Preoperative axillary nodal staging of invasive lobular breast cancer with ultrasound guided fine needle aspiration in patients with suspicious ultrasound findings versus aspiration in all patients - A retrospective single institutional analysis.

INTRODUCTION: - At present, surgical strategies for breast cancer patients with >2 lymph nodes (LN) involved differ from those with no or lower degree of nodal involvement. Preoperative assessment of the axilla is less sensitive in patients with lobular carcinoma (ILC) than patients with other histological tumour types. MATERIALS AND METHODS: - A retrospective analysis of axillary staging by palpation, axillary ultrasound (AXUS) and AXUS-guided fine-needle aspiration cytology (FNAC) of 153 patients with ILC diagnosed and operated on between January 2013 and December 2020 was performed. Patients had either sentinel node biopsy or axillary lymph node dissection according to current practice. In period 1, patients had FNAC only when AXUS suggested nodal involvement (n = 106), and in period 2, all ILC patients had axillary FNAC (n = 47). RESULTS: - Of the factors associated with >2LNs involvement, logistic regression suggested only AXUS/FNAC based staging as independent variable for all patients. Patients with AXUS-guided FNAC had a significantly higher proportion of true negative and lower proportion of true positive cases in the P2 period (0 vs 55% and 72% vs 11% for >2 LNs involvement, respectively; both p < 0.0001). CONCLUSIONS: - AXUS-guided FNAC of all ILC patients did not result in improved preoperative identification of patients with >2 metastatic LNs but increased the false-negative rate of the assessment by producing false-negative results in patients who would not have undergone a biopsy due to negative AXUS findings.

Sentinel lymph node biopsy following previous axillary surgery in recurrent breast cancer.

INTRODUCTION: Ipsilateral breast recurrence or second primary breast cancer can develop in patients who have undergone breast conserving surgery (BCS) and axillary surgery. The purpose of this study was to examine the feasibility of a reoperative sentinel lymph node biopsy (SLNB) as a repeated axillary staging procedure. PATIENTS AND METHODS: From August 2014 through January 2017 patients with locally recurrent breast cancer or with BRCA mutation requiring risk reduction mastectomy as a second surgical procedure, underwent repeat SLNB in three Hungarian Breast Units with a radiocolloid (and blue dye) technique. RESULTS: Hundred and sixty repeat SLNBs were analysed, 80 after previous SLNB and 80 after previous total or partial axillary lymph node dissection (ALND). SLN identification was successful in 106 patients (66%); 77/80 (77.5%) and 44/80 (55%) in the SLNB and ALND groups, respectively. (p < 0.003). Extra-axillary lymph drainage was more frequent in the ALND group (19/44, 43,2% versus 7/62, 11,3%; p < 0.001). Lymphatic drainage to the contralateral axilla was observed in 14 patients (11 in the ALND group, p = 0.025), isolated parasternal drainage was detected in 4 patients (p = 0.31). Only 9/106 patients with successful repeat SLNB (8,8%, all with 1 SLN removed) had SLN metastases CONCLUSIONS: Repeat SLNB is feasible in patients with ipsilateral breast tumor recurrence or new ipsilateral primary tumor after previous BCS and axillary staging. Repeat SLNB should replace routine ALND as the standard axillary restaging procedure in recurrent disease with a clinically negative axilla. Preoperative lymphoscintigraphy is important to explore extra-axillary lymphatic drainage in this restaging setting.

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors.

Background: Based on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor. Patients and methods: We used a previously published next generation sequencing dataset of 21 matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also carried out the myChoice HRD analysis on an independent cohort of 17 breast cancer patients with matched primary/brain metastasis pairs. Results: All of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort, the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria. Conclusions: The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.

Inflammatory breast cancer: The pathologists' perspective.

