Invasive Mammary Carcinoma Research Articles

F-18 fluoride uptake in primary breast cancer.

Bone-specific radiotracers are known to accumulate in breast lesions. Tc-99m diphosphonates have been widely studied in differentiating breast lesions. In this retrospective study, we aimed to assess the uptake of the bone-specific PET radiotracer, F-18 fluoride (NaF), in primary breast cancers to determine its sensitivity and to identify any differences in NaF uptake between calcified and non-calcified tumors, histological subtypes, and patients with or without axillary lymphadenopathy. NaF positron emission tomography/computed tomography (PET/CT) images of 69 newly diagnosed breast cancer patients were reviewed. F-18 fluoride uptake as maximum standardized uptake value (NaF SUVmax) was measured in the primary tumor, enlarged axillary lymph nodes and contralateral normal/non-tumoral breast tissue. Low-dose CT images were reviewed to locate the primary tumor and grossly assess its calcification and check for ipsilateral axillary lymphadenopathy. Whole body NaF PET/CT images were reviewed to search for bone metastases. Eighteen patients also underwent F-18 fluorodeoxyglucose (FDG) PET/CT study. The primary breast tumor was clearly seen as focal or diffuse uptake on NaF PET images in 27 of 69 patients (39%) (mean NaF SUVmax: 2.0 ± 1.0). In the rest, there was only mild bilateral diffuse breast uptake. When analyzing images per histological subtype (42 patients, 43 tumors), 14 of 31 invasive ductal carcinomas (IDC) (45%) and 3 of 4 ductal carcinoma in situ (DCIS) were visible on PET. Five invasive lobular carcinomas, 2 invasive mammary carcinomas, and 1 mucinous carcinoma were not visible on PET. Mean NaF SUVmax of contralateral normal/non-tumoral breast tissue was 1.0 ± 0.4. There was no significant difference in mean NaF SUVmax of primary tumor in cases with and without calcification or with and without axillary lymphadenopathy (p 0.892 and 0.957). There was no correlation between NaF SUVmax and FDG SUVmax values of the primary tumors (r 0.072, p 0.797, Pearson correlation). NaF PET has relatively low sensitivity in detecting breast cancer. However, abnormal breast uptake on NaF PET requires further evaluation. F-18 fluoride uptake in the primary breast tumor does not seem to be correlated with axillary lymphadenopathy (metastasis potential), gross tumor calcification or metabolic activity of the tumor.

