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Background: The activity impairment of Phosphatase and tensin homolog (PTEN), a tumor suppressor and negative regulator of the PI3K/Akt pathway, is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing for the identification of high-risk breast cancer is improved by the analysis of PTEN status.Methods: The study group consisted of 608 breast cancers (group A) extracted from our tissue microarray biobank and a total of 4,265 patients (group B) from the METABRIC and MSK studies available at cBioPortal. Cases from the group A were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT) according to the PTEN expression levels by immunohistochemistry (IHC) and scored based on the ratio between normal and tumor tissue. Clinical and genomic data from group B were also analyzed, and, together with those from group A, relationships between PTEN and the clinicopathologic and molecular features were assessed using Fisher’s exact test, Chi-squared test, or Shapiro-Wilk test for continuous variables. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for each variable. To identify factors associated with PTEN expression, multinomial logistic regression models were defined considering a stepwise selection procedure. Survival curves were built according to the Kaplan-Meier method and compared using the log-rank test.Results: Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from group A, while genetic aberrations in only 315/4,265 (7.4%) cases of group B. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n=48, 17.1%) compared to PTEN-WT tumors (n=22, 6.7%; p=0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival but not disease-free survival in PTEN-L but not in PTEN-WT breast cancers (p Citation Format: Nicola Fusco, Elham Sajjadi, Konstantinos Venetis, Marco Invernizzi, Donatella Gambini, Letterio Runza, Stefano Ferrero, Elena Guerini-Rocco. Combined analysis of PTEN and routinely assessed biomarkers reveals new high-risk subgroups of HR- or HER2+ breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-23.

Background: Breast cancer is the most common malignancy occurring during gestation and should be managed with the same protocols as for young non-pregnant women. In early-stage breast cancer during pregnancy (PrBC), breast-conserving surgery (BCS) with delayed radiation therapy (RT) is a reasonable alternative to radical mastectomy. Regrettably, no specific and widely adopted guidelines on the surgical management of these patients are available. In this study, we investigated the feasibility and safety of BCS during the first trimester of pregnancy in women with early-stage PrBC. Method: The first trimester was defined as 12 weeks and 6 days after the first day of the last menstruation. As for internal protocols, the surgical strategy for PrBC followed the same conservative-oriented schemes applied for nonpregnant patients. Only women with early-stage PrBC treated with BCS during pregnancy followed by planned RT to the whole breast after delivery were included. Exclusion criteria were i) clinical diagnosis or suspicion of inflammatory breast cancer; ii) multicentric disease; iii) diffuse malignant microcalcifications on mammography; iv) previous; v) connective tissue disease, and vi) syndromic breast cancers. All cases underwent central pathological review at the Pathology Department of the European Institute of Oncology. The primary outcome was the isolated local recurrence (ILR). Results: Among 168 PrBC patients, 67 (39.9%) were diagnosed during the first trimester of gestation. Of these, 30 patients (age range, 23-43 years; median=36 years; gestational age, 2-12 weeks; median=7 weeks; median follow-up time=6.5 years) met the inclusion criteria. None of the patients included in this study experienced perioperative surgical complications. No ILR was observed within three months (n=30), 1 year (n=27), and 5 years (n=18) after surgery. The 5-year overall survival rate for all patients was 97% (n=29/30). Four patients experienced ILR or new carcinomas after 6-13 years. These patients are still alive and disease-free after 14-17 years of follow-up. Discussion: In our study, both adjuvant endocrine therapy and anti-HER2 treatment were postponed after delivery. Local recurrences/second primary tumors were observed in 4 out of 30 patients treated with BCS. Given that patient #4 did not receive postoperative RT, but an after-delivery mastectomy for preoperative diagnostic underestimation during pregnancy, this case does not represent a post-BCS recurrence. On the other hand, cases #1-3 could be considered real relapses. Two of these tumors occurred in patients that underwent CT during pregnancy, in which the interval between the end of systemic therapies and the onset of RT was not influenced by the pregnancy. In a single patient (not eligible for systemic treatment in pregnancy), the RT was performed with a longer interval than the usual one of the non-pregnant patients. Survival was not affected by local relapse, underlining the efficacy of salvage treatment.Conclusion: The findings of this study suggest that BCS in the first trimester of pregnancy can be considered reasonably safe for both mother and the child. Mammography should be mandatory in all patients for whom conservative surgery is recommended. Given that the availability of data concerning PrBC and its treatment is scarce and heterogeneous, multicentric studies are warranted. Citation Format: Nicola Fusco, Concetta Blundo, Massimo Giroda, Elham Sajjadi, Konstantinos Venetis, M. Cristina Leonardi, Elisa Vicini, Luca Despini, Claudia F. Rossi, Letterio Runza, Eugenia Di Loreto, Giovanna Scarfone, Elena Guerini-Rocco, Giuseppe Viale, Paolo Veronesi, Barbara Buonomo, Fedro A. Peccatori, Viviana E. Galimberti. Feasibility and safety of breast-conserving surgery in early-stage breast cancers during the first trimester of pregnancy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-08.

Context.— Extramedullary hematopoiesis (EMH) is an uncommon occurrence, usually associated with hematologic disorders, but it rarely presents as an isolated finding. Objective.— To determine the frequency, immunomorphologic features, and clinicopathologic background of EMH in orchiectomies from pediatric patients. Design.— All orchiectomy specimens removed from children from 2008 to 2020 in our institution were retrospectively reviewed. Biopsies and neoplasias were excluded. The EMH diagnosis was rendered when hematopoietic cell precursors were present. Immunohistochemical stainings were performed to characterize the hematopoietic components. Results.— Seventy-nine orchiectomies from 77 children (mean age, 5 years; range, 0–17 years) were included in our study. Forty-three patients (55.8%) underwent surgery for testicular atrophy, 30 (39.0%) for torsion, and 4 (5.2%) for intersex conditions. EMH was identified in 6 of 79 orchiectomies (7.6%), all performed for testicular torsion. All patients but one were newborns, and the remaining patient was 15 years old. No patient had evidence of a hematologic disorder. All EMH foci were in a background of reactive changes with a variable extension, either in the epididymis (4 cases) or in the deferens duct (2 cases). Immunostaining confirmed an association of myeloid (myeloperoxidase+) and erythroid precursors (E-cadherin+) in all 6 cases. One case also presented rare megakaryocytes, and one showed benign TdT+ B-cell precursors. Conclusions.— To our knowledge, this is the first study that demonstrates EMH as a common finding in orchiectomy samples, especially from newborns. Despite the lack of pathologic potential, it is important to recognize EMH in order to avoid misdiagnosis.

Background Bladder cancer (BC) usually metastasizes to the lymph nodes, bone, lung, liver and peritoneum, but rarely in the breast. Case report We present a case of a 66-year-old female diagnosed with a massive bladder tumor, who presented a right mammary nodule after neo-adjuvant chemotherapy. A biopsy of the nodule did not permit a definite diagnosis of metastatic spread, which was confirmed by excision of the nodule. In the literature, we found only 7 other similar cases of BC metastasis to the breast. Currently, a non-invasive method for differentiating a breast metastasis from primary cancer is lacking, although there are some clinical and radiological aspects that may help the diagnosis. Histological examination provides diagnostic certainty. Conclusion Breast metastases from BC are unusual and consequently difficult to identify without non-invasive tools. Clinical history and histological study play a pivotal role in determining the correct diagnosis.

Introduction: Breast cancer (BC) occurring during gestation or lactation is rare, yet highly challenging under both biological and clinical standpoints. This condition, referred to as pregnancy-associated (PA) BC (PABC), shows enrichment in mismatch repair (MMR) deficiency mutational signature, higher expression of immune-checkpoint genes, and less tumor-infiltrating lymphocytes (TILs) compared to non-PA BCs. Despite these insights, no comprehensive data on MMR protein status, immune checkpoints, and immune microenvironment are currently available for these tumors. The aim of this study was to characterize the MMR status and immunologic milieu of PABC. Methods: Among a multi-Institutional database comprising 142 PABCs, we conducted a comparative analysis of a cohort of PABC (n=29) and a control group of age-matched non-PA BCs (n=74). Distinct areas of each tumor and the corresponding normal breast tissue were incorporated into a tissue microarray (4-6 cores per case, mean 4.5). For all cases, both stromal and intratumoral TILs were quantified according to the International TILs Working Group recommendations. Representative slides were subjected to immunohistochemical (IHC) analysis of the MMR proteins (i.e. MLH1, MSH2, MSH6, and PMS2), programmed death-ligand 1 (PD-L1), CD4, and CD8. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and, when the protein was expressed only in a part of the tumor, MMR-heterogeneous (hMMR). PD-L1 expression was evaluated separately in the tumor cells, stromal TILs, and intratumoral TILs. Finally, the relative proportion of CD4+ and CD8+ cells was assessed in both stromal and intratumoral TILs. Results: The study group included 4 (14%) Luminal A, 10 (35%) Luminal B, 4 (14%) non-luminal HER2+, and 11 (37%) triple-negative (TN) PABCs. Taken together, both the dMMR and hMMR status were more common in PABCs than in non-PA BC (n=3/29, 19% vs. n=6/74, 8% and n=7/29, 24% vs. 14/74, 19%, respectively). Specifically, dMMR was seen in Luminal A (n=2, 50%) and in TN (n=1, 9%) PABCs. Conversely, in non-PA BCs, all Luminal A (n=15, 100%) were pMMR, while 5/45(11%) Luminal B and 1/13 (7%) TNBC were dMMR. Despite no differences were observed in intratumoral TILs, PABCs showed significantly higher levels of stromal TILs (p=0.01). Compared to the control group, PD-L1 expression in PABCs was significantly higher in the tumor cells and in stromal TILs (p Discussion: This study is the first to investigate the immune response alongside the MMR status by IHC in PABCs. Our findings broaden the understanding of the immunobiology underpinning PABC, suggesting that in these tumors i) MMR protein alterations occur at higher frequency than in non-PA BCs; ii) the tumor cells and tumor microenvironment may be capable to suppress the adaptive arm of immune system through the expression of PD-L1; and iii) lymphocytes located at the periphery rather than those inside of the tumor are likely to be implicated in the immune modulation. Conclusion: The MMR system and immune microenvironment may play a consistent role in the natural history of PABCs. An intimate knowledge of the multifaceted interplay between tumor and tumor immune microenvironment is likely to unveil clinically relevant mechanisms that may have a positive net health impact for women with BC during gestation or lactation. Citation Format: Nicola Fusco, Elena Guerini-Rocco, Barbara Buonomo, Roberto Croci, Caterina Fumagalli, Gianluca Lopez, Giorgio A Croci, Letterio Runza, Elham Sajjadi, Concetta Blundo, Luca Despini, Massimo Giroda, Viviana E Galimberti, Paolo Veronesi, Massimo Barberis, Stefano Ferrero, Giovanna Scarfone, Silvano Bosari, Giuseppe Viale, Fedro Peccatori. Integrated analysis of mismatch repair, PD-L1, and immune microenvironment status in pregnancy-associated breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-03.

We defined prostate-specific antigen (PSA) thresholds from a well calibrated risk prediction model for identifying and excluding advanced prostate cancer (PCa). We retrieved 902 biopsied patients with a pre-biopsy PSA determination (Roche assay). A logistic regression model predictive for PCa including the main effects [i.e., PSA, age, histological evidence of glandular inflammation (GI)] was built after testing the accuracy by calibration plots and Hosmer-Lemeshow test for goodness of fit. PSA thresholds were derived by assuming a diagnostic sensitivity of 95% (rule-out) and 80% (rule-in) for overall and advanced/poorly differentiated PCa. In patients without GI, serum PSA concentrations ≤ 4.1 (&lt, 65 years old) and ≤3.7 μg/L (≥65 years old) excluded an advanced PCa (defined as Gleason score ≥ 7 at biopsy), with a negative predictive value of 95.1% [95% confidence interval (CI): 83.0–98.7] and 88.8% (CI: 80.2–93.9), respectively, while PSA &gt, 5.7 (&lt, 65) and &gt, 6.1 μg/L (≥65) should address biopsy referral. In presence of GI, PSA did not provide a valid estimate for risk of advanced cancer because of its higher variability and the low pre-test probability of PCa. The proposed PSA thresholds may support biopsy decision except for patients with asymptomatic prostatitis who cannot be pre-biopsy identified.

Noninvasive breast lesions encompass a heterogeneous group of risk indicators and nonobligate precursors of breast cancer, such as apocrine hyperplasia (AH) and columnar cell lesions (CCLs). Given the different expression of ER and ER-regulated genes in AH and CCL, these two alterations are currently considered discrete conditions. However, whether they share early biologic changes is not clear to date. Here, we sought to define the clinicopathologic and immunohistochemical features of a prospective series of combined lesions made up by CCLs and AH forming a continuum within single terminal duct-lobular units. The study group included 19 cases, whereas 25 cases of synchronous contiguous CCLs and AH served as control group. The different components of each case were subjected to immunohistochemical analysis for ER, PR, AR, HER2, BCL2, CCND1, MUC1, and PIP. Although CCLs and AHs arising in continuity showed opposite patterns of ER expression, the PIP-positive apocrine signature was consistently present in both components. In conclusion, apocrine changes are highly recurrent in CCLs growing within foci of AH, regardless of the ER activation. Our results suggest that PIP-positive and PIP-negative CCLs are likely to represent biologically distinct conditions and that apocrine changes might occur earlier than ER activation in the natural history of breast precursor lesions.

Background Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer. Methods A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher’s exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method. Results Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p p = 0.002). Conclusions The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer.

Background Miescher’s cheilitis granulomatosa (MCG) is a rare chronic inflammatory disease and is known as the monosymptomatic clinical form of Melkersson-Rosenthal syndrome (MRS). It is characterised by swelling of one or both lips and more frequently affects the upper lip. Histopathological findings show the presence of numerous inflammatory infiltrates and granuloma formations. Pharmacological treatments and surgery have provided results that are positive yet insufficiently stable in the long term. The clinical case described is of a 68-year-old female patient with a diagnosis of MCG of the upper lip. Case presentation The patient was diagnosed and treated at the Oral Medicine and Oral Pathology outpatient clinic of Maxillofacial and Odontostomatology Unit, Fondazione Cà Granda IRCCS Ospedale Maggiore Policlinico. The patient was recommended localised treatments of photobiomodulation (PBM) using a diode laser with a 635 nm and 980 nm dual-wavelength (λ) approach, a 600-micron fibre, and a handpiece with a 1-cm-diameter lens at 300 mW. Three treatments a week were administered for four weeks for a total of 12 treatment sessions (T1–T12). After that, the patient had a long follow-up period of about 2 years. The therapeutic results were clear from the initial stages of treatment. There was an immediate, gradual, and consistent reduction in labial swelling. A reduction in the size of the lip by about 35% at T10–T12 was observed, returning the size and volume of the upper lip within the normal clinical range. The painful symptoms subsided after the seventh treatment (T7). The histopathological check at 3 months and the follow-up in particular confirmed the disease was in remission with satisfactorily stable treatment results. Moreover, the patient did not use any other treatments on the area from the early laser treatments through to the end of the follow-up period. Conclusions Our experience describes a clinical case of MCG treated with PBM and effectively resolved with a reduction of the lip swelling. The real success of the treatment emerged over time, showing that the tissue healing was stable. In absence of any collateral phenomena, this confirms the effective and documented therapeutic potential of PBM for chronic inflammatory infiltrates.

Breast cancer related lymphedema (BCRL) is a detrimental condition characterized by fluid accumulation in the upper limb in breast cancer patients subjected to axillary surgery and/or radiations. Its etiology is multifactorial and include also tumor-specific pathological features, such as lymphovascular invasion (LVI) and extranodal extension (ENE). To date, no widely employed guidelines for the early diagnosis of BCRL are available. Here, we illustrate a protocol for a digitally assisted BCRL assessment using a 3D laser scanner (3DLS) and a tablet computer. It has been specifically optimized in a discovery cohort of high-risk breast cancer patients. This study provides a proof-of-principle that augmented reality tools, such as 3DLS, can be incorporated into the clinical workup of BCRL to allow for a precise, reproducible, reliable, and cheap diagnosis.

The authors present an unusual case of a patient suffering from visual deficit due to pituitary granulomatosis with polyangiitis (GPA) associated with Rathke's cleft cyst (RCC). The patient was referred to our Neurosurgery Department presenting right eye amaurosis, third cranial nerve palsy, and left temporal hemianopsia. Magnetic resonance imaging documented a sellar or suprasellar lesion with solid and cystic components. The dura mater of the skull base was also strongly enhanced. The patient underwent surgery. Histologic examination revealed RCC associated with pituitary GPA. To our knowledge, this is the first reported case of concomitant pituitary GPA and RCC. Pituitary involvement in GPA is rare, usually diagnosed in hormonal dysfunctions. The patient in case first presented optic chiasm compression, probably due to inflammation of both the pituitary gland and the previously asymptomatic RCC. We focus on the symptoms that led us to diagnose GPA pituitary involvement and on the peculiar and unusual Magnetic resonance imaging of the case presented.

// Chiara Pesenti 1, 2 , Leda Paganini 1, 2 , Laura Fontana 1 , Emanuela Veniani 2 , Letterio Runza 2 , Stefano Ferrero 2, 3 , Silvano Bosari 1, 2 , Maura Menghi 4 , Giovanni Marfia 5, 6 , Manuela Caroli 6 , Rosamaria Silipigni 7 , Silvana Guerneri 7 , Silvia Tabano 1 and Monica Miozzo 1, 2 1 Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy 2 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 3 Department of Biomedical, Surgical and Dental Sciences, Universita degli Studi di Milano, Milan, Italy 4 Diatech Pharmacogenetics, Jesi, Italy 5 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy 6 Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy 7 Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy Correspondence to: Silvia Tabano, email: silvia.tabano@unimi.it Keywords: glioma, 1p/19q LOH, massARRAY, IDH, TERT Received: March 13, 2017 Accepted: June 19, 2017 Published: July 08, 2017 ABSTRACT The World Health Organization recently revised the diagnosis of glioma, to integrate molecular parameters, including IDH mutations and codeletion (loss of heterozygosity; LOH) of chromosome arms 1p/19q, into the definitions of adult glioma histological subtypes. Mutations in the TERT promoter may also be useful for glioma diagnosis and prognosis. The integration of molecular markers into routine diagnosis requires their rapid and reliable assessment. We propose a MassARRAY (MS)-based test that can identify 1p/19q codeletion using quantitative SNP genotyping and, simultaneously, characterize hotspot mutations in the IDH1 , IDH2 , and TERT genes in tumor DNA. We determined the reliability of the MS approach testing 50 gliomas and comparing the MS results with those obtained by standard methods, such as short tandem repeat genotyping, array comparative genomic hybridization (array-CGH) and Fluorescence In Situ Hybridization (FISH) for 1p/19q codeletion and Sanger sequencing for hotspots mutations. The results indicate that MS is suitable for the accurate, rapid, and cost-effective evaluation of chromosome deletions combined with hotspot mutation detection. This MS approach could be similarly exploited in evaluation of LOH in other situations of clinical and/or research importance.

Breast cancer related lymphedema (BCRL) is frequent but strategies for an individualized risk assessment are lacking. We aimed to define whether tumor-specific pathological features, coupled with clinical and therapeutic data, could help identify patients at risk. Data from 368 patients with node-positive breast cancers were retrospectively collected, including 75 patients with BCRL (0.4&ndash, 25.6 years follow-up). BCRL was assessed during the standard follow-up oncology visits using the circumferential measurement. Clinicopathologic and therapeutic factors associated with BCRL were integrated into a Cox proportional hazards regression model. Lymphovascular invasion (LVI) was more common in BCRL patients (n = 33, 44% vs. n = 85, 29%, p = 0.01), akin extra nodal extension (ENE) of the metastasis (n = 57, 76% vs. n = 180, 61%, p = 0.02). Sentinel lymph node excision without axillary dissection and extra-axillary radiotherapy were BCRL-unrelated. A higher number of BCRL-positive patients were treated with taxane-based chemotherapy with or without trastuzumab, compared to BCRL-negative patients (p &lt, 0.01). Treatment with trastuzumab and/or taxanes, adjusted for systemic infections, laterality, therapy, and pathological features (i.e., LVI and ENE), had a significant impact in BCRL-free survival (p &lt, 0.01). This work offers new insights on BCRL risk stratification, where the integration of clinical, therapeutic, and tumor-specific pathological data suggests a possible role of anti-human epidermal growth factor receptor 2 (HER2) therapy in BCRL pathogenesis.

Targeted therapies against the human epidermal growth factor receptor 2 (HER2) have radically changed the outcome of patients with HER2-positive breast cancers. However, a minority of cases displays a heterogeneous distribution of HER2-positive cells, which generates major clinical challenges. To date, no reliable and standardized protocols for the characterization and quantification of HER2 heterogeneous gene amplification in large cohorts have been proposed. Here, we present a high-throughput methodology to simultaneously assess the HER2 status across different topographic areas of multiple breast cancers. In particular, we illustrate the laboratory procedure to construct enhanced tissue microarrays (TMAs) incorporating a targeted mapping of the tumors. All TMA parameters have been specifically optimized for the silver in situ hybridization (SISH) of formalin-fixed paraffin-embedded (FFPE) breast tissues. Immunohistochemical analysis of the prognostic and predictive biomarkers (i.e., ER, PR, Ki67, and HER2) should be performed using automated procedures. A customized SISH protocol has been implemented to allow a high-quality molecular analysis across multiple tissues that underwent different fixation, processing, and storage procedures. In this study, we provide a proof-of-principle that specific DNA sequences could be localized simultaneously in distinct topographic areas of multiple and heterogeneously processed breast cancers using an efficient and cost-effective method.

Extracranial carotid artery aneurysms (ECAA) are a rare cause of embolic stroke. The underlying etiology is variable, with atherosclerosis being the most common entity in older subjects. Several treatments have been developed over the last 20 years, but the preferred method remains unknown. Notwithstanding the widespread use of endovascular techniques, surgical reconstruction by means of a bifurcated venous bypass graft should be applied in younger patients. In this way, it is possible to avoid major concerns about the development of long-term intrastent restenosis, and also to spare the external carotid artery which represents the main branch for the ipsilateral cerebral and facial perfusion. We propose ECAA resection and interposition of the inverted great saphenous vein to both the internal and external carotid artery by means the use of a tributary, i.e., the Giacomini vein.

Olmesartan is an angiotensin II receptor blocker (ARB) approved for the treatment of hypertension since 2002. Olmesartan-associated enteropathy (OAE), first described in 2012 by Rubio-Tapia, has seldom been considered as a diagnosis in patients with villous atrophy and negative serology for celiac disease. The clinical presentation could be extremely heterogenous. In contrast to celiac disease, there is no response to a gluten-free diet. The exact mechanism of intestinal injury still remains unknown. The histological pattern, at the upper gastrointestinal endoscopy, usually reveals a variable degree of villous atrophy and a moderate infiltration of lymphocytes at mucosal level. Symptoms usually improve upon olmesartan discontinuation and the repeat endoscopy could demonstrate complete resolution of inflammatory change with normal villous architecture. The differential diagnosis for this kind of clinical and pathological features include celiac disease, tropical sprue, autoimmune enteropathy, inflammatory bowel disease, and drug induced enteropathy. With this background, we report the case of a patient with a clinical picture compatible with seronegative celiac disease and symptoms that rapidly improved clinically and histologically after olmesartan discontinuation. In conclusion, although this condition is rare, physicians should be consider this medication in the differential diagnosis of this enteropathy.

Aims: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology. Methods and results: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E-cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2–STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2–STAT6 fusion variant (exon 4–exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified. Conclusions: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours

Phosphatase and tensin homolog (PTEN), a potent downregulator of the PI3K-Akt pathway, has been shown to mediate the interaction between poly (ADP-ribose) polymerases (PARPs) and the mismatch repair (MMR) complex in endometrial and ovarian cancer. Drugs inhibiting PARPs (iPARPs) are currently considered promising therapeutic tools in a subset of PTEN-defective tumors. Regrettably, the frequency and significance of MMR alterations in breast cancer is debated, and their relationship with PTEN status has not been investigated in the breast. Furthermore, many of the studies on the DNA damage response and its therapeutic implications in breast cancer focus on inherited syndromes (e.g. Lynch syndrome and hereditary breast-ovarian cancer syndrome). Aims: We sought to explore the interplay between PTEN and the MMR system and to define whether PTEN immunohistochemistry (IHC) is a predictor of MMR proficiency in non-familial breast cancers. Methods: 373 cases of non-familial breast cancers, including a representative number of no special (n=295) and special types (n=78), carefully characterized from clinical and pathological standpoints, were reviewed and used to construct 14 tissue microarrays (TMAs). For each case, a mean of 4.5 tumor tissue cores (range 3 to 6 cores) was sampled, incorporating distinct topographic areas of the tumor, as well as matched non-neoplastic breast tissue. Taken together, 1876 spots were generated. Each TMA was subjected to IHC for PTEN and the DNA MMR proteins MLH1, MSH2, MSH6 and PMS2. In order to minimize human-related biases, each stained slide was digitalized and two pathologists blindly analyzed each tumor spot using a dedicated software able to segment and randomize TMA cores. The pattern of expression was therefore annotated manually on a digital database using a specific add-on module to reconstruct the original topography. Results: According to clinicopathologic surrogate definition of intrinsic subtypes, PTEN protein loss or heterogeneous expression was more frequent in estrogen receptor negative cancers. Furthermore, 100% of the MMR-proficient luminal B-like (HER2+) and triple-negative breast cancers displayed strong and diffuse homogeneous PTEN expression, while PTEN-positive status identified MMR-proficient luminal A-like and luminal B (HER2-) like tumors with accuracy rates of 89.3% and 92.7%, respectively (p=0.001, Fisher's exact test). Conclusions: The present study is the first to investigate PTEN protein loss in a large set of non-familial breast carcinomas based on their DNA MMR status by IHC. Here, we demonstrated that PTEN strong and homogeneous expression by IHC is able to capture the vast majority of MMR-proficient non-familial breast cancers. Our findings broaden the understanding of the biology underpinning these tumors, suggesting that PTEN is likely play a role in the development of MMR alterations. Given that PTEN-defective breast cancers have the propensity to develop additional somatic alterations in the MMR system, our results suggest that IHC for PTEN and MMR proteins may be emplyed as an ancillary study to define new subclasses of sporadic breast cancers potentially eligible for iPARPs therapies. Citation Format: Fusco N, Gambini D, Runza L, Lopez G, Ercoli G, Despini L, Bosari S. PTEN immunohistochemistry is a predictor of mismatch repair status in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-07.

Background The level of HER2/neu (HER2) amplification, defined as HER2/centromeric region of chromosome 17 (CEP17) ratio at dual-color fluorescent in-situ hybridization (FISH) test presents wide variations in clinical practice but its clinical significance is still undefined. We designed this retrospective study to investigate the correlations between level of HER2 amplification in primary (T) and/or metastases (M) and outcome in a cohort of HER2+ AdvBrCa pts treated with a H-containing therapy. Methods Retrospective multicentric study designed according to REporting recommendations for tumor MARKer prognostic studies (REMARK). To be included pts must have all the following: metastatic or locally advanced (not amenable of curative surgery) BrCa, HER2+ tumour defined as score 3+ at immunohistochemistry or FISH positive, treatment with a H-containing regimen (no H in neo- or adjuvant setting was allowed), at least one tumour sample from T and/or M available, measurable or evaluable disease, adequate follow up (FU) information.Outcome parameters included event-free survival (EFS) and overall survival (OS). All FISH tests were prospectively performed in a central laboratory of cytogenetic specifically for this study and in accordance with the international guidelines on FISH testing. Results Ninety-one females were identified and 63 included in the final analysis. Forty-seven pts had one specimen available from T or M, 16 pts had two specimens from either T and a corresponding M. All M samples were obtained before treatment with H. Median FU time is 19.2 months (range 1.2−94.6). In 11 out of 16 cases (69%) with two tumour specimens HER2/CEP17 ratio was higher in M than in T with a statistically significant difference in the median HER2/CEP17 ratio between T (8.3, range: 3.1−18.4) and the corresponding M (10.9, range: 4.6−20.8) (p=0.004). The incremental gain in HER2/CEP17 ratio was associated with significantly shorter OS after trastuzumab-based therapy (p=0.023). A trend towards a correlation between increase in level of HER2 amplification assessed in M and shorter EFS and OS was observed. No statistically significant correlation was found between level of HER2 amplification assessed in T and EFS and OS. Conclusions Level of HER2 amplification reported as HER2/CEP17 ratio is a dynamic parameter in HER2+ AdvBrCa as it increases from T to the matched M in a significant proportion of pts. The gain in HER2 gene copies may represent a prognostic factor for shorter OS when pts with HER2+ AdvBrCa are treated with a H-based therapy. Further studies on the level of HER2 amplification in BrCa metastases are strongly warranted to better understand the biology of HER2−positive breast cancer and to better identify patients with a poorer prognosis after treatment with H. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-22.

Among angiosarcomas, radiation-induced breast sarcomas (RIBS) represent a well-known entity generally characterized by a poor outcome, especially in patients with advanced disease. Despite the unfavorable prognosis, some chemotherapeutic agents have been used to treat these malignancies, occasionally with success. Treatments with demonstrated activity against sarcomas include ifosfamide-based regimens and, more recently, taxane derivatives. We report a case of a patient having a secondary breast angiosarcoma recurring early after surgery, who achieved complete remission following treatment with weekly paclitaxel. After 4 years of maintenance therapy, with an interval between consecutive administrations of no longer than 3 weeks, the patient is still in complete remission. A locoregional recurrence was documented twice during this period, the first as a consequence of a brief treatment interruption and the second because of a treatment delay. Nonetheless, in both instances a new complete remission was rapidly achieved with the resumption of the same treatment, without evidence of any significant adverse effects. We discuss the highly unusual behavior of this malignancy and the possible role of the two different mechanisms of action of paclitaxel-antiangiogenic versus cytotoxic-depending on the schedule of administration, with evidence of “false” drug-resistance.

Aims and background Often neglected by large clinical trials, patients with uncommon breast malignancies have been rarely analyzed in large series. Patients and methods Of 2,052 patients diagnosed with breast cancer and followed in our Institution from January 1985 to December 2009, we retrospectively collected data on those with uncommon histotypes, with the aim of investigating their presentation characteristics and treatment outcome. Results Rare histotypes were identified in 146 patients (7.1% of our total breast cancer population), being classified as follows: tubular carcinoma in 75 (51.4%), mucinous carcinoma in 36 (24.7%), medullary carcinoma in 25 (17.1%) and papillary carcinoma in 10 patients (6.8%). Whereas age at diagnosis was not significantly different among the diverse diagnostic groups, patients with medullary and papillary subtypes had a higher rate of lymph node involvement, similar to that of invasive ductal carcinoma. Early stage diagnosis was frequent, except for medullary carcinoma. Overall, in comparison with our invasive ductal carcinoma patients, those with rare histotypes showed a significantly lower risk of recurrence, with a hazard ratio of 0.28 (95% CI, 0.12–0.62; P = 0.002). Conclusions According to our analysis, patients with uncommon breast malignancies are often diagnosed at an early stage, resulting in a good prognosis with standard treatment.

Background The level of HER2/neu amplification may vary widely in breast cancers with HER2/neu alteration. The clinical significance of this phenomenon is still unclear. This study was aimed to explore the level of HER2/neu amplification in primary tumours and metastases in HER2-positive metastatic breast cancer (MBC) and its potential impact on survival after a trastuzumab-containing therapy. Methods We retrospectively identified MBC patients treated with a trastuzumab-containing therapy and performed dual-colour FISH on tumour samples from either primary tumour and/or metastasis in a central laboratory. Results We retrieved 110 tumour samples from 91 patients and included 79 tumour samples (primary = 56; metastasis = 23) from 63 patients in the final analysis. We found higher level of HER2/neu amplification in the metastases than in the primary tumours (median HER2/CEP17 ratio: 10.5 vs 7.0, respectively). In 69% of patients ( n = 16) with two tumour samples, the level of HER2/neu amplification was higher in the metastasis than in the paired primary tumour (median HER2/CEP17 ratio: 10.9 vs 8.3, respectively, p = 0.004). The incremental gain in level of HER2/neu amplification was associated with significantly shorter OS after trastuzumab-containing therapy ( p = 0.023, HR 1.014, CI95%: 1.002–1.025). Conclusions The level of HER2/neu amplification tends to increase from the primary tumour to the paired metastases in a significant proportion of patients with HER2-positive MBC. This phenomenon, although still not completely understood, could lead to a shorter OS after trastuzumab therapy.

e22174 Background: Uncommon breast tumors are often neglected by large clinical trials, even if their incidence is not so low. Methods: We investigated stage, treatment and outcome of 112 patients affected by uncommon breast cancer, out of 2,185 breast cancer patients diagnosed and followed in our Institution from January 1985 to October 2008. Results: Rare subtypes were represented as follows: tubular 2.7% (58 pts), mucinous 1.1% (25 pts), medullary 1% (21 pts), papillary 0.4% (8 pts). Median age at diagnosis was 56.5 years among patients with tubular histotype, 68.9 years for mucinous, 55 and 61.7 years for medullary and papillary, respectively. Stage I tumors were 87.7% among patients with tubular differentiation, 60% for mucinous, 26.3% for medullary and 50% for papillary, (compared to 45.7% in invasive ductal carcinoma: 1,626 pts). Stage II represented 12.3% among patients with tubular carcinoma, 32% for mucinous, 57.9% for medullary and 37.5% for papillary. Surgical option for stage I and stage II was usually conservative surgery (quadrantectomy, lumpectomy) plus local radiotherapy, followed by estrogenic blockade. In stage III radical mastectomy was often performed, followed by hormonal suppression. Median DFS for patients with tubular cancer was 4.1 years, for mucinous 3.7 years, 10.5 and 5.1 years for medullary and papillary, respectively. Median OS for patients with tubular cancer was 4.3 years, whereas for mucinous 4.2 years, for medullary 11 years and 5.3 years for papillary. Conclusions: In our retrospective analysis, uncommon breast tumors are often diagnosed at limited stages, resulting in good prognosis, with standard treatment. Further studies are warranted for a better management of these diseases. No significant financial relationships to disclose.

Background Coeliac disease is characterised by villous atrophy, which usually normalises after gluten withdrawal. Sometimes the revaluation of duodenal histology is required during follow-up, even if the methodology for comparing duodenal histology before and after introducing a gluten-free diet is not yet established. Our aim was to evaluate a novel criterion to compare duodenal histology in coeliac disease before and after gluten withdrawal. Methods Duodenal biopsies from coeliac patients were retrospectively reviewed to compare duodenal histology at diagnosis and after at least one year on a gluten-free diet. Two different methods were used: the first was represented by the classical Marsh-Oberhuber score, the second compared the areas covered by each Marsh-Oberhuber grade and expressed as percentages, the final grade being calculated from the analysis of ten power fields per duodenal biopsy. Results Sixty-nine patients (17 males 52 females, age at diagnosis 36 ± 15 years) who underwent duodenal biopsies, were considered. According to the classical Marsh-Oberhuber scale, 32 patients did not present atrophy during follow-up while 37 showed duodenal atrophy, among whom 26 improved the grade of severity and 11 retained the same one. Of these latter, according to the second method, eight patients were considered improved, two showed a worsened duodenal damage and only one remained unchanged; the evaluation changed in 91 % of cases. Conclusions The proposed semi-quantitative approach (i.e. the second method) for the evaluation of histology at follow-up provides additional information about the progression/regression of the mucosal damage. Electronic supplementary material The online version of this article (doi:10.1186/s12876-015-0361-8) contains supplementary material, which is available to authorized users.