Inflammatory breast cancer (IBC) is a clinico-pathological entity, which has specific features of inflammation and pathological evidence of cancer, most often involving dermal lymphatics. This review looks at IBC from the pathologists point of view. The diagnostic criteria and differential diagnosis are summarized first. The staging implications are described next. Despite the overall poor prognosis of IBC, it is heterogeneous in terms of most prognostic and predictive factors (such as histological type, grade, receptor status, intrinsic subtype, inflammatory infiltrate). It seems that some molecular features (genes expressed) are unique to IBC, and this may help to identify them as IBC at the molecular level. The key carcinogenetic pathways activated in IBC, the inflammatory pathways present in the disease as well as the relation of IBC to cancer stem cells are also briefly covered. Due to the relative rarity of IBC, preclinical trials are very important in the study of this entity, and models with stromal and microenvironmental elements are expected to outperform the traditional models without these features, as the microenvironment seems to be a key component of IBC.

Prognostic impact of macrometastasis linear size in sentinel node biopsy for breast carcinoma.

AIM: The aim of the present study was to evaluate the risk of axillary non-sentinel lymph-node metastases (ALN) in breast cancer patients presenting macrometastasis (Mac-m) in the sentinel lymph node (SN). MATERIALS AND METHODS: A retrospective series of 1464 breast cancers from patients who underwent ALN dissection following the diagnosis of Mac-m in the sentinel node (SN) was studied. In all the cases the MAC-m linear size was evaluated and correlated with presence or absence of non-SN ALN metastases. RESULTS: Non-SN metastases were detected in 644∖1464 cases (43.98%). The risk of further axillary metastases ranged from 20.2% (37/183) in cases with Mac-m between 2 and 2.9 mm, to 65.3% (262/401) in cases with Mac-m measuring > 10 mm. The risk of non-SN ALN metastases showed a 3% increase, parallel to each mm increment in SN metastasis size. The data evaluated with the receiver operating characteristic (ROC) curve showed that the Mac-m could be subdivided according to a new cut-off of 7 mm. pT1 tumours, with Mac-m < 7 mm had a risk of non-SN ALN metastases of <30%. Furthermore 109/127 of these (85.8%) had 3 or less non-SN ALN -metastases. CONCLUSIONS: The present data give a detailed description on the risk of non-SN ALN involvement, that may be useful in the evaluation of breast cancer patients. It is suggested that a Mac-m size of <7 mm is related to a low residual axillary disease burden in breast cancer patients with small (pT1) tumours.

Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100% agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Pathological non-response to chemotherapy in a neoadjuvant setting of breast cancer: an inter-institutional study.

To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the adjuvant setting. Sixteen pathologists of the European Working Group for Breast Screening Pathology reviewed the core biopsies of breast cancers treated with NAC and recorded the clinico-pathological findings (histological type and grade; estrogen, progesterone receptors, and HER2 status; Ki67; mitotic count; tumor-infiltrating lymphocytes; necrosis) and data regarding the pathological response in corresponding surgical resection specimens. Analyses were carried out in a cohort of 490 cases by comparing the groups of patients showing pathological complete response (pCR) and partial response (pPR) with the group of non-responders (pathological non-response: pNR). Among other parameters, the lobular histotype and the absence of inflammation were significantly more common in pNR (p < 0.001). By ROC curve analyses, cut-off values of 9 mitosis/2 mm(2) and 18% of Ki67-positive cells best discriminated the pNR and pCR + pPR categories (p = 0.018 and < 0.001, respectively). By multivariable analysis, only the cut-off value of 9 mitosis discriminated the different response categories (p = 0.036) in the entire cohort. In the Luminal B/HER2- subgroup, a mitotic count <9, although not statistically significant, showed an OR of 2.7 of pNR. A lobular histotype and the absence of inflammation were independent predictors of pNR (p = 0.024 and <0.001, respectively). Classical morphological parameters, such as lobular histotype and inflammation, confirmed their predictive value in response to NAC, particularly in the Luminal B/HER2- subgroup, which is a challenging breast cancer subtype from a therapeutic point of view. Mitotic count could represent an additional marker but has a poor positive predictive value.

A predictive tool to estimate the risk of axillary metastases in breast cancer patients with negative axillary ultrasound.

