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.

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.

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.

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 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.

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.

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.

Guidelines on the standards for the training of specialised health professionals dealing with breast cancer.

According to EUSOMA position paper 'The requirements of a specialist breast unit', each breast unit should have a core team made up of health professionals who have undergone specialist training in breast cancer. In this paper, on behalf of EUSOMA, authors have identified the standards of training in breast cancer, to harmonise and foster breast care training in Europe. The aim of this paper is to contribute to the increase in the level of care in a breast unit, as the input of qualified health professionals increases the quality of breast cancer patient care.

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.

The value of cytokeratin immunohistochemistry in the evaluation of axillary sentinel lymph nodes in patients with lobular breast carcinoma.

BACKGROUND: Cytokeratin immunohistochemistry (IHC) reveals a higher rate of occult lymph node metastases among lobular carcinomas than among ductal breast cancers. IHC is widely used but is seldom recommended for the evaluation of sentinel lymph nodes in breast cancer patients. OBJECTIVE: To assess the value of cytokeratin IHC for the detection of metastases in sentinel lymph nodes of patients with invasive lobular carcinoma. METHODS: The value of IHC, the types of metastasis found by this method, and the involvement of non-sentinel lymph nodes were analysed in a multi-institutional cohort of 449 patients with lobular breast carcinoma, staged by sentinel lymph node biopsy and routine assessment of the sentinel lymph nodes by IHC when multilevel haematoxylin and eosin staining revealed no metastasis. RESULTS: 189 patients (42%) had some type of sentinel node involvement, the frequency of this increasing with increasing tumour size. IHC was needed for identification of 65 of these cases: 17 of 19 isolated tumour cells, 40 of 64 micrometastases, and 8 of 106 larger metastases were detected by this means. Non-sentinel-node involvement was noted in 66 of 161 cases undergoing axillary dissection. Although isolated tumour cells were not associated with further lymph node involvement, sentinel node positivity detected by IHC was associated with further nodal metastases in 12 of 50 cases (0.24), a proportion that is higher than previously reported for breast cancer in general. CONCLUSIONS: IHC is recommended for the evaluation of sentinel nodes from patients with lobular breast carcinoma, as the micrometastases or larger metastases demonstrated by this method are often associated with a further metastatic nodal load.

Discriminating between micrometastases and isolated tumor cells in a regional and institutional setting.

The reproducibility of diagnosing isolated tumor cells (ITC) and micrometastases has been recently tested by expert breast pathologists, but might be different in a community setting. Digital images of 50 cases of low volume nodal involvement were circulated among pathologists from the Piedmont region (Italy) and from the Helios Medical Center in Berlin. Participants were asked to categorize the lesions into micrometastasis, ITC or others. The test was performed on the basis of a previous consensus statement. Kappa statistics were used for the assessment of interobserver variability. The kappa values for the consistency of categorizing cases were 0.47 and 0.57 for the regional and the institutional tests, respectively. Our study suggests that the reproducibility of diagnosing micrometastases and ITC in a community setting may reach that of experts, but is in the moderate range, and this may interfere with studies trying to solve the prognostic significance of these diagnostic categories.

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 work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Gastric pathology in Meckel's diverticulum. Review of cases resected between 1965 and 1995.

One hundred forty-nine case files of Meckel's diverticulum resected at our hospital between 1965 and 1995 were reviewed for the presence of heterotopic gastric mucosa. Of these, 140 cases were evaluated, and 25 demonstrated ectopic gastric mucosa. Six of these heterotopic tissue specimens contained no assessable surface mucosa; therefore only 19 were evaluated for gastric histopathologic changes. "Gastritis" was present in all reviewed cases, but the predominant pattern was that of reflux-type gastritis or gastropathy, which had not previously been documented at this location. This gastropathy was demonstrated in 58% of the cases and could also account for some of the symptoms that prompted removal of appendixes without inflammation. Chronic and chronic active gastritis were also demonstrated in a minority of cases, and those with moderate or severe activity were associated with peptic ulceration. No Helicobacter pylori-like organisms were detected with either modified Giemsa stain or hematoxylin-and-cosin (H&E) stain. Findings were inconclusive with regard to erosive gastritis related to nonsteroidal anti-inflammatory drugs in Meckel's diverticulum. That the proportion of ectopic gastric mucosa found in several studies (including this one) is about half that suggested in textbooks indicates a need for a better workup of resected Meckel's diverticulum and a search for all types of gastric disease if gastric heterotopia is present. Emphasis must be placed on identification of reflux-type chemical gastritis and gastropathy, which are often documented as normal mucosa.

