Publications by authors named "Fernando C Schmitt"

104 Publications

Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management.

Histopathology 2020 Oct 28. Epub 2020 Oct 28.

Department of Histopathology, The University of Nottingham and the Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.

Aims: Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence-based approach to improve the consistency of diagnosis and management for such cases.

Methods And Results: A large series (n = 140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18 years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. Forty-seven cases (34%) showed foci of conventional type invasive breast carcinoma or ductal carcinoma in situ (DCIS), while 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. Ninety-seven cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for five or more CKs. Eight cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in five cases, and three were diagnosed as MBC following extensive diagnostic work-up and based on our experience.

Conclusion: This study suggests that MBC represents a spectrum of neoplasms, with some lacking CK expression. Sarcomatoid neoplasms of the breast lacking evidence of carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive work-up).
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http://dx.doi.org/10.1111/his.14290DOI Listing
October 2020

Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries.

Cancer Cytopathol 2020 Dec 27;128(12):885-894. Epub 2020 Oct 27.

Department of Public Health, University of Naples Federico II, Naples, Italy.

Background: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported.

Methods: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach.

Results: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%).

Conclusions: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted.
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http://dx.doi.org/10.1002/cncy.22373DOI Listing
December 2020

Predictive molecular pathology in the time of coronavirus disease (COVID-19) in Europe.

J Clin Pathol 2020 Jul 31. Epub 2020 Jul 31.

Department of Public Health, University of Naples Federico II, Naples, Italy

Aims: Lung cancer predictive biomarker testing is essential to select advanced-stage patients for targeted treatments and should be carried out without delays even during health emergencies, such as the coronavirus (COVID-19) outbreak.

Methods: Fifteen molecular laboratories from seven different European countries compared 4 weeks of national lockdown to a corresponding period in 2019, in terms of tissue and/or plasma-based molecular test workload, analytical platforms adopted, number of cases undergoing programmed death-ligand1 (PD-L1) expression assessment and DNA-based molecular tests turnaround time.

Results: In most laboratories (80.0%), tissue-based molecular test workload was reduced. In 40.0% of laboratories (6/15), the decrease was >25%, and in one, reduction was as high as 80.0%. In this instance, a concomitant increase in liquid biopsy was reported (60.0%). Remarkably, in 33.3% of the laboratories, real-time PCR (RT-PCR)-based methodologies increased, whereas highly multiplexing assays approaches decreased. Most laboratories (88.9%) did not report significant variations in PD-L1 volume testing.

Conclusions: The workload of molecular testing for patients with advanced-stage lung cancer during the lockdown showed little variations. Local strategies to overcome health emergency-related issues included the preference for RT-PCR tissue-based testing methodologies and, occasionally, for liquid biopsy.
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http://dx.doi.org/10.1136/jclinpath-2020-206957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397978PMC
July 2020

Journal Impact Factor Returned to Acta Cytologica in 2020.

Acta Cytol 2020 29;64(4):280. Epub 2020 Jun 29.

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http://dx.doi.org/10.1159/000507601DOI Listing
July 2020

A Proposal for the Performance, Classification, and Reporting of Lymph Node Fine-Needle Aspiration Cytopathology: The Sydney System.

Acta Cytol 2020 26;64(4):306-322. Epub 2020 May 26.

Department of Medicine and Surgery, Università degli Studi di Salerno, Fisciano, Salerno, Italy,

Background: The evaluation of lymph nodes (LN) by fine-needle aspiration cytology (FNAC) is routinely used in many institutions but it is not uniformly accepted mainly because of the lack of guidelines and a cytopathological diagnostic classification. A committee of cytopathologists has developed a system of performance, classification, and reporting for LN-FNAC.

Methods: The committee members prepared a document that has circulated among them five times; the final text has been approved by all the participants. It is based on a review of the international literature and on the expertise of the members. The system integrates clinical and imaging data with cytopathological features and ancillary techniques. The project has received the endorsement and patronage of the International Academy of Cytology and the European Federation of the Cytology Societies.