Invasive Ductal Mammary Carcinoma in a Cow

Background: Mammary gland carcinoma is a malignant epithelial neoplasm that can be classified as solid, papillary, ductal, invasive micropapillary, or invasive ductal. They are rarely diagnosed in livestock animals. Reports describing the breast as primary site of tumor in cows are scarce. In this case report, pathological and clinical findings of primary carcinoma ofthe mammary gland in a cow are reported.Case: A 7-year-old crossbred pregnant cow exhibited an increase in volume in the posterior region of the udder. Palpation raised suspicion of mastitis. The prefemoral lymph nodes (LNs) were enlarged. After calving, the clinical condition worsened, and edema was observed in the ventral region, from the udder to the neck. Poisoning by Amaranthus sp. was suspected. The cow died fifteen days after calving. Necropsy was performed. The affected mammary gland and its LNs, fragments of abdominal organs, brain, pelvic limbs, and udder skin were routinely prepared and stained with hematoxylin and eosin. Gross examination revealed significant alterations in the mammary gland, and in the mammary and prefemoral LNs. The mammary gland was firm and swollen; with loss of normal architecture, and released purulent, pinkish, fetid contents. The mammary LNs were enlarged, with diffuse coalescentmultifocal lesions, loss of corticomedullary delimitation, and the content was similar to that observed in the udder. The internal prefemoral LNs were also enlarged and contained the same fetid contents. Histopathology revealed proliferation of neoplastic ducts coated by numerous neoplastic cells; some areas were solid. There was moderate to severe pleomorphism, with moderate anisocytosis and anisokariosis. Most of the cells had vesicular nuclei, with up to two evident nucleoli. Other cells had dense chromatin, and moderately eosinophilic cytoplasm. There was marked cell dissociation, and cell detachment. The central portionsof the ducts were necrotic, with a predominantly neutrophilic inflammation. The mitotic index was low, but some areas had up to four mitotic figures per high power field. Numerous areas exhibited multiple foci of deposition of organized granular basophilic material, interpreted as mineralized areas, and stained positively for Von Kossa stain. Some areas of the mammary gland exhibited proliferative acini and ducts, composed of a single layer of cuboidal or columnar cells with moderately eosinophilic, vacuolated cytoplasm, and a basal rounded nucleus of generally aggregated chromatin (mammary hyperplasia). Many acini were dilated, and some contained circumscribed basophilic material (corpora amylacea). The structural architecture of the LNs was altered by malignant neoplastic infiltration, similar to that found in the mammary gland. No metastatic lesions were detected in the other organs. Immunohistochemistry (IHC) was performed using the streptavidin-biotin-peroxidase technique. Anti-pan-cytokeratin and antivimentin antibodies were used. Neoplastic cells exhibited strong and uniform cytoplasmic immunoreactivity for pan-cytokeratin. Expression of vimentin was absent in the neoplastic cells, but was present in the connective tissue associated with the neoplasm.Discussion: Invasive ductal mammary carcinoma was confirmed by histopathological and IHC analyses. Edema can be explained by the neoplasm in the mammary gland and in the mammary LNs, with accumulation of fluid in the interstitium, caused by growth of the tumor and compression of large blood and lymphatic vessels. IHC confirmed the epithelial origin of the tumor and demonstrated the presence of epithelial tumor cells in the LNs, proving to be metastatic. Similar findingswere reported in a cow with a highly aggressive secretory mammary carcinoma, in which neoplastic cells exhibited immunoreactivity to cytokeratin, indicative of their epithelial origin.Keywords: histology, immunohistochemistry, neoplasms, ruminant.

SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways.

Salt Inducible Kinase2 (SIK2) has been shown to contribute to tumorigenesis in multiple tumor types in a dichotomous manner. However, little is known about its contribution to breast malignancies. Here, we report SIK2 as a potential tumor suppressor in breast cancer whose expression was reduced in tumor tissues and breast cancer cell lines compared to normal counterparts. In vitro loss- and gain-of-function experiments combined with xenograft studies demonstrated that SIK2-mediated attenuation of proliferation and survival of breast cancer cells with parallel inhibition of both Ras/Erk and PI3K/Akt pathways. Our findings elucidated that SIK2 has also an inhibitory role in migration/invasion ability of breast cancer cells through regulation of epithelial mesenchymal transition. Immunostaining of patient tumors revealed that SIK2 protein level is frequently downregulated in invasive mammary carcinomas and negatively correlated with the mitotic activity of the cells in triple negative breast cancers and hormone positive tumors. Strikingly, patient survival analysis indicated that higher levels of SIK2 are significantly associated with better survival, especially in basal breast cancer cases. Overall, our findings suggest SIK2 as a potential tumor suppressor in the control of breast tumorigenesis, at least in part, via inhibiting PI3K/Akt and Ras/ERK signaling cascades simultaneously and a novel prognostic marker, especially in basal subtypes of breast cancer.

Abstract P5-20-08: HER2 in-Situ hybridization positive breast cancers with HER2/CEP17 ratio ≥2.0 and average HER2 copy number <4.0 are frequently discordant with HER2 immunohistochemistry results: Implications for potential modification of testing algorithm