Mapping metastases in sentinel lymph nodes of breast cancer.

Localization of metastases within the sentinel lymph nodes (SLNs) of breast cancer has not been studied. Forty SLNs from 36 patients with operable primary breast cancers were identified by means of lymphatic mapping with patent blue dye. The junction between the patent blue-stained lymphatic vessel draining the tumor and the SLN was labeled with alcian blue. Metastases within the serially sectioned SLNs were assigned to the alcian blue-labeled side, to the opposite side of the virtually halved nodes, or both. Eight SLNs were negative for metastasis. Eleven SLNs had metastases only in the blue half. Only 4 cases had larger metastases in the nonblue half. Metastases are more likely to be located in the vicinity of the inflow junction of the identifiable lymphatic draining the tumor and the SLN. This should be considered when SLNs are examined, especially when they are halved for different studies.

Complete sectioning of axillary sentinel nodes in patients with breast cancer. Analysis of two different step sectioning and immunohistochemistry protocols in 246 patients.

AIMS: To evaluate two detailed step sectioning protocols for sentinel lymph nodes (SLNs). METHODS: After vital dye or combined dye and radiocolloid guided biopsy, SLNs were fixed in formalin and embedded in paraffin wax. In protocol A, SLNs from 123 patients were sectioned in steps of 50-100 micro m, whereas in protocol B, SLNs from 123 patients were sectioned at steps of 250 micro m. Epithelial marker immunohistochemistry (IHC) was performed on multiple levels in cases with negative haematoxylin and eosin findings. RESULTS: In groups A and B, 74 and 47 patients were found to have tumour cells in their axillary SLNs, and 19 (28%) and 18 (19%) patients, respectively, were upstaged as compared with the standard histological assessment. Nodal involvement detected by deeper sections was often micrometastatic or in isolated tumour cells CONCLUSIONS: Serial sectioning and IHC are recommended for the evaluation of SLNs. The optimal extent of the histopathological work up should be studied further.

Axillary staging of breast cancer and the sentinel node.

Pathological aspects of axillary nodal staging of breast cancer and in particular sentinel lymph node (SLN) biopsy are reviewed. SLN biopsy seems an almost ideal staging procedure because it has both high accuracy and a low false negative rate. It may also allow a cost effective use of more sensitive methods of metastasis detection. However, the biological relevance of metastases detected only by modern tools remains to be elucidated. This review focuses on standard axillary staging and the histopathological investigation of SLNs, with emphasis on the intraoperative setting. Future trends including ancillary studies, quality control issues, prediction of non-SLN involvement, and suggestions concerning the minimum requirements for the histology of axillary SLNs are also discussed.

Tumour histological grade may progress between primary and recurrent invasive mammary carcinoma.

AIMS: To assess the constancy of the histological grade of invasive breast carcinomas by comparing primary tumours with their axillary metastases and local or regional recurrences. METHODS: Eighty four recurrent invasive breast carcinomas with a primary tumour or previous recurrence were available for histological review from the period 1980 to 2000. These and any further recurrences were graded by one observer. RESULTS: Nine, 24, and 51 tumours with grades 1, 2, and 3, respectively, recurred. Grade 1, 2, and 3 tumours recurred within a median time of 88, 42, and 23 months, respectively. The intraobserver reproducibility of the histological grade was good (kappa = 0.66), and the grades of the primary tumours and their axillary metastases or next recurrence also exhibited good agreement. However, when further (second to sixth) recurrences were included in the analysis, the agreement between the grade of the tumours and their last recurrence was only moderate (kappa = 0.48). Only two of the nine grade 1 and 15 of the 24 grade 2 tumours retained their grade in their last recurrence. CONCLUSIONS: Low grade carcinomas require a longer follow up. These long term data support the possibility of a transition from low grade invasive breast carcinomas to higher grade tumours. It is suggested that low grade (well differentiated) breast carcinomas are not a single entity: some may progress to high grade tumours, whereas others appear not to progress.