Results: Clinical, imaging, and serological data of lymphadenopathies, indications for LN-FNAC, technical procedures, and ancillary techniques are evaluated with specific recommendations. The reporting system includes two diagnostic levels. The first should provide basic diagnostic information and includes five categories: inadequate/insufficient, benign, atypical lymphoid cells of undetermined/uncertain significance, suspicious, and malignant. For each category, specific recommendations are provided. The second diagnostic level, when achievable, should produce the identification of specific benign or malignant entities and additional information by utilizing ancillary testing.

Conclusion: The authors believe that the introduction of this system for performing and reporting LN-FNAC may improve the quality of the procedure, the report, and the communication between cytopathologists and the clinicians. This system may lead to a greater acceptance and utilization of LN-FNAC and to a better interdisciplinary understanding of the results of this procedure.
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http://dx.doi.org/10.1159/000506497DOI Listing
July 2020

Predictive molecular pathology in the time of COVID-19.

J Clin Pathol 2020 May 19. Epub 2020 May 19.

Public Health, University of Naples Federico II, Naples, Italy

Aims: In the time of COVID-19, predictive molecular pathology laboratories must still timely select oncological patients for targeted treatments. However, the need to respect social distancing measures may delay results generated by laboratory-developed tests based on sequential steps a long hands-on time. Laboratory workflows should now be simplified.

Methods: The organisation of the University of Naples Federico II predictive pathology laboratory was assessed before (March-April 2019) and during (March-April 2020) the Italian lockdown.

Results: The number of patients undergoing single or multiple biomarker testing was similar in 2019 (n=43) and in 2020 (n=45). Considering adequate samples for molecular testing, before the outbreak, next-generation sequencing was mostly used (35/42, 83.3%). Testing six genes had a reagent cost of €98/patient. Conversely, in 2020, almost all cases (38/41, 92.7%) were analysed by automated testing. This latter had for any single assay/gene a significant reagent cost (€95-€136) and a faster mean turnaround time (5.3 vs 7.9 working days).

Conclusion: In the times of coronavirus, laboratory fully automated platforms simplify predictive molecular testing. Laboratory staff may be more safely and cost-effectively managed.
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http://dx.doi.org/10.1136/jclinpath-2020-206711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242869PMC
May 2020

The Role of Telecytology in the Primary Diagnosis of Thyroid Fine-Needle Aspiration Specimens.

Acta Cytol 2020 1;64(4):323-331. Epub 2019 Nov 1.

IPATIMUP, Institute of Molecular Pathology and Immunology of University of Porto, Porto, Portugal.

Introduction: The Acibadem Health Group (AHG) has been using telepathology/digital pathology stations since 2006. In 2013, the system was changed from videoconferencing to digital pathology (whole-slide imaging) utilizing 3DHISTECH scanners and software. In 2017, digital cytology started to be used for routine cytopathologic diagnosis for thyroid fine-needle aspiration (FNA) cases.

Material And Methods: Two hundred and twenty-seven thyroid cases were received for analysis using telecytology (TC) during the period from November 2017 to May 2018. Rapid on-site evaluation was performed at the Atakent Hospital of the AHG by a cytotechnologist and scanned on the same day. For every case, there were Diff-Quik- and Papanicolaou-stained FNA smears. Each glass slide was digitized with a 3DHISTECH whole-slide scanner in 1 focal Z-plane at ×40 magnification.

Results: Two hundred and twenty-seven thyroid FNA specimens were retrieved, of which 25 had histologic follow-up. Samples were classified as nondiagnostic in 3%, benign in 74%, atypia of undetermined significance/follicular lesion of undetermined significance in 13%, suspicious for follicular neoplasia/follicular neoplasia in 3%, suspicious for malignancy in 4%, and malignant in 3%. When only the "suspicious for malignancy" and "malignancy" categories were considered positive tests, cytology sensitivity and specificity using TC for diagnosis was 100%.