BACKGROUND: Sentinel node biopsy (SNB) is the "gold standard" in axillary staging in clinically node-negative breast cancer patients. However, axillary treatment is undergoing a paradigm shift and studies are being conducted on whether SNB may be omitted in low-risk patients. The purpose of this study was to evaluate the risk factors for axillary metastases in breast cancer patients with negative preoperative axillary ultrasound. METHODS: A total of 1,395 consecutive patients with invasive breast cancer and SNB formed the original patient series. A univariate analysis was conducted to assess risk factors for axillary metastases. Binary logistic regression analysis was conducted to form a predictive model based on the risk factors. The predictive model was first validated internally in a patient series of 566 further patients and then externally in a patient series of 2,463 patients from four other centers. All statistical tests were two-sided. RESULTS: A total of 426 of the 1,395 (30.5 %) patients in the original patient series had axillary lymph node metastases. Histological size (P < 0.001), multifocality (P < 0.001), lymphovascular invasion (P < 0.001), and palpability of the primary tumor (P < 0.001) were included in the predictive model. Internal validation of the model produced an area under the receiver operating characteristics curve (AUC) of 0.731 and external validation an AUC of 0.79. CONCLUSIONS: We present a predictive model to assess the patient-specific probability of axillary lymph node metastases in patients with clinically node-negative breast cancer. The model performs well in internal and external validation. The model needs to be validated in each center before application to clinical use.

Internal Mammary Sentinel Node Biopsy in Breast Cancer. Is it Indicated?

Axillary sentinel node (A-SN) biopsy is a standard procedure in breast cancer surgery. Sampling of intenal mammary sentinel nodes (IM-SN) is not performed routinly, although it is also considered an important prognostic factor of breast cancer. The role of this latter procedure was investigated in cases of IM-SN visualized on lymphoscintigraphy. Between January 2001 and June 2012 1542 patients with clinically node negative operable primary breast cancer had sentinel node biopsy (SNB). Both axillary and IM-SN were sampled (whenever detected), based on lymphoscintigraphy, intraoperative gamma probe detection and blu dye mapping. Lymphoscintigraphy showed IM-SN in 83 cases. IM-SN biopsy (IM-SNB) was succesfull in 77 patients (93%). A total of 86 IM-SNs were removed. IM-SN involvement was identified in 14 cases, representing 18% of patients who underwent IM-SNB. This included macrometastases (MAC) in 5 cases, micrometastases (MIC) in 2 cases, isolated tumor cells (ITC) in 7 cases. No significant differences were found between patients with and without IM-SN involvement in terms of age, tumor location, tumor size, axillary involvement, tumor grade or estrogen receptor status. The IM-SN involvement has lead to new therapeutic indications in 2 cases (2.6%), both of them due to MAC in the IM-SN: in 1 case change in chemotherapy and in 1 case change in radiotherapy, with the addition of iradiation of the internal mammary chain. Based on this series and information from the literature, we conclude that the indication for an IM-SNB procedure is very limited and its routine use should not be recommended.

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases.

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.

Selective ductectomy for the diagnosis and treatment of intraductal papillary lesions presenting with single duct discharge.

Solitary ductal papilloma of the breast, although considered a benign disorder has a potential association with carcinomas. We studied and analyzed the role of selective ductectomy (SD) for the diagnosis and treatment of intraductal lesions presenting with single duct discharge and ductography suggestive of intraductal (papillary) lesions. During a ten-year-period, files of patients presenting with single (or rarely dual) duct discharge were retrospectively reviewed. The examinations included mammography, ductography and ultrasonography and cytology of the fluid discharged from the duct in all patients. Patients treated with SD were considered further and their histological diagnosis and treatment were analyzed. The series included 100 patients. In 6 cases malignancy was found in the specimen consisting of four in situ and two invasive ductal carcinomas. These 6 patients had a second operation and this was followed by adjuvant treatment. Nine further patients had atypical ductal hyperplasia in or around papillomas and one patient had lobular neoplasia around her papilloma. In the present series, the incidence of carcinoma associated with the clinical suspicion of papillary lesions was 6%, and further 10% had low grade neoplastic proliferations resulting in the diagnosis of atypical papillomas or atypical ductal hyperplasia or lobular neoplasia around the papilloma, indicating that single duct discharge may be a symptom a malignancy, and that ductal papillomas have malignant potential. For such a low risk and grade of malignancy simple follow-up could be one option, but in some cases SD could be applied to relieve the patients from symptoms and establish a diagnosis.

Unifocal, multifocal and diffuse carcinomas: a reproducibility study of breast cancer distribution.

Multifocality of invasive breast carcinoma has been associated with prognostic disadvantage. Unifocal, multifocal and diffuse distributions have been recently defined for both inasive carcinomas and in situ components, and these have been combined into categories of prognostic relevance. Eight observers analyzed the same series of 30 megaslides from 29 carcinomas, and had to classify the lesions into the three distribution patterns of unifocal, multifocal or diffuse (or not present/non influential). The reproducibility of the distribution patterns of invasive carcinomas was better than that of the in situ carcinoma components, but was still only fair to moderate on the basis of kappa values. The reproducibility of DCIS was poor to slight with some kappa values reflecting agreement by chance only. The results suggest the definitions of these distribution patterns require refinements for a more reliable and reproducible diagnosis if one wants to associate prognostic information with this variable.

Spatial clustering of childhood acute lymphoblastic leukaemia in hungary.

The aetiology of childhood acute lymphoblastic leukaemia has been linked with spatially heterogeneous environmental exposures. The presence of spatial clustering would be consistent with geographically localized environmental exposures over long periods of time. The present study is the first to examine spatial clustering amongst children aged 0-4 years using population-based data from Hungary. The data set consisted of 134 children diagnosed with acute lymphoblastic leukaemia who were resident in part of Hungary during the period 1981-2000. Two levels of spatial aggregation were examined: counties and settlements. The Potthoff-Whittinghill and Moran I autocorrelation methods were used to test for spatial clustering. Additionally, an evaluation of the environmental changes during the study period was considered. Specifically analyses were carried out on sub-periods to investigate a possible effect of the Chernobyl catastrophe. There was statistically significant spatial clustering both at the county (estimate of extra-Poisson variation [Formula: see text], P = 0.04) and settlement levels (estimate of extra-Poisson variation [Formula: see text], P = 0.0003). At county level, the finding was attributable to clustering amongst female cases, but at settlement level, the finding was limited to male cases. There was significant spatial autocorrelation in the sub-periods immediately following the accident (1986-1990 & 1991-1995), but not before 1986, nor after 1995. A significant autocorrelation was observed during the 5 year period immediately following the accident (1986-1990, global Moran I = 0.1334, p = 0.005). The centre of significant excesses of ALL cases was located in the county of Baranya. Our study is consistent with an environmental aetiology for acute lymphoblastic leukaemia in children associated with constant exposure to an, as yet unknown, environmental factor in small geographical areas. Although a possible effect of the Chernobyl accident was found in the autocorrelation analysis, the role of chance cannot be excluded.

Multicentre validation of different predictive tools of non-sentinel lymph node involvement in breast cancer.

Sentinel lymph node (SN) biopsy offers the possibility of selective axillary treatment for breast cancer patients, but there are only limited means for the selective treatment of SN-positive patients. Eight predictive models assessing the risk of non-SN involvement in patients with SN metastasis were tested in a multi-institutional setting. Data of 200 consecutive patients with metastatic SNs and axillary lymph node dissection from each of the 5 participating centres were entered into the selected non-SN metastasis predictive tools. There were significant differences between centres in the distribution of most parameters used in the predictive models, including tumour size, type, grade, oestrogen receptor positivity, rate of lymphovascular invasion, proportion of micrometastatic cases and the presence of extracapsular extension of SN metastasis. There were also significant differences in the proportion of cases classified as having low risk of non-SN metastasis. Despite these differences, there were practically no such differences in the sensitivities, specificities and false reassurance rates of the predictive tools. Each predictive tool used in clinical practice for patient and physician decision on further axillary treatment of SN-positive patients may require individual institutional validation; such validation may reveal different predictive tools to be the best in different institutions.

Quality indicators in breast cancer care.

To define a set of quality indicators that should be routinely measured and evaluated to confirm that the clinical outcome reaches the requested standards, Eusoma has organised a workshop during which twenty four experts from different disciplines have reviewed the international literature and selected the main process and outcome indicators available for quality assurance of breast cancer care. A review of the literature for evidence-based recommendations have been performed by the steering committee. The experts have identified the quality indicators also taking into account the usability and feasibility. For each of them it has been reported: definition, minimum and target standard, motivation for selection and level of evidence (graded according to AHRO). In overall 17 main quality indicators have been identified, respectively, 7 on diagnosis, 4 on surgery and loco-regional treatment, 2 on systemic treatment and 4 on staging, counselling, follow-up and rehabilitation. Breast Units in Europe are invited to comply with these indicators and monitor them during their periodic audit meetings.

[Sentinel node biopsy in breast cancer: pathological analysis and interpretation]. / Sentinel-Node-Biopsie beim Mammakarzinom: Pathologische Untersuchung und Interpretation.

This overview examines how the introduction of sentinel lymph node biopsy (SLNB) has changed the pathological staging of breast cancer. The more intensive analysis of the sentinel lymph nodes (gross slicing, step sections, immunohistological or molecular analysis) has lead to stage shifting in breast cancer. Regarding the rate of up-staging by positive results of SLNB, there are significant differences between institutes, some method-related, some related to the interpretation of results. Methodological differences should be reduced by means of reliable guidelines with the goal of systematically identifying metastases of a particular size (a macrometastasis over 2 mm being the minimum criterion). The next review of the TNM classification should result in a reduction in interobserver variability as a result of better definitions of staging categories for isolated tumor cells and micrometastases. In addition, a staging category is expected for metastases which have been identified by calibrated quantitative molecular tests only and which are larger than isolated tumors. Even in settings where nodal staging by SLNB is based on molecular tests at least a proportion of the lymph node should be investigated histologically.

Axillary sentinel lymph node micrometastases with extracapsular extension: a distinct pattern of breast cancer metastasis?

AIMS: To examine the frequency of extracapsular extension (ECE) of sentinel lymph node (SLN) metastases in breast cancer according to metastasis size, and to characterise ECE in micometastases. METHODS: If initially negative, SLNs were examined by step-sectioning and immunohistochemistry. Non-SLNs were not subjected to enhanced pathology. Positive axillary SLNs were analysed for metastasis size and the presence of ECE. RESULTS: Of 885 successful SLN biopsy cases, 343 (39%) exhibited SLN involvement, and 115 (34%) displayed ECE. Of the latter, 107 underwent axillary dissection, and 63 (59%) of these demonstrated non-SLN metastases. The presence of ECE correlated with metastasis size (coefficient 0.92). Eight (10%) of the 84 micrometastatic SLN cases had ECE, and two of these were associated with non-SLN metastases. Only ECE and only the intraparenchymal nodal part of the micrometastasis were seen in some sections of five cases each. The primary tumours of the micrometastatic cases with ECE were non-high-grade and often of tubular type. CONCLUSIONS: The frequency of ECE increases with increasing nodal metastasis size. Minimal nodal metastases with ECE may represent a distinct pattern of nodal involvement with a predominant capsular and extracapsular, but only minimal or no nodal parenchymal component, predominantly seen in non-poorly differentiated and/or tubular carcinomas. This presentation of nodal metastasis can sometimes pose differential diagnostic problems, and should be distinguished from massive metastases presenting with ECE because it does not seem to be so commonly associated with non-SLN metastases or a massive metastatic load to the axilla as ECE of SLN metastases in general.