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Case # 13: Pleomorphic lobular carcinoma in situ showing discohesive atypical cells, with nuclear pleomorphism and comedonecrosis. Hematoxylin and eosin (A – 100×). Lobular cells are negative for E-cadherin (B – 100×; D – 400×) and for β-catenin (C – 100×).
Source publication
The distinction between lobular neoplasia of the breast and ductal carcinoma in situ has important therapeutic implications. In some cases, it is very difficult to determine whether the morphology of the lesion is ductal or lobular. The aim of this study was to evaluate the value of E-cadherin and beta-catenin expression through the immunophenotypi...
Citations
... A prototype tumour with EMT is lobular carcinoma of the breast (LBC), which can be associated with sporadic or familiar defects in CDH1, the gene encoding for E-cad. Nevertheless, in a small proportion (10-15%) of LBC, the defect lies in accessory molecules of the cadherin-catenin complex, which include α-catenin, β-catenin and p120 catenin [44]. The addition of IHC for β-cat has proven helpful in understanding the loss of cell-to-cell adhesion [45,46], and both markers are now used routinely in breast pathology, providing a more accurate diagnosis of LBC [47,48]. ...
Simple Summary
Personalised cancer treatment improves outcome for patients but requires that each individual tumour is classified using molecular tools. Extensive genomic studies for each individual patients are out of reach for the majority of the population, therefore, pathologists need to apply readily available tests to achieve molecular classification for all cancer patients. This paper describes how gastric cancer can be classified using on slide tests already used by histopathologists. Using this classification, oncologists can select more effective treatment for each patient.
Abstract
Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein–Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial–mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.
... A prototype tumour with EMT is lobular carcinoma of the breast (LBC), which can be associated with sporadic or familiar defects in CDH1, the gene encoding for E-cad. Nevertheless, in a small proportion (10-15%) of LBC, the defect lies in accessory molecules of the cadherin-catenin complex which includes αcatenin, β-catenin and p120 catenin [45]. The addition of IHC for β-cat has proven helpful in understanding loss of cell-to-cell adhesion [46,47] and both markers are now used routinely in breast pathology, providing more accurate diagnosis of LBC [48,49]. ...
Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancer and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia et al. proposed an on-slide classification, however this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with functional loss of p53 due to mutation (GC p53m), CG with intact p53 (GC p53wt) and GC not otherwise specified (GC NOS). This classification also has provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms, and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC p53m cases were 23%, GC p53wt cases were 29% and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in Histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.
... Briefly, cells were either permeabilized with 0.5% peroxide and carbonyl-free Triton X-100 (Sigma-Aldrich) in cytoskeleton buffer (100 mM NaCl, 300 mM sucrose, 10 mM PIPES pH 6.8, 5 mM MgCl 2 , 1 mM pefabloc, 10 µg/ml aprotinin, 250 µM NaF) prior to fixation in 4% paraformaldehyde (Sigma-Aldrich), or directly fixed with 4% paraformaldehyde. Antibodies used were rabbit polyclonal against Cx43 (0.5 mg/ml; C6219, Sigma-Aldrich; Tong et al., 2009), Ki67 (100 μg/ml; VP-K451, Vector; Knezevic et al., 2015), mouse monoclonal against NuMA (1:2; B1C11, a gift from Dr Jeffrey Nickerson, University of Massachusetts, Worcester, MA; Vidi et al., 2011), ZO-1 (2.5 μg/ml; 33-9100, Life Technologies; Grand Island, NY; Mao et al., 2017), α-tubulin (1:500; T5168, Sigma-Aldrich; Piao et al., 2014), β-catenin (2.5 μg/ml; C19220, BD Biosciences; Gomes et al., 2013), E-cadherin (1:50; 610181, BD Biosciences; Elisha et al., 2018), and rat anti-α6 integrin (5 μg/ml; clone NKI-GoH3, EMD Millipore, Billerica, MA; Villa-Diaz et al., 2016). For immunostaining for lysosomal associated membrane 2 (LAMP-2) (1:100; mouse, A15464, Life Technologies), cells were fixed with methanol acetone solution (1:1 ratio) without permeabilization. ...
Cell–cell communication is essential for tissue homeostasis, but its contribution to disease prevention remains to be understood. We demonstrate the involvement of connexin 43 (Cx43, also known as GJA1) and related gap junction in epithelial homeostasis, illustrated by polarity-mediated cell cycle entry and mitotic spindle orientation (MSO). Cx43 localization is restricted to the apicolateral membrane of phenotypically normal breast luminal epithelial cells in 3D culture and in vivo. Chemically induced blockade of gap junction intercellular communication (GJIC), as well as the absence of Cx43, disrupt the apicolateral distribution of polarity determinant tight junction marker ZO-1 (also known as TJP1) and lead to random MSO and cell multilayering. Induced expression of Cx43 in cells that normally lack this protein reestablishes polarity and proper MSO in 3D culture. Cx43-directed MSO implicates PI3K–aPKC signaling, and Cx43 co-precipitates with signaling node proteins β-catenin (CTNNB1) and ZO-2 (also known as TJP2) in the polarized epithelium. The distribution of Cx43 is altered by pro-inflammatory breast cancer risk factors such as leptin and high-fat diet, as shown in cell culture and on tissue biopsy sections. The control of polarity-mediated quiescence and MSO may contribute to the tumor-suppressive role of Cx43.
... Lobular carcinomas are less cohesive tumors that are characterized by impaired cell-cell adhesion with reduced expression of the adhesion molecule e-cadherin. 19,20 Reduced cell and tissue adhesion may lead to an easier spread of tumor cells and could be one explanation for the association of presence of CTCs with lobular carcinomas. In general, HER2 is rarely amplified or overexpressed in lobular carcinomas 21 ; thus, the fact that we observed an association between presence of HER2-positive CTCs and lobular carcinomas is surprising and not easily explained. ...
Aim: The DETECT study program evaluates whether treatment efficacy in women with metastatic breast cancer (MBC) is increased by taking into account the molecular characteristics of circulating tumor cells (CTCs). Here, we present data on both prevalence and HER2 phenotype of CTCs in patients with HER2 negative MBC screened within the DETECT program. The aim of this study is to evaluate the rate of discordance in HER2 phenotype between primary tumor and CTCs and to analyze whether primary tumor and/or patient characteristics can predict discordance in HER2-status.
Methods: The number of CTCs in 7.5 ml of peripheral blood (using the FDA-cleared CellSearch® System; Janssen Diagnostics, LLC) and their HER2 status were evaluated. Patients were defined as having a positive HER2-status on CTCs if at least 1 CTC with a strong (+++) immunocytochemical HER2 staining intensity was found. To assess which factors predict discordance of HER2 phenotype between primary tumor and CTCs, we used a multivariate binary logistic regression model with backward selection procedure. Patient and primary tumor characteristics included as independent factors were patient age, time since primary diagnosis, tumor stage, nodal stage, grading, histological type, and hormone receptor status (HRS).
Results: 1123 women with HER2-negative MBC were screened for CTCs. Based on a cutoff of ≥ 1 CTC, 711 (63.3%) of 1123 screened patients were positive for CTCs, while 412 (36.7%) of the 1123 screened patients were categorized as CTC positive if a cutoff of ≥ 5 CTCs was used.
At least one HER2-positive CTC was found in 134 of the 711 HER2-negative MBC patients with one or more CTCs (median 2 HER2-positive CTCs, range 1 – 80), indicating a discordance between primary tumor and CTCs with regard to HER2-status in 18.8% of patients. If the analysis was restricted to the 412 patients with 5 or more CTCs, at least one HER2-positive CTC was found in 121 patients, resulting in 29.4% discordance rate.
A multivariate logistic regression with discordance in HER2 phenotype (yes/no) as binary response variable, including number of CTCs (1 – 4 CTCs vs. 5 or more CTCs) to account for the difference in discordance rate observed at different cutoff values for CTC positivity, showed that histological type (lobular vs. ductal, odds ratio OR 2.66, 95% confidence interval CI 1.62 – 4.37, p < 0.001), HRS (positive vs. negative, OR 2.89, 95% CI 1.16 – 7.19, p = 0.022) and CTC number (5 or more CTCs vs. 1 – 4 CTCs, OR 7.57, 95% CI 3.93 – 14.89, p < 0.001) significantly predicted discordance in HER2 phenotype between primary tumor and CTCs.
Conclusion: Our data revealed discordance in HER2 status between primary tumor and CTCs in 19% to 29% of patients with HER2 negative MBC. Discordance in HER2 status was predicted by histological type and HRS of the primary tumor, as well as by the number of CTCs detected. Individualized breast cancer treatment based on CTC phenotype is currently investigated in Phase III trials and not part of clinical routine yet. However, the knowledge of factors associated with discordance in HER2 status may be incorporated in today's clinical practice by guiding the decision process for performing a biopsy to characterize a metastatic relapse.
Citation Format: Janni W, Schramm A, Friedl TWP, Schochter F, Huober J, Rack B, Alunni-Fabbroni M, Fasching PA, Taran F-A, Hartkopf A, Schneeweiss A, Müller V, Aktas B, Krawczyk N, Pantel K, Fehm T. Predictors for discordance in HER2 phenotype between primary tumor and circulating tumor cells in women with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-02.
... Detecting the origin of the metastatic lesion involved IHC determinations with the following antibodies: anti-cytokeratin 7 (CK7), anti-p63, anti-mammaglobin, anti-E-cadherin, and anti-estrogen receptor (ER) [5,6]. Additional sections from the paraffin blocks were placed on specially treated slides to insure a better adherence during the antigenic restoration process. ...
