2−positive and negative hormonal status have a significant risk of distant recurrence and should be considered for anti-HER2 adjuvant therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-14.

BACKGROUND: The objective of this study was to evaluate prognostic factors of local and distant recurrence in patients diagnosed with T1a and T1b, lymph node-negative breast carcinoma (BC) with emphasis on human epidermal growth factor receptor 2 (HER2) status. METHODS: The authors reviewed 704 women with T1aT1bN0M0 BC who received treatment at the Radiation-Oncology Center of Florence University between November 2002 and December 2008. Patients with ductal carcinoma in situ or recurrent BC at presentation and patients who received adjuvant chemotherapy were excluded from the analysis. RESULTS: In total, 75 patients had HER2-positive BC (10.7%). At a mean follow-up of 4.9 years (standard deviation, 2.6 years; range, 0.5-10.8 years), 19 events were identified, including 10 distant recurrences. Patients with HER2-positive BC had worse distant recurrence-free survival (DRFS) than patients with HER2-negative BC (hazard ratio, 3.66; 95% confidence interval, 0.94-14.69; P = .045). Negative hormone receptor (HR) status was associated significantly with worse DRFS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.93; P = .026). In multivariate analysis, younger age was the only significant risk factor for an event of recurrence (hazard ratio, 0.61;95% confidence interval, 0.20-1.82; P = .029). CONCLUSIONS: The current results indicated that patients with T1a/T1b, lymph node-negative BC have a low risk of distant and local recurrence, but younger age is a significant risk factor for events occurrence. Young women with HER2-positive and HR-negative status have a significant risk of distant recurrence and should be considered for future clinical trials with anti-HER2 adjuvant therapy. Cancer 2011. © 2011 American Cancer Society.

Isolated tumour cells and micrometastases represent two different staging categories and are often dealt with differently when identified in sentinel lymph nodes of breast cancer patients. The reproducibility of these categories was found to be suboptimal in several studies. The new edition of the TNM (Tumour Node Metastasis) is expected to improve the reproducibility of these categories. Fifty cases of possible low-volume nodal involvement were represented by one to four digital images and were analysed by members of the European Working Group for Breast Screening Pathology (EWGBSP). The kappa value for interobserver agreement of the pN (TNM) staging categories and of the isolated tumour cells category were 0.55 and 0.56 reflecting moderate reproducibility, and the kappa of the micrometastatic category (0.62) reflected substantial reproducibility. This is an improvement over the results gained on the basis of the previous edition of the TNM. Maximal adherence to the category definitions supplemented by explanatory texts in the staging manual should result in more homogeneous nodal staging of breast cancer.

Core needle biopsy (CNB) diagnoses of ductal carcinoma-in-situ (DCIS) may represent understaged invasive breast cancer (IBC). We aimed to develop a model that helps identify preoperatively women with IBC after a CNB diagnosis of DCIS.Retrospective study of all women with DCIS on vacuum-assisted CNB of microcalcifications (1999-2008), with prospective classification of imaging variables independently by two radiologists. Variables included lesion size and level of suspicion on imaging, morphology and distribution of microcalcifications, DCIS nuclear grade on CNB, number of cores, and age. Multivariate logistic regression models of the probability of IBC were developed; the accuracy of these models was examined for each radiologist.Excision histology showed IBC in 77 (17.4%) of 442 subjects with DCIS on CNB. Lesion size on imaging yielded the best model fit and highest accuracy, and had the highest agreement between radiologists. Addition of grade to a model which included size improved model fit (P 0.0001). However, model fit and accuracy were not improved by inclusion of any other variables. A model based on size and grade had similar areas under the receiver operating characteristic curve (accuracy of 74%) for each radiologist. Modeled sensitivity, specificity, and predictive values for different combinations of size and grade thresholds are reported. If the imaging lesion is50 mm and the CNB grade is high, the model's positive predictive value is ≥50%.A model based on imaging size of microcalcifications and CNB nuclear grade can identify women at high risk of having IBC with moderate accuracy and may be used to guide informed preoperative discussion in women with newly diagnosed DCIS on CNB.

Zito F A, Verderio P, Simone G, Angione V, Apicella P, Bianchi S, Conde A F, Hameed O, Ibarra J, Leong A, Pennelli N, Pezzica E, Vezzosi V, Ventrella V, Pizzamiglio S, Paradiso A & Ellis I (2010) Histopathology 56, 720–726 Reproducibility in the diagnosis of needle core biopsies of non-palpable breast lesions: an international study using virtual slides published on the world-wide web Aims: To conduct an internet-based study using virtual slides (VS) of sterotactic core biopsy specimens of non-palpable breast lesions in order to evaluate interobserver reproducibility between pathologists. Methods and results: A total of 18 breast lesions, determined to be histologically complex by two pathologists, were selected. Digitized VSs were then created using QuickTime Virtual Reality technology (Apple, Cupertino, CA, USA) and posted on the world-wide web. In all, 10 pathologists completed the evaluations of 18 VSs using the five diagnostic categories (B1–B5) from the European guidelines for quality assurance in breast cancer screening and diagnosis. Their results were compared with those of every other participating pathologist, and were then individually compared with the results of a highly experienced breast pathologist (referee). Of the 18 cases, 10 (56%) were classified by the referee as borderline (B3 and B4). Comparisons with reference values showed a less than satisfactory level of reproducibility (median κw = 0.60). As regards interobserver reproducibility, results showed that, in general, the level of agreement was not satisfactory (median κw = 0.53). Conclusions: Overall, the findings are comparable to those quality control studies using circulating slides when analysis is done on borderline cases.

In a prospective study, we attempted to predict axillary metastases in 135 breast cancer patients by a preoperative multiparameter evaluation including axillary ultrasound scanning (US). After surgery, factors associated with lymph node metastases by univariate analysis were included in a multivariate model. By multivariate analysis, the stronger independent predictors of lymph node metastases were suspicious axillary US (p0.001), tumor location in the outer quadrants (p=0.001) and high Ki-67 index (10%) (p=0.002). A predictive model based on these variables, identified a high-risk group (20.0%) represented by women with suspicious axillary US, tumor in the outer quadrants and high Ki-67 index, with axillary metastases in 100%, whereas all patients with opposite features (8.1%) had uninvolved axillary lymph nodes. This multiparameter evaluation including axillary US may be used to optimize the selection of breast cancer patients candidate to sentinel lymph node biopsy or axillary lymph node dissection. The accuracy of this predictive model still requires prospective validation in a larger sample of women.

Background Male breast cancer (MBC) is a rare and scarcely investigated disease. The strongest genetic risk factor for MBC is represented by inherited BRCA2 mutations, whereas the association between MBC and BRCA1 mutations is less clear. MBC appears to be biologically similar to breast cancer in females, however the phenotypic characteristics of BRCA1/2-related MBCs are not yet well elucidated. Objective To investigate the genetic and phenotypic characteristics of MBC in a large and well-characterized population-based series of 108 MBCs from Tuscany (Central Italy) and to evaluate associations between BRCA1/BRCA2 mutation status and clinical-pathological features including breast/ovarian cancer first-degree family history, tumor histology and grade, proliferative activity, estrogen/progesterone receptors (ER/PR) and epidermal growth factor receptor 2 (HER2) expression. Results BRCA1/BRCA2 mutations were identified in ten MBCs, in particular, two cases (1.9%) carried BRCA1 and eight cases (7.4%) carried BRCA2 mutations. The same BRCA1 mutation (3347delAG) was detected in two unrelated MBC cases. Three novel BRCA2 pathogenic mutations were found. Statistically significant associations emerged between BRCA2-related tumors and absence of PR expression (P = 0.008), HER2 over-expression (P = 0.002) and high tumor grade (P = 0.005). Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior. Overall, our results may have important implications on clinical management for this rare disease.

One-hundred-fourteen consecutive cases of breast ultrasound-guided 14-gauge needle core biopsy (14G NCB) performed from January 2001 to June 2013 and diagnosed as non-malignant papillary lesion (PL)-B3, were reviewed and compared with definitive histological diagnosis on surgical excision (SE) to evaluate the diagnostic accuracy of ultrasound-guided 14G NCB. PL with epithelial atypia on 14G NCB were associated to malignancy on definitive histological diagnosis on SE in 22 (7 DCIS and 15 invasive carcinomas) of 46 cases with an underestimation rate of 47.8 %, while 9 (4 DCIS and 5 invasive carcinomas) cases out of 68 cases of PL without epithelial atypia were upgraded to carcinoma with an underestimation rate of 13.2 %. In cases of PL with epithelial atypia on ultrasound-guided 14G NCB, SE appears mandatory due to the high risk of associated malignancy. The diagnosis of PL without epithelial atypia on ultrasound-guided 14G NCB does not exclude malignancy at subsequent SE, consequently further assessment (by surgical or vacuum-assisted excision) is recommended to avoid the risk of delaying a diagnosis of malignancy, although this tends to be lower (1 in 8 patients).