Conclusions: Our data demonstrate that TC is suitable to provide a primary diagnosis in daily routine cytology practice. Despite the promising results, there were some challenges stemming from the novelty of using TC for the primary diagnosis. The study also addresses both advantages and disadvantages of TC in daily practice to increase the efficiency of the technique in primary diagnosis.
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http://dx.doi.org/10.1159/000503914DOI Listing
July 2020

Variants of Papillary Thyroid Carcinoma: An Algorithmic Cytomorphology-Based Approach to Cytology Specimens.

Acta Cytol 2020 21;64(4):288-298. Epub 2019 Oct 21.

Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.

Background: Thyroid cancer accounts for 1% of cancer cases in developed countries, in which papillary thyroid carcinoma (PTC) is the most common type. There are multiple variants of PTC described to date, some of them with aggressive behavior and poor clinical outcome. These variants are well described and accepted in recent guidelines of many international societies, and the prognostic and management implications are well laid out. Due to their established clinical importance and to guide appropriate surgical management, it is now imperative in clinical practice, including cytopathology, to differentiate aggressive variants from nonaggressive ones. This review aims to describe the variants of PTC and to provide a practical algorithmic approach to facilitate the cytological diagnosis of these variants.

Summary: Subtyping PTC variants on fine needle aspiration cytology (FNAC) is challenging even for the most experienced cytopathologist. To facilitate a correct subtyping on FNAC, we propose a stepwise approach that is mainly designed for conventional smear methodology. This approach requires first to stratify the lesions into oncocytic and nononcocytic features before analyzing further details in cell morphology and pattern. Key Messages: (1) Subtyping in PTC is possible on cytopathology. (2) The main aim of the cytopathologist is to differentiate aggressive from nonaggressive variants. (3) The subtyping of PTC can help in the surgical management of the patients.
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http://dx.doi.org/10.1159/000503576DOI Listing
July 2020

Liquid Biopsy: A New Tool in Oncology.

Acta Cytol 2019 2;63(6):448. Epub 2019 Jul 2.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal,

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http://dx.doi.org/10.1159/000501355DOI Listing
October 2019

Ancillary Tests in Breast Cytology: A Practical Guide.

Acta Cytol 2019 29;63(4):302-313. Epub 2019 May 29.

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)/I3S, Porto, Portugal,

Utilization of fine-needle aspiration biopsy (FNAB) cytology for the diagnosis of diseases of the breast has been met with both excitement and uncertainty during the last couple of decades. Presently, FNAB for the diagnosis of primary and metastatic breast lesions is on the rise again. This is probably due to its fast turnaround time, cost efficiency, and minimal invasiveness, characteristics of this sampling modality which are particularly crucial for patients requiring frequent repeat biopsy in the setting of metastatic lesions. In this article, we will briefly review the main modern applications of FNAB of the breast when coupled with contemporary ancillary techniques. Such contemporary ancillary techniques range from classic immunocytochemistry (ICC) to the most modern molecular techniques, particularly next-generation sequencing. Coupled with contemporary ICC and molecular methods, FNAB of the breast can be used for several applications. The applications reviewed in this article include the primary diagnosis of a breast lesion, the identification of the breast as a primary source of a metastatic lesion, the evaluation of breast prognostic/predictive markers, and the tracking of tumor evolution. In our opinion, FNAB of the breast is an ideal sampling method, sharing many of the advantages of truly liquid and of tissue biopsies. Ultimately, we aim at demystifying the complexity of many of the challenges traditionally associated with the application of ancillary techniques to FNAB of the breast and provide insights into some of the most cutting-edge and clinically useful application scenarios.
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http://dx.doi.org/10.1159/000499697DOI Listing
July 2019

The International Academy of Cytology Yokohama System for Reporting Breast Fine Needle Aspiration Biopsy Cytopathology.

Acta Cytol 2019;63(4):255-256. Epub 2019 May 28.

Institute of Molecular Pathology and Immunology of Porto University (IPATIMUP), Instituto de Investigação e Inovação em Saúde and Medical Faculty, University of Porto, Porto, Portugal.