Abstract Background: The current ASCO/CAP guidelines for the determination of HER2 status indicate that dual-probe in-situ hybridization (ISH) samples demonstrating a HER2/CEP17 ratio ≥ 2.0 and average HER2 copy number <4.0 must be reported as positive. Patients with tumors showing these rare features were included in the first generation adjuvant trastuzumab clinical trials. In the absence of data showing lack of efficacy of HER2-targeted in this small subset of patients, these cases continue to be classified as positive without requiring additional work-up. Given that the HER2/CEP17 ratio is skewed in these cases by complex segmental deletions in chromosome 17, additional work-up may improve the final HER2 classification of these tumors. The objective of this study is to assess the potential impact of integrating HER2 IHC into the testing algorithm for these tumors by correlating the HER2 IHC results with ISH positive breast cancers demonstrating HER2/CEP17 ratio ≥2.0 and average HER2 copy number <4.0. Methods: All invasive mammary carcinomas demonstrating a HER2/CEP17 ratio ≥2.0 and average HER2 copy number <4.0 were identified from our database for years 2009-2017. All ISH testing was performed using the PathVysion HER2 DNA probe kit (Abbott Molecular). During the study interval, HER2 FISH was the institutional primary testing methodology to determine HER2 status. HER2 IHC (Ventana 4B5) was performed on the same sample for all identified cases and scored using 2013 ASCO/CAP scoring guidelines. Results: A total of 96 (1.4%) of 6,976 consecutive FISH cases met criteria for inclusion into the study. The majority of cases tested negative (67%) or equivocal (29%) by IHC. HER2 protein overexpression was observed in 4% of cases. The results of HER2 IHC testing are summarized below. HER2 IHC results for HER2 ISH positive tumors showing ratio≥2.0 and average HER2 copy number <4.0Cases (n)IHC Score 0IHC score 1+IHC score 2+IHC score 3+9612 (13%)52 (54%)28 (29%)4 (4%) Conclusions: HER2 ISH positive breast cancers demonstrating a HER2/CEP17 ratio ≥2.0 and average HER2 copy number <4.0 are rare (1.4% of cases in this study). HER2 IHC results for these tumors are negative in majority of cases. The observed HER2 protein overexpression rate was only 4% in this study. Integration of HER2 IHC into the testing algorithm for tumors demonstrating these uncommon ISH findings would result in reclassification of HER2 status to negative for most tumors. Citation Format: Livasy C, Johnson N, Domfeh A. HER2 in-Situ hybridization positive breast cancers with HER2/CEP17 ratio ≥2.0 and average HER2 copy number <4.0 are frequently discordant with HER2 immunohistochemistry results: Implications for potential modification of testing algorithm [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-08.

Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas.

Located at 6q22-23, Ccn6 (WISP3) encodes for a matrix-associated protein of the CCN family, characterized by regulatory, rather than structural, roles in development and cancer. CCN6, the least studied member of the CCN family, shares the conserved multimodular structure of CCN proteins, as well as their tissue and cell-type specific functions. In the breast, CCN6 is a critical regulator of epithelial-to-mesenchymal transitions (EMT) and tumor initiating cells. Studies using human breast cancer tissue samples demonstrated that CCN6 messenger RNA and protein are expressed in normal breast epithelia but reduced or lost in aggressive breast cancer phenotypes, especially inflammatory breast cancer and metaplastic carcinomas. Metaplastic carcinomas are mesenchymal-like triple negative breast carcinomas, enriched for markers of EMT and stemness. RNAseq analyses of the TCGA Breast Cancer cohort show reduced CCN6 expression in approximately 50% of metaplastic carcinomas compared to normal breast. Our group identified frameshift mutations of Ccn6 in a subset of human metaplastic breast carcinoma. Importantly, conditional, mammary epithelial-cell specific ccn6 (wisp3) knockout mice develop invasive high-grade mammary carcinomas that recapitulate human spindle cell metaplastic carcinomas, demonstrating a tumor suppressor function for ccn6. Our studies on CCN6 functions in metaplastic carcinoma highlight the potential of CCN6 as a novel therapeutic approach for this specific type of breast cancer.

Potential Anticancer Properties of Osthol: A Comprehensive Mechanistic Review.

Cancer is caused by uncontrolled cell proliferation which has the potential to occur in different tissues and spread into surrounding and distant tissues. Despite the current advances in the field of anticancer agents, rapidly developing resistance against different chemotherapeutic drugs and significantly higher off-target effects cause millions of deaths every year. Osthol is a natural coumarin isolated from Apiaceaous plants which has demonstrated several pharmacological effects, such as antineoplastic, anti-inflammatory and antioxidant properties. We have attempted to summarize up-to-date information related to pharmacological effects and molecular mechanisms of osthol as a lead compound in managing malignancies. Electronic databases, including PubMed, Cochrane library, ScienceDirect and Scopus were searched for in vitro, in vivo and clinical studies on anticancer effects of osthol. Osthol exerts remarkable anticancer properties by suppressing cancer cell growth and induction of apoptosis. Osthol’s protective and therapeutic effects have been observed in different cancers, including ovarian, cervical, colon and prostate cancers as well as chronic myeloid leukemia, lung adenocarcinoma, glioma, hepatocellular, glioblastoma, renal and invasive mammary carcinoma. A large body of evidence demonstrates that osthol regulates apoptosis, proliferation and invasion in different types of malignant cells which are mediated by multiple signal transduction cascades. In this review, we set spotlights on various pathways which are targeted by osthol in different cancers to inhibit cancer development and progression.

Epstein Barr virus and invasive mammary carcinomas: EBNA, EBERs and molecular profile in a population of West Algeria

Breast cancer is the common malignancy that affects women worldwide, but conventional risk factors account for only a small proportion of these cases. A possible viral etiology for breast cancer has been proposed and Epstein-Barr virus (EBV) is a widely studied candidate virus. The objective of this study is to determine the association of EBV infection with infiltrating ductal carcinomas (IDC). This descriptive study was carried out in the laboratory of developmental biology and differentiation, from 2012 to 2014. Of 39 cases, we determined the clinicopathological characteristics of the population. Of the 23 cases of IDC, we implemented the techniques Elisa, immunohistochemistry and in situ hybridization. To determine the serological profile, overexpression of onco-proteins EBNA-1, HER2, the mitotic index Ki67 and detection of the presence of the viral genome. The mean age is 57.40±4, SBR II predominates with 70%, pN+ (27%), RE+ (58%), RP+ (52%), HER2 (81%), Luminal A (34%), Luminal B (14%), HER2 (24%), and triple negative (28%). The serological profile of IgG VCA + in IgG EBNA-1 (87%), EBNA-1 P79 (82%) with a positive relationship between the IgG EBNA-1 and EBNA-1 P79 serology profile (p=0.001), HER2 (p=0.003) and with the molecular profile (p=0.051), EBNA-1 overexpression in (13%). The viral genome (EBER) is found in the tumors 43% representing an inverse relationship with the overexpression of Ki67 and a positive relationship with the overexpression of HER2. In our study we found an association with the presence of the EBV virus and the IDC studied.

Immunohistochemical study of GATA-3 expression versus estrogen and progesterone receptor in invasive mammary carcinomas

Background Estrogen receptor (ER)-positive and progesterone receptor (PR)-positive breast tumors are characterized by a gene expression profile exhibiting profound differences from that of ER and PR-negative tumors. GATA-3 gene expression is correlated with ER in breast cancer. Aim We aimed to evaluate immunohistochemically the expression of GATA-3 in invasive breast carcinoma, comparing this with ER and PR status and available clinicopathological features, and also to detect the association between GATA-3 and the included breast cancer molecular subtypes. Materials and methods Fifty invasive breast carcinomas were studied for immunohistochemical demonstration of GATA-3 in the tumor cells. Cases were classified into two equal groups: group 1, that is, ER and PR positive, and group 2, that is, ER and PR negative. Molecular subtyping was applied. Results GATA-3 expression was detected in 88% of cases of group 1 and 56% of cases of group 2, showing direct association with ER and PR (P=0.031) and also significant association with luminal-like breast tumors. In addition, GATA-3 showed an inverse association with Ki-67 (P=0.0269); however, GATA-3 failed to show significant association with any of the clinicopathological parameters. Conclusion GATA-3 is an important luminal marker showing strong association with ER and PR in breast cancers, suggesting being a promising new breast-specific immunomarker that could be used for detection of breast cancer origin in metastatic tumors.

Foxp3+ Regulatory T Cells in and Around Feline Invasive Mammary Carcinomas are Associated with Aggressiveness

Foxp3+ Regulatory T Cells in and Around Feline Invasive Mammary Carcinomas are Associated with Aggressiveness

HER2-expressing breast tumors are associated with breast cancer stem-cell phenotype CD44+/CD24-

ABSTRACT INTRODUCTION: According to the cancer stem-cell theory, tumors originate from a small population of cancer stem cells, which lose the mechanism of self-regulation and begin to differentiate and proliferate indefinitely. The CD44+/CD24- phenotype may be considered a stem-cell marker in breast cancer. OBJECTIVE: To evaluate the correlation between CD44+/CD24- phenotype and different molecular subtypes of breast cancer in invasive ductal carcinoma samples. METHODS: The expression of CD44, CD44v6, and CD24 markers was investigated in 133 cases of invasive mammary carcinoma with immunohistochemistry. CD44+/CD24- phenotype was identified and correlated with the molecular subtypes and classical prognostic factors such as age, histological grade, tumor size, and lymph node status. RESULTS: Eighteen (14%) cases were positive for CD44+/CD24- (CD44+/CD24- or CD44v6+/CD24-) phenotype; among these, 11.1%, 27.8%, 38.9%, and 22.2% were luminal, luminal B-human epidermal growth factor receptor 2 (HER2), HER2, and triple-negative subtype, respectively. CD44+/ CD24- phenotype was more common in HER2 subgroup (p = 0.0197). CONCLUSION: CD44+/CD24- phenotype was correlated with molecular subtypes of breast cancer. The highest expression of CD44+/CD24- phenotype was reported in patients with HER2+ disease, a molecular subtype associated with more aggressive behavior and worse prognosis.

Correlation between invasive mammary carcinoma grade and size in ultrasound-guided core needle biopsy and subsequent surgical excision.

The purpose of this study was to correlate the histologic grade, mitotic rate and size of invasive mammary carcinomas (IMC) on ultrasound (US) core needle biopsy (CNB) and the follow-up excision (FUE). The underestimation and overestimation of the grades by CNB were 11% and 8%. CNBs were more specific for grade 3 tumors. Tumors >10mm by US examination showed greater concordance in grades. The size in the FUE was the best determinant of pT followed by US examination. The extent of IMC on CNB was larger than FUE in 8% resulting in pT upstaging in 3% of cases.

Tumor-Associated Macrophages: Oblivious Confederates in Invasive Mammary Carcinoma

The infiltrating margins of carcinomas are associated with the presence of inflammatory cell infiltrate which are an integral part of the tumor microenvironment. Among the inflammatory cells, tumor-associated macrophages (TAMs) play a key role in the tumorigenesis. This study elucidates the density of TAMs in invasive mammary carcinomas and attempts to establish an association with the following pathological variables: tumor size, histological grade, nodal status, hormonal expression status and Her2Neu overexpression. Ninety diagnosed archival cases of invasive mammary carcinomas at a tertiary care center were included. Density of TAMs was assessed by using CD68 which is a pan-macrophage marker by immunohistochemistry on the archival tissue blocks. The density of TAMs (CD68 positive cells) was dichotomized into high (> 50 CD68 positive cells/HPF) and low (< 50 CD68 positive cells/HPF) and compared with the above-mentioned pathological variables using appropriate statistical tests. The density of TAMs was significantly higher around the infiltrating edge of the carcinoma in comparison with the adjoining normal terminal duct lobular units. The density of TAMs was more in the infiltrating edge of the tumor than within the tumor nodule/nests. A higher TAM density showed a significant association in tumors having large tumor size, higher histological grade, nodal metastasis, the absence of ER and PR expression and Her2Neu overexpression (p value < 0.05). TAMs play an important role in tumor progression in invasive mammary carcinomas. This is as a result of the multiple roles enacted by TAMs in the various stages of tumor development starting from tumor growth, invasion, angiogenesis and metastases. Targeted therapy against TAMs has great potential in being important components of future treatment strategies against breast carcinomas.

GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer.

The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen biosynthesis and metabolism. For instance, CYP1B1 catalyzes the hydroxylation of E2 leading to the production of 4-hydroxyestradiol that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in different tumors including breast cancer. In this scenario, it is worth mentioning that CYP1B1 expression is triggered by estrogens through the estrogen receptor (ER)α in breast cancer cells. In the present study, we evaluated whether the G protein estrogen receptor namely GPER may provide an alternate route toward the expression and function of CYP1B1 in ER-negative breast cancer cells, in main players of the tumor microenvironment as cancer associated fibroblasts (CAFs) that were obtained from breast cancer patients, in CAFs derived from a cutaneous metastasis of an invasive mammary ductal carcinoma and in breast tumor xenografts. Our results show that GPER along with the EGFR/ERK/c-Fos transduction pathway can lead to CYP1B1 regulation through the involvement of a half-ERE sequence located within the CYP1B1 promoter region. As a biological counterpart, we found that both GPER and CYP1B1 mediate growth effects in vitro and in vivo. Altogether, our data suggest that estrogens in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1 regulation. Estrogen-CYP1B1 landscape via GPER should be taken into account in setting novel pharmacological approaches targeting breast cancer development.

Expression of Stathmin and CD10 in Invasive Mammary Carcinoma with Relation to Triple Markers

Expression of Stathmin and CD10 in Invasive Mammary Carcinoma with Relation to Triple Markers

Canine invasive mammary carcinomas as models of human breast cancer. Part 1: natural history and prognostic factors

PurposeDogs have been proposed as spontaneous animal models of human breast cancer, based on clinicopathologic similarities between canine and human mammary carcinomas. We hypothesized that a better knowledge of the natural history and prognostic factors of canine invasive mammary carcinomas would favor the design of preclinical trials using dogs as models of breast cancer.MethodsThe 2-year outcome of 350 female dogs with spontaneous invasive mammary carcinoma was studied. The investigated prognostic factors included age at diagnosis, pathologic tumor size, pathologic nodal stage, lymphovascular invasion, histological grade, and expression of Estrogen Receptor alpha (ERα), Progesterone Receptor, Ki-67, Human Epidermal Growth Factor Receptor 2, basal cytokeratins 5/6, and Epidermal Growth Factor Receptor. Multivariate survival analyses were performed using the Cox proportional hazards model.ResultsThe overall survival after mastectomy was 11 months. Within 1 year post mastectomy, 41.5% of dogs (145/350) died from their mammary carcinoma. By multivariate analysis, the significant prognostic factors for overall survival included a pathologic tumor size larger than 20 mm [HR 1.47 (95% confidence interval 1.15–1.89)], a positive nodal stage [pN+, HR 1.89 (1.43–2.48)], a histological grade III [HR 1.32 (1.02–1.69)], ERα negativity [HR 1.39 (1.01–1.89)], a high Ki-67 proliferation index [HR 1.32 (1.04–1.67)], and EGFR absence [HR 1.33 (1.04–1.69)].ConclusionThe short natural history of spontaneous canine invasive mammary carcinomas and high rate of cancer-related death allow for rapid termination of preclinical investigations. The prognostic factors of invasive mammary carcinomas are remarkably similar in dogs and humans, highlighting the similarities in cancer biology between both species.

Canine invasive mammary carcinomas as models of human breast cancer. Part 2: immunophenotypes and prognostic significance

PurposeRelevant animal models of human breast cancer are currently needed, especially for the aggressive triple-negative breast cancer subtype. Recent studies and our results (Part 1) indicate that spontaneous canine invasive mammary carcinomas (CMCs) resemble human breast cancer by clinics and pathology as well as behavior and prognostic indicators. We hypothesized that the current molecular classifications of human breast cancer, used for therapeutic decision, could be relevant to dogs.MethodsThree hundred and fifty female dogs with spontaneous CMC and a 2-year follow-up were retrospectively included. By immunohistochemistry, CMCs were classified according to Nielsen (Clin Cancer Res 10:5367–5374, 2004) and Blows (PlosOne doi: 10.1371/journal.pmed.1000279, 2010) into the subtypes of human breast cancer.ResultsFour immunophenotypes were defined either according to Nielsen classification (luminal A 14.3%, luminal B 9.4%, triple-negative basal-like 58.6%, and triple-negative nonbasal-like 17.7% CMCs); or to Blows classification (luminal 1−: 11.4%, luminal 1+: 12.3%, Core basal phenotype: 58.6%, and five-negative phenotype: 17.7%). No HER2-overexpressing CMC as defined by a 3 + immunohistochemical score was observed in our cohort. By univariate and multivariate analyses, both immunophenotypical classifications applied to CMCs showed strong prognostic significance: luminal A or luminal 1+ CMCs showed a significantly longer disease-free interval (HR = 0.46), Overall (HR = 0.47), and Specific Survival (HR = 0.56) compared to triple-negative carcinomas, after adjustment for stage.ConclusionsIn our cohort, triple-negative CMCs largely predominated (76%), were much more prevalent than in human beings, and showed an aggressive natural behavior after mastectomy. Dogs are thus potent valuable spontaneous models to test new therapeutic strategies for this particular subtype of breast cancer.

Severe cognitive decline following chemotherapy of breast cancer

Chemotherapy for different types of cancer is often life-saving. On the other hand, the spectrum of side effects may involve the central nervous system (CNS) and lead to severe emotional and cognitive disturbances, a syndrome often referred to as “The Chemo Brain”. Here we report on a then 43-year-old female patient who first presented to our clinic in 2013 and in whom breast cancer of the right breast had been diagnosed four years earlier. At that time she became a patient of the Comprehensive Cancer Center of the University of Ulm (CCCU) and underwent breast-conserving therapy starting with systemic chemotherapy according to the rules of the GeparQuinto Study. This was followed by breast-conserving operation including axillary lymphonodectomy. Histological examination of the excised material revealed an invasive ductal mammary carcinoma the exact staging of which will be reported in detail. Convalescence of the patient was protracted, and she continued complaining of difficulties to concentrate and to remember what she had been told or read shortly before. In addition, she complained of frequent mood swings. Therefore, she was referred to our department. Exploring her case history, we learned that she had worked as a manager of a car rental company which she had no longer been able to do after her cancer treatment because of her cognitive deficits. Beside clinical and psychiatric examination, our diagnostic procedures included electroencephalography (EEG), magnetic resonance tomography (MRT) of the brain using gadolinium enhancement, and extensive neuropsychological testing. In detail, components of the Wechsler Adult Intelligence Scale (WAIS), the Ray Auditory Verbal Learning Test (RAVLT), the Multiple Choice Vocabulary (“Mehrfachwahl-Wortschatztest”), the “Regensburger Wortflussigkeitstest” (Regensburg Word Fluency Test, RWT), and the “Testbatterie zur Aufmerksamkeitsprufung” (Test Battery for the Assessment of Attention, TAP) were applied. Whereas the EEG was unremarkable, the MRT performed in 2013 showed brain atrophy with frontotemporal accentuation. As an accessory finding, an arachnoid cyst was detected at the left temporal pole. No metastases were found. Interestingly, we had the opportunity to compare these findings with those of an earlier MRT performed in 2011. In the latter one, the arachnoid cyst was also visible, but there was no pronounced brain atrophy. These observations raise the question if progressive brain atrophy might be associated with the syndrome of “Chemo Brain”. Neuropsychological examination revealed severe cognitive deficits in this patient – details of which will be reported – apparently due to the chemotherapy she had undergone. Possible mechanisms of action, treatment options, and ethical implications will be discussed.

Tumor-associated macrophages: Oblivious confederates in invasive mammary carcinoma

Abstract Background: The infiltrating margins of carcinomas are associated with presence of inflammatory cell infiltrate which are an integral part of the tumor microenvironment. Amongst the inflammatory cells, Tumor Associated Macrophages (TAMs) play a key role in the tumorigenesis. This study elucidates the density of TAMs in invasive mammary carcinomas and attempts to establish aa association with the following pathological variables: tumor size, histological grade, nodal status, hormonal expression status and Her2Neu overexpression. Materials and Methods: 90 diagnosed archival cases of invasive mammary carcinomas at a tertiary care centre were included. Density of TAMs was assessed by using CD68 which is a pan-macrophage marker by immunohistochemistry on the archival tissue blocks. The density TAMs (CD68 positive cells) was dichotomised into high (&gt;50 CD68 positive cells/HPF) and low (&lt;5050 CD68 positive cells/HPF) and compared with the above mentioned pathological variables using appropriate statistical tests. Results: The density of TAMs was significantly higher around the infiltrating edge of the carcinoma in comparison to the adjoining normal terminal duct lobular units. The density of TAMs was more in the infiltrating edge of the tumor than within the tumor nodule/nests. A higher TAM density showed a significant association in tumors having large tumor size, higher histological grade, nodal metastasis, absence of ER and PR expression and Her2Neu overexpression (p value &lt;0.05). Conclusion: TAMs play an important role in tumor progression in invasive mammary carcinomas. This is as a result of the multiple roles enacted by TAMs in the various stages of tumor development starting from tumor growth, invasion, angiogenesis and metastases. Targeted therapy against TAMs has great potential in the being important components of future treatment strategies against breast carcinomas.

Concordant clear cell \u201cmesonephric\u201d carcinoma of the bladder and lung adenocarcinoma with clear cell features \u2013 multiple primaries versus metastatic neoplasms: a case report

BackgroundClear cell carcinoma of the bladder is a rare variant of urinary bladder adenocarcinoma. We report a case of a patient with clear cell carcinoma of the bladder and a concordant right upper lobe pulmonary adenocarcinoma with clear cell features, and we address the role of immunohistochemistry and cytogenetic analysis in distinguishing the two primary malignancies.Case presentationOur patient was a 59-year-old African American woman who presented with hematuria. Her past medical history included invasive mammary carcinoma and end-stage renal disease treated with hemodialysis. A computed tomographic urogram revealed a 3-cm polypoid bladder mass. A follow-up chest computed tomographic scan revealed a 1-cm right upper lobe nodule. The patient underwent transurethral biopsy and subsequent radical cystectomy, as well as a transthoracic core needle biopsy of the lung nodule. Histologically, the bladder tumor consisted of flat, cuboidal to columnar cells with clear or eosinophilic cytoplasm and a hobnail appearance, organized in tubulocystic and papillary patterns. The neoplastic cells were diffusely positive for α-methylacyl-coenzyme A racemase, cancer antigen 125, and cytokeratin 7; focally positive for cytokeratin 20, P53, and carcinoembryonic antigen; and negative for thyroid transcription factor 1. The lung tumor demonstrated a glandular architecture with mucin production (positive for mucin with mucicarmine and periodic acid-Schiff with diastase stain). The neoplastic cells were diffusely positive for cytokeratin 7, napsin A, and thyroid transcription factor 1, and they were negative for cytokeratin 20 and cancer antigen 125. Genetic testing of the pulmonary neoplasm demonstrated ARID2 genomic alterations.ConclusionsThe presence of clear cell features in both neoplasms raised the possibility of lung metastasis from the primary bladder tumor. However, the glandular architecture of the lung neoplasm along with its distinctive immunohistochemical and genetic profiles confirmed the presence of two separate primaries.

Is tumor cellularity in primary invasive breast carcinoma of prognostic significance?

Many methods of analysis to predict survival of invasive mammary carcinoma in the post-neoadjuvant setting utilize tumor cellularity alone or in combination with other tumor features. The goal of this study was to evaluate the prognostic value of tumor cellularity in primary non-treated carcinoma. We used 366 cases of invasive breast carcinoma to determine invasive tumor cellularity (%) by reviewing a representative excisional tumor section and correlated this with breast cancer recurrence (BCR) and overall mortality (OM). Mean patient age was 58years (range, 21-91) and median follow-up was 87months (range, 0.7-165). Of the cases, 25% were Nottingham grades I, 41% grade II, and 32% grade III. The Nottingham Prognostic Index (NPI) ranged from 2.06 to 6.8 (mean 3.93). Estrogen receptor was positive in 66% and negative in 25% of cases. Cellularity ranged from 2 to 99% (mean 47.6%). The OM hazard ratio increased by 1.73 for every unit increase in NPI (P<0.00005; 95% confidence interval 1.45-2.05) The BCR hazard ratio increased by 2.011 for every unit increase in NPI BCR (P<0.00005; 95% confidence interval 1.62-2.50). Cellularity, unadjusted for other covariates, was not significantly associated with either OM or BCR. When adjusted for NPI, cellularity still showed no significant relation to OM or BCR. The same analysis performed on estrogen receptor-positive and estrogen receptor-negative subgroups continued to show no relation between cellularity and OM or BCR. In conclusion, despite its utility in the neoadjuvant setting, we were unable to show that cellularity is predictive of survival in primary breast carcinomas.