Cell-free DNA (cfDNA) quantity and quality in plasma has been investigated as a non-invasive biomarker in cancer. Previous studies have demonstrated increased cfDNA amount and length in different types of cancer with respect to healthy controls. The present study aims to test the hypothesis that the presence of longer DNA strands circulating in plasma can be considered a biomarker for tumor presence in thyroid cancer. We adopted a quantitative real-time PCR (qPCR) approach based on the quantification of two amplicons of different length (67 and 180 bp respectively) to evaluate the integrity index 180/67. Cell-free DNA quantity and integrity were higher in patients affected by nodular thyroid diseases than in healthy controls. Importantly, cfDNA integrity index was higher in patients with cytological diagnosis of thyroid carcinoma (Thy4/Thy5) than in subjects with benign nodules (Thy2). Therefore, cfDNA integrity index 180/67 is a suitable parameter for monitoring cfDNA fragmentation in thyroid cancer patients and a promising circulating biomarker in the diagnosis of thyroid nodules.

The Ki67 labelling index (LI – proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. © 2014 Elsevier Ltd.

Aims and background The association of p53 protein accumulation and prognosis in node-negative breast cancer patients has been alternately demonstrated and denied in literature reports, and opinions on the use of p53 expression as an indicator of high risk of recurrence and as a guide for adjuvant therapy are controversial. Study design The association of p53 protein accumulation with prognosis was retrospectively evaluated in a series of 221 node-negative breast cancer patients treated with surgery alone and followed up for a minimum of 10 years. p53 accumulation was determined by immunohistochemistry on archive material, and classified into four grades of increasing immunostaining. Results No association was observed between p53 and age or pT category, whereas a significant association with nuclear grade was found (P = 0.0014). Univariate and multivariate analysis of 10-yr disease-free and overall survival showed a significant and independent prognostic association for tumor size (pT category) and nuclear grading but not for p53 expression, whatever grade grouping was used. Conclusions We did not find any evidence supporting the use of p53 immunostaining in current practice as an independent prognostic indicator or as a discriminant factor for adjuvant treatment of node-negative breast cancer patients.

The HER-2 gene (HER-2/neu or c-erbB-2) encodes an 185-kDa transmembrane glycoprotein that is a member of the type I family of growth factor receptors. HER-2 is constitutively activated by overexpression and contributes to cell growth, angiogenesis, survival, and metastasis (1). The assessment of HER-2 status in breast carcinomas provides valuable prognostic and predictive information. Immunohistochemistry, fluorescence in situ hybridization, chromosomal in situ hybridization, and quantitative reverse transcription-PCR (RT-PCR) may be used for this purpose. Other approaches have been proposed for the assessment of HER-2 status in peripheral blood, including evaluating either circulating HER-2 extracellular domain (ECD) or nucleated cell-associated HER-2 mRNA. Some studies have indicated that circulating ECD/HER-2 is frequently increased in metastatic disease (2)(3)(4). In addition, high concentrations of ECD/HER-2 are associated with cancer aggressiveness (5) and predict response to trastuzumab (6)(7)(8) and antiestrogen (4) therapies in advanced breast cancer. Recently, Martin et al. (9), using an array to assess circulating mRNA, pointed out that HER-2 mRNA was generally low in the blood of healthy individuals but was increased in 31% of patients with untreated invasive breast cancer. Almost all of these studies evaluated blood markers in patients with advanced or metastatic breast cancer using a single presurgical sample. Our study included 40 consecutive patients (median age, 58 years; range, 29–80 years) undergoing surgery for early breast cancer. Patients did not receive any systemic therapy before surgery and provided informed consent for the study. According to tumor size, 28 patients were classified as T1, whereas the remaining 12 were T2 or T3. Twenty-two were node negative, and 35 were positive for estrogen receptors. From each patient, we collected 12 mL of venous blood in EDTA tubes and divided the blood into two 5-mL aliquots. The first was centrifuged, and the plasma …

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center’s series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model’s area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. Women diagnosed with a first primary invasive breast cancer in the 2004–2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2−, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher’s exact test, and a multinomial logistic regression model was used. Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2−, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. Significant association between breast cancer histotypes and molecular subgroups was found.

Background Axillary treatment of breast cancer patients is undergoing a paradigm shift, as completion axillary lymph node dissections (ALNDs) are being questioned in the treatment of patients with tumor-positive sentinel nodes. This study aims to develop a novel multi-institutional predictive tool to calculate patient-specific risk of residual axillary disease after tumor-positive sentinel node biopsy. Methods Breast cancer patients with a tumor-positive sentinel node and a completion ALND from five European centers formed the original patient series (N = 1000). Statistically significant variables predicting nonsentinel node involvement were identified in logistic regression analysis. A multivariable predictive model was developed and validated by area under the receiver operating characteristics curve (AUC), first internally in 500 additional patients and then externally in 1068 patients from other centers. All statistical tests were two-sided. Results Nine tumor- and sentinel node-specific variables were identified as statistically significant factors predicting nonsentinel node involvement in logistic regression analysis. A resulting predictive model applied to the internal validation series resulted in an AUC of 0.714 (95% confidence interval [CI] = 0.665 to 0.763). For the external validation series, the AUC was 0.719 (95% CI = 0.689 to 0.750). The model was well calibrated in the external validation series. Conclusions We present a novel, international, multicenter, predictive tool to assess the risk of additional axillary metastases after tumor-positive sentinel node biopsy in breast cancer. The predictive model performed well in internal and external validation but needs to be further studied in each center before application to clinical use.

In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes.We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki6714 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables.Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709).Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

The objective of this study was to evaluate prognostic factors of local and distant recurrence in patients diagnosed with T1a and T1b, lymph node-negative breast carcinoma (BC) with emphasis on human epidermal growth factor receptor 2 (HER2) status.The authors reviewed 704 women with T1aT1bN0M0 BC who received treatment at the Radiation-Oncology Center of Florence University between November 2002 and December 2008. Patients with ductal carcinoma in situ or recurrent BC at presentation and patients who received adjuvant chemotherapy were excluded from the analysis.In total, 75 patients had HER2-positive BC (10.7%). At a mean follow-up of 4.9 years (standard deviation, 2.6 years; range, 0.5-10.8 years), 19 events were identified, including 10 distant recurrences. Patients with HER2-positive BC had worse distant recurrence-free survival (DRFS) than patients with HER2-negative BC (hazard ratio, 3.66; 95% confidence interval, 0.94-14.69; P = .045). Negative hormone receptor (HR) status was associated significantly with worse DRFS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.93; P = .026). In multivariate analysis, younger age was the only significant risk factor for an event of recurrence (hazard ratio, 0.61;95% confidence interval, 0.20-1.82; P = .029).The current results indicated that patients with T1a/T1b, lymph node-negative BC have a low risk of distant and local recurrence, but younger age is a significant risk factor for events occurrence. Young women with HER2-positive and HR-negative status have a significant risk of distant recurrence and should be considered for future clinical trials with anti-HER2 adjuvant therapy.

The aim of this study is to evaluate the prognostic values of some biological parameters in a population based series of female breast cancer patients. Through the Tuscan Cancer Registry all the invasive breast cancer cases diagnosed during the period 2004–2005 in the provinces of Florence and Prato, central Italy, were retrieved. Molecular subtypes were analyzed defined by immunohistochemical markers, by age, tumor size, lymph node status, histotype, grade of differentiation and proliferative marker. Out of 1487 patients 70.3% were luminal A subtype (ER/PR + HER2-), 15.6% luminal B (ER/PR + HER2+), 8.1% triple negative (ER/PR-HER2-), 6.0% HER2+ (ER/PR-HER2+); the 3 year survival rates were 93.3%, 89.5%, 86.3%, 82.7% respectively (p < 0.001). Analysis of survival by the Cox proportional hazards model showed an independent prognostic value of molecular classification. Our study revealed significant differences in clinicopathological characteristics among breast cancer molecular subtypes and confirmed their prognostic independent role.

Purpose Application of current nodal status classification is complicated in lobular breast carcinoma metastases. The aim of this study was to define the optimal interpretation of the pTNM classification in sentinel node (SN) –positive patients to select patients with limited or with a high risk of non-SN involvement. Patients and Methods SN metastases of 392 patients with lobular breast carcinoma were reclassified according to interpretations of the European Working Group for Breast Screening Pathology (EWGBSP) and guidelines by Turner et al, and the predictive power for non-SN involvement was assessed. Results Reclassification according to definitions of EWGBSP and Turner et al resulted in different pN classification in 73 patients (19%). The rate of non-SN involvement in the 40 patients with isolated tumor cells according to Turner et al and with micrometastases according to EWGBSP was 20%, which is comparable to the established rate for micrometastases. The rate of non-SN involvement in the 29 patients with micrometastases according to Turner et al and with macrometastases according to EWGBSP was 48%, which is comparable to the established rate for macrometastases. Therefore, the EWGBSP method to classify SN tumor load better reflected the risk of non-SN involvement than the Turner et al system. Conclusion Compared with the guidelines by Turner et al, the EWGBSP definitions better reflect SN metastatic tumor load and allow better differentiation between patients with lobular breast carcinoma who have a limited or a high risk of non-SN metastases. Therefore, we suggest using the EWGBSP definitions in these patients to select high-risk patients who may benefit from additional local and/or systemic therapy.

The clinical significance of micropapillary growth pattern in ductal carcinoma in situ is controversial and the impact of nuclear grading in terms of recurrence of this lesion is yet to be clarified. Our aim was to evaluate, on a series of micropapillary in situ carcinomas, the histological features correlated with recurrence and whether the micropapillary subtype had a different behavior from other non-micropapillary ductal carcinoma in situ. We collected 55 cases of micropapillary in situ carcinomas from four institutions. All cases were reviewed for nuclear grade, extent, necrosis, microinvasion and tested for estrogen and progesterone receptors, Ki67, HER2, EGFR and p53 expression. Clinical data, type of surgery and follow up were obtained for all patients. Our results showed that the nuclear grade is crucial in determining the biology of micropapillary carcinoma in situ, so that the high nuclear grade micropapillary ductal carcinoma in situ more frequently overexpressed HER2, showed higher proliferation index, displayed necrosis and microinvasion and was more extensive than low/intermediate nuclear grade. Logistic regression analysis confirmed the high nuclear grade (Odds ratio: 6.86; CI: 1.40–33.57) as the only parameter associated with elevated risk of local recurrence after breast-conserving surgery. However, the recurrence rate of 19 micropapillary carcinoma in situ, which were part of a cohort of 338 consecutive ductal carcinoma in situ, was significantly higher (log-rank test, P-value=0.019) than that of non-micropapillary, independently of the nuclear grade. In conclusion, although nuclear grade may significantly influence the biological behavior of micropapillary ductal carcinoma in situ, micropapillary growth pattern per se represents a risk factor for local recurrence after breast-conserving surgery.

The widespread implementation of mammography screening has resulted in an increased frequency of needle core biopsies (NCB). The aim of this study was that of evaluating the diagnostic reproducibility on breast NCB, according to the B-classification, among several pathologists from different Italian regions. Fifty single slides of NCBs performed for non palpable breast lesions were selected to evaluate the diagnostic reproducibility, according to the B classification, among 31 pathologists from different Italian areas, involved in the pathologic diagnosis of screen-detected breast lesions. According to the study majority diagnosis (MD), 21 cases were classified as B2 (benign lesion), 23 B3 (lesion of uncertain malignant potential) and 6 B5 (malignant lesion). Overall, individual kappa coefficients in comparison to MD were good (mean 0.61, range 0.31–0.88). The level of inter-observer agreement, however, appeared lower in differentiating the two intermediate categories B2 and B3, thus potentially leading to over-treatment (false-positives: 26%) or under-treatment (false-negatives: 17%) of individual patients. Specific sub-types of B3 need an improvement of the diagnostic definition. A multidisciplinary approach and consultation with expert colleagues are recommended.

The increased rate of early detection of breast cancer due to widespread mammographic screening has led to an increased incidence not only of in situ but also microinvasive carcinoma (MC). MC has been reported to have a favourable prognosis, but specific definitions have varied in the past making the clinical significance of this entity a subject of debate. In fact, although the diagnosis of MC often appears in pathology reports, this term has not been used in a consistent, standardized manner. In addition, the histological diagnosis of MC can be problematical for the pathologist due to a variety of in situ patterns and artefacts that may be misinterpreted as stromal invasion. Definitions and diagnostic criteria of MC are reviewed and discussed. Based on a review of literature, incidence of axillary lymph node involvement, according to different definitions of microinvasion, is reported.

Breast cancers with nodal isolated tumour cells (ITC) and micrometastases are categorised as node-negative and node-positive, respectively, in the tumour node metastasis (TNM) classification. Two recently published interpretations of the TNM definitions were applied to cases of low-volume sentinel lymph node (SLN) involvement and their corresponding non-SLNs for reclassification as micrometastasis or ITC. Of the 517 cases reviewed, 82 had ITC and 435 had micrometastasis on the basis of one classification, and the number of ITC increased to 207 with 310 micrometastases on the basis of the other. Approximately 24% of the cases were discordantly categorised. The rates of non-SLN metastases associated with SLN ITCs were 8.5% and 13.5%, respectively. Although the second interpretation of low-volume nodal stage categories has better reproducibility, it may underestimate the rate of non-SLN involvement. The TNM definitions of low-volume nodal metastases need to be better formulated and supplemented with visual information in the form of multiple sample images.