Atraumatic subtrochanteric fractures represent a serious injury of the lower limb as they represent the clinical expression of a preexisting pathology. Atypical subtrochanteric femur fractures can result from long-term bisphosphonate therapy but a primary or metastatic tumor of the proximal femur should always be included in the differential diagnosis. We present the case of a young female patient without any previous pathological conditions that presented to the emergency room with a subtrochanteric fracture. She was admitted to our clinic and treated with a long cephalomedullary device (CMD). Tissue from the fracture zone was harvested and sent for a pathology analysis. While pathologic bone fractures are not a new entity by any mean in orthopedic practice, they seldom are the first sign of a metastatic disease. This presents a therapeutic challenge especially in young patients because of the reserved overall prognosis in the medium and long term. Better screening methods should be employed in a bid to eliminate this category of patients. We consider this case of a young woman with undetected breast cancer and one skeletal-related event (SRE) in the form of a pathological bone subtrochanteric fracture as an interesting development of the underlying pathology since as the literature shows these cases are quite rare and she did not present any of the usual symptoms associated with a bone metastasis.
... In our series we evaluated nuclear grade, tumour size, comedonecrosis and age that are well established critical elements in the reporting of DCIS. Although recent genetic, molecular and immunohistochemical studies have contributed to advances in the understanding of the pathogenesis of DCIS, age and histopathological features remain the most established predictors of behavior in DCIS [1,8,[20][21][22][23][24][25][26]. ...
Background:
The histopathological subtype, nuclear grade and presence or absence of comedonecrosis are established as critical elements in the reporting of ductal carcinoma in situ (DCIS) of the breast. The aims of this study were to determine the frequencies of morphological subtypes of DCIS, nuclear grade and comedonecrosis; to compare the age of patients with the histopathological characteristics of DCIS, and to assess the agreement of grade between in situ and invasive components in DCIS cases that were associated with invasive carcinoma.
Methods:
We evaluated a series of 403 cases of DCIS, pure or associated with invasive mammary carcinoma, consecutively identified from the histopathology files of the Breast Pathology Laboratory, Federal University of Minas Gerais, Brazil, from 2003 to 2008.
Results:
DCIS displayed a single growth pattern in most cases (55.1%) and the solid subtype was the most common morphology (42.2% of the total). High-grade DCIS was identified in 293/403 cases (72.7%) and comedonecrosis was present in 222/403 cases (55%). Among DCIS with a single architectural pattern, high grade was more common in the solid subtype (151/168 cases, 89.9%; p < 0.001). Only 32% of tumours with a cribriform pattern had high nuclear grade. Comedonecrosis was more common in the solid morphology than in the cribriform, papillary and micropapillary subtypes (p < 0.001). Patients with high-grade DCIS were younger in relation to patients with low-grade DCIS (p = 0.027) and patients with tumours with comedonecrosis were also younger in comparison to patients with tumours without comedonecrosis (p = 0.003). Fair agreement was observed between in situ and invasive components with regard to grade (weighted kappa = 0.23).
Conclusions:
The high nuclear grade and the presence of comedonecrosis were identified more frequently in younger patients and more often correlated with the solid pattern of DCIS.
Virtual slides:
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_227.
... extracellular matrix formation such as snail, Twist, transforming growth factor-B (TGF-B) along with down regulation of E-cadherin [13]. Demonstration of down regulation of this molecule is demonstrated by immunohistochemistry. Loss of E-cadherin is a very useful stain in the classification of breast carcinomas in situ with mixed pattern as well as it is useful in differentiating lobular from ductal carcinoma [14]. ...
... The differential of MBC include wide range of pathological diagnosis, including lobular carcinoma, Pleomorphic carcinoma and other rare sarcoma such as angiosarcoma. E-cadherin is a very useful stain in the classification of breast carcinomas with mixed pattern [14]. Also a rare entity that was recognized by the World Health Organization (WHO) classification of tumours of the breast adopts the terminology of Pleomorphic carcinoma(PC) should be included in the differential diagnosis. ...
Metaplastic breast carcinoma is a rare entity of breast cancer expressing epithelial and/or mesenchymal tissue within the same tumor. The aim of this study is to evaluate the clinicopathological features of metaplastic breast carcinoma and to confirm the triple negative, basal-like and/or luminal phenotype of this type of tumor by using immunohistochemical staining.
Seven cases of MBC were evaluated for clinico-pathological features including follow up data. Cases were studied immunohistochemically by CK-Pan, Vimentin, ER, PR, HER2, basal markers (CK5/6, p63, EGFR, SMA and S-100), luminal cytokeratins (CK8, CK18 and CK19), markers for syncytial cells (β-HCG and PLAP), as well as prognostic markers (p53, ki-67 and calretinin).
The mean age of the patients was 36 years. Three cases showed choriocarcinomatous features. All of our cases were negative for ER, PR and HER2. Six out of the 7 cases showed basal-like differentiation by demonstrating positivity with at least one of the basal/myoepithelial markers. Also 6 out of the 7 cases expressed luminal type cytokeratins (CK8, CK18 and/or CK19). P53 was positive in 3 cases, ki-67 was strongly expressed in only one case, while calretinin was expressed in 6 cases.
Metaplastic breast carcinoma presents in our population at a younger age group than other international studies. All cases are categorized immunohistochemically under the triple negative group of breast cancer and 86% of them exhibited basal-like and luminal phenotype. Majority of cases developed local recurrence and distant metastasis in a relatively short period of time.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1101289295115804
... However, there were other conflicting diagnoses for these cases, including ADH (14%), DCIS (1.4%), and usual ductal hyperplasia (10%) [6]. In fact, the differential diagnosis of LN and intraductal proliferative lesions can be difficult, especially when concerning classic LN versus low-grade solid DCIS, and pleomorphic LCIS versus high-grade DCIS [2,18]. Despite the low number of pleomorphic LCIS cases in our study, the interobserver agreement was poor (Kappa index = 0.22). ...
... Despite the low number of pleomorphic LCIS cases in our study, the interobserver agreement was poor (Kappa index = 0.22). The immunophenotypic criteria of E-cadherin, β-catenin, and p120-catenin expression in combination with the careful identification of cytological and architectural alterations are useful tools in the morphological classification of these lesions [18,19]. ...
BackgroundThis study aimed to assess inter-observer variability between the original diagnostic reports and later review by a specialist in breast pathology considering lobular neoplasias (LN), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) of the breast.MethodsA retrospective, observational, cross-sectional study was conducted. A total of 610 breast specimens that had been formally sent for consultation and/or second opinions to the Breast Pathology Laboratory of Federal University of Minas Gerais were analysed between January 2005 and December 2010. The inter-observer variability between the original report and later review was compared regarding the diagnoses of LN, CCL, ADH, and DCIS. Statistical analyses were conducted using the Kappa index.ResultsWeak correlations were observed for the diagnoses of columnar cell change (CCC; Kappa = 0.38), columnar cell hyperplasia (CCH; Kappa = 0.32), while a moderate agreement (Kappa = 0.47) was observed for the diagnoses of flat epithelial atypia (FEA). Good agreement was observed in the diagnoses of atypical lobular hyperplasia (ALH; Kappa = 0.62) and lobular carcinoma in situ (LCIS; Kappa = 0.66). However, poor agreement was observed for the diagnoses of pleomorphic LCIS (Kappa = 0.22). Moderate agreement was observed for the diagnoses of ADH (Kappa = 0.44), low-grade DCIS (Kappa = 0.47), intermediate-grade DCIS (Kappa = 0.45), and DCIS with microinvasion (Kappa = 0.56). Good agreement was observed between the diagnoses of high-grade DCIS (Kappa = 0.68).ConclusionsAccording to our data, the best diagnostic agreements were observed for high-grade DCIS, ALH, and LCIS. CCL without atypia and pleomorphic LCIS had the worst agreement indices.Virtual SlidesThe virtual slide(s) for this article can be found here:
http://www.diagnosticpathology.diagnomx.eu/vs/1640072350119725.
Introdução: O carcinoma ductal invasor corresponde ao tipo histológico mais comum da mama coexistindo com formas diferentes de evolução clínica, graduação histológica, expressão de determinados marcadores teciduais e perfis genômicos que procuram melhor entendimento da doença. Objetivos: Analisar a correlação dos marcadores β-catenina e AXL com a agressividade tumoral, tendo como referência a sobrevida global, progressão tumoral e fatores prognósticos histopatológicos. Métodos: Foi realizado estudo de 101 amostras de carcinoma mamário ductal invasor. Foram incluídas aquelas com diagnóstico do tipo ductal, submetidas inicialmente à biópsia ou tratamento cirúrgico definitivo. Incluiu-se para fins de controle 20 amostras de carcinoma intraductal, 35 de fibroadenoma mamário e 10 de tecido mamário sem qualquer alteração. Foram excluídos os submetidos à quimioterapia neoadjuvante, que não tivessem amostra tumoral prévia ao tratamento quimioterápico, que perderam o seguimento, e com dados incompletos. Resultados: Quando analisada a expressão da β-catenina, foi negativa. Quanto ao AXL foram observados diferentes graus de expressão sem significância estatística entre eles. Conclusão: Quando analisados adenocarcinoma mamário do tipo ductal invasor em TMA não houve correlação na expressão de ß-catenina e AXL quando comparados a sobrevida global, progressão tumoral e grau histológico.