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http://dx.doi.org/10.1159/000501055DOI Listing
July 2019

Exploring Collagen Parameters in Pure Special Types of Invasive Breast Cancer.

Sci Rep 2019 05 22;9(1):7715. Epub 2019 May 22.

Laboratory of Investigative and Molecular Pathology, CIPED - Faculty of Medical Sciences - State University of Campinas, Rua Tessália Vieira de Camargo, 126, Zip code: 13083-970, Campinas, São Paulo, Brazil.

One of the promising tools to evaluate collagen in the extracellular matrix is the second-harmonic generation microscopy (SHG). This approach may shed light on the biological behavior of cancers and their taxonomy, but has not yet been applied to characterize collagen fibers in cases diagnosed as invasive breast carcinoma (BC) of histological special types (IBC-ST). Tissue sections from 99 patients with IBC-ST and 21 of invasive breast carcinoma of no special type (IBC-NST) were submitted to evaluation of collagen parameters by SHG. Tissue microarray was performed to evaluate immunohistochemical-based molecular subtype. In intratumoral areas, fSHG and bSHG (forward-SHG and backward-SHG) collagen parameters achieved their lowest values in mucinous, papillary and medullary carcinomas, whereas the highest values were found in classic invasive lobular and tubular carcinomas. Unsupervised hierarchical cluster analysis and minimal spanning tree using intratumoral collagen parameters allowed the identification of three main groups of breast cancer: group A (classic invasive lobular and tubular carcinomas); group B (IBC-NST, metaplastic, invasive apocrine and micropapillary carcinomas); and group C (medullary, mucinous and papillary carcinomas). Our findings provide further characterization of the tumor microenvironment of IBC-ST. This understanding may add information to build more consistent tumor categorization and to refine prognostication.
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http://dx.doi.org/10.1038/s41598-019-44156-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531485PMC
May 2019

Role of Cytomorphology in the Era of Liquid Biopsy.

Acta Cytol 2019 3;63(6):497-505. Epub 2019 Apr 3.

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.

In the late stages of non-small cell lung cancer, the detection of sensitizing mutations of the epidermal growth factor receptor (EGFR) is mandatory to select patients' treatment with first- or second-generation tyrosine kinase inhibitors (TKIs). In patients showing progressive disease, the assessment of the EGFR exon 20 resistance point mutation p.T790M is required for third-generation TKI administration. However, molecular analysis does not capture all the different mechanisms of resistance against these molecules. A variety of morphological changes associated with acquired resistance have also been described. Since an altered morphology may be the only clue to acquired resistance, cytopathology still plays a relevant role in this setting. In this comprehensive review, we have focused on the relevance of squamous cell carcinoma, small cell lung cancer and large-cell neuroendocrine carcinoma transitions from adenocarcinoma resistant to TKIs.
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http://dx.doi.org/10.1159/000499338DOI Listing
October 2019

Breast Fine Needle Aspiration Biopsy Cytology Using the Newly Proposed IAC Yokohama System for Reporting Breast Cytopathology: The Experience of a Single Institution.

Acta Cytol 2019 Feb 15:1-6. Epub 2019 Feb 15.

Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal,

Objective: Recently the International Academy of Cytology (IAC) proposed a new reporting system for breast fine needle aspiration biopsy (FNAB) cytology. We aimed to categorize our samples according to this classification and to assess the risk of malignancy (ROM) for each category as well as the diagnostic yield of breast FNAB.

Study Design: Breast FNAB specimens obtained between January 2007 and December 2017 were reclassified according to the newly proposed IAC Yokohama reporting system. The ROM for each category was determined. Diagnostic yield was evaluated based on a three-category approach, benign versus malignant.

Results: The samples were distributed as follows: insufficient material 5.77%, benign 73.38%, atypical 13.74%, suspicious for malignancy 1.57%, and malignant 5.54%. Of the 3,625 cases collected, 776 (21.4%) had corresponding histology. The respective ROM for each category was 4.8% for category 1 (insufficient material), 1.4% for category 2 (benign), 13% for category 3 (atypical), 97.1% for category 4 (suspicious for malignancy), and 100% for category 5 (malignant). When only malignant cases were considered positive tests, the sensitivity, specificity, and diagnostic accuracy were 97.56, 100, and 99.11%, respectively.

Conclusions: Our study is the first to categorize breast FNAB cytology samples according to the proposed IAC reporting system and to evaluate patient outcomes based on this categorization.
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http://dx.doi.org/10.1159/000492638DOI Listing
February 2019

Stromal Cellular Fragments in Breast Fine Needle Aspirates: Think Outside of the Box.

Acta Cytol 2018 24;62(5-6):450-455. Epub 2018 Sep 24.

Pathology Department, Faculdade de Medicina da Universidade do Porto, Porto,

Background: The presence of highly cellular stromal fragments in breast fine needle aspirates (FNA) suggests some classical differential diagnoses such as cellular fibroadenoma, phyllodes tumour (PT), metaplastic carcinomas, and some mesenchymal/myoepithelial proliferations. The other components of the smears can help in the differential diagnosis, but the presence of a low-grade epithelial proliferation does not always represent a fibro-epithelial lesion as we demonstrate in these two cases.

Cases: We discuss two cases of breast FNA, previously presented in a slide seminar at the 29th European Congress of Pathology in Amsterdam, where the common cytological finding was the presence of stromal cellular fragments together with an epithelial component. One case is a typical PT and the other is a case of a mammary carcinoma with osteoclast-like giant cells.

Conclusion: Mammary carcinoma with osteoclast-like giant cells is an unusual type of breast carcinoma that should be included in the differential diagnosis of breast lesions containing cellular stroma. Since the associated carcinoma is usually low grade, careful evaluation for malignant cells on cytological smears is necessary for an accurate differential diagnosis with PT where the epithelial component is benign.
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http://dx.doi.org/10.1159/000492566DOI Listing
January 2019

Invasion in breast lesions: the role of the epithelial-stroma barrier.

Histopathology 2018 Jun 13;72(7):1075-1083. Epub 2018 Feb 13.

Department of Histopathology, Nottingham City Hospital NHS Trust, Nottingham University, Nottingham, UK.

Despite the significant biological, behavioural and management differences between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast, they share many morphological and molecular similarities. Differentiation of these two different lesions in breast pathological diagnosis is based typically on the presence of an intact barrier between the malignant epithelial cells and stroma; namely, the myoepithelial cell (MEC) layer and surrounding basement membrane (BM). Despite being robust diagnostic criteria, the identification of MECs and BM to differentiate in-situ from invasive carcinoma is not always straightforward. The MEC layer around DCIS may be interrupted and/or show an altered immunoprofile. MECs may be absent in some benign locally infiltrative lesions such as microglandular adenosis and infiltrating epitheliosis, and occasionally in non-infiltrative conditions such as apocrine lesions, and in these contexts this does not denote malignancy or invasive disease with metastatic potential. MECs may also be absent around some malignant lesions such as some forms of papillary carcinoma, yet these behave in an indolent fashion akin to some DCIS. In Paget's disease, malignant mammary epithelial cells extend anteriorly from the ducts to infiltrate the epidermis of the nipple but do not typically infiltrate through the BM into the dermis. Conversely, BM-like material can be seen around invasive carcinoma cells and around metastatic tumour cell deposits. Here, we review the role of MECs and BM in breast pathology and highlight potential clinical implications. We advise caution in interpretation of MEC features in breast pathology and mindfulness of the substantive evidence base in the literature associated with behaviour and clinical outcome of lesions classified as benign on conventional morphological examination before changing classification to an invasive lesion on the sole basis of MEC characteristics.
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http://dx.doi.org/10.1111/his.13446DOI Listing
June 2018

Expectations and Projections for the Future of Nongynecolgical Cytology 10 Years Ago: Did They Materialize and How Did We Do?

Acta Cytol 2017 11;61(4-5):373-407. Epub 2017 Jul 11.

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.

In 2007, an article entitled "How Technology Is Reshaping the Practice of Nongynecologic Cytology: Frontiers of Cytology Symposium" [Bibbo: Acta Cytol 2007;51:123-152] was published. The moderator and editor was Marluce Bibbo, previous Editor-in-Chief of Acta Cytologica, and 17 participants from countries throughout the world were asked to answer how new technologies were being applied in their respective laboratories and whether future advances and challenges can be predicted. Ten years later, two previous participants in this Golden Anniversary Cytology Symposium were asked by Kari Syrjänen, current Editor-in-Chief of Acta Cytologica, to make a reappraisal of the 2007 predictions.
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http://dx.doi.org/10.1159/000477713DOI Listing
August 2017

Prognostic value of stromal tumour infiltrating lymphocytes and programmed cell death-ligand 1 expression in breast cancer.

J Clin Pathol 2017 Oct 3;70(10):860-867. Epub 2017 Apr 3.

Epithelial Interactions in Cancer (EPIC), i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.

Aim: The present work aims to evaluate the presence of stromal tumour-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PDL1) expression in breast carcinomas and their correlation with available clinicopathological features.

Methods: Two independent series of invasive breast cancer (IBC), one including ductal carcinoma in situ (DCIS) pair-matched cases, were selected, and quantification of TILs was accomplished in each case. Immunohistochemistry was also performed to evaluate the expression of PDL1.

Results: In both cohorts evaluated, increased stromal TILs and PDL1 expression were present in about 10% of IBCs, being significantly associated with each other and both with grade 3 and triple-negative subtype. We observed a similar distribution of stromal TILs and PDL1 expression between DCIS and IBC. Finally, we observed that increased stromal TILs and PDL1 expression were significantly associated with cancer stem cell (CSC) markers, basal cell markers and vimentin expression. Interestingly, in IBC cases with vimentin expression, increased stromal TILs, as well as decreased PDL1 expression, disclosed a better clinical outcome, independently of the main classical BC prognostic factors.

Conclusions: We have confirmed the association of stromal TILs and PDL1 expression with aggressive forms of BC and that both are already found in in situ stages. We also showed that stromal TILs and PDL1 expression are associated with clinical outcome in cases enriched for a mesenchymal immunophenotype. We describe for the first time a close relationship between CSC markers and PDL1 expression.
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http://dx.doi.org/10.1136/jclinpath-2016-203990DOI Listing
October 2017

Cytological Criteria for Predicting the Luminal Phenotype of Breast Carcinoma.

Acta Cytol 2016 17;60(5):406-412. Epub 2016 Sep 17.

Department of Pathology, Faculty of Medicine, São Paulo State University, Botucatu, Brazil.

Background: Specific cytological criteria for the luminal phenotype of breast carcinoma, despite it being the most common and having a better prognosis as well as targeted therapies under study, remain to be established. Using fine-needle aspiration cytology (FNAC), we aimed to identify the luminal phenotype through the evaluation of cytological criteria recognized in routine practice.

Methods: We correlated 169 FNACs of breast carcinomas with their tissue specimens, classified into phenotypes by immunohistochemistry (applying tissue microarray technology) as luminal A, luminal B, HER2 overexpression, and triple negative. All FNAC samples were blindly reviewed according to cellularity, cell cohesion, necrosis, nucleoli, and nuclear atypia. Fisher's exact test was used to test associations between the cytological criteria and phenotypes.

Results: The following phenotypes were obtained - luminal A: 107 (63.3%), luminal B: 39 (23.1%), HER2 overexpression: 8 (4.7%), and triple negative: 15 (8.9%). The luminal phenotype showed mild/moderate cellularity (40.4%) (OR = 7.12, 95% CI: 1.61-31.52), inconspicuous, present nucleoli (55.5%) (OR = 8.31, 95% CI: 2.36-29.19), and mild/moderate nuclear atypia (44.5%) (OR = 8.42, 95% CI: 1.90-37.25).

Conclusion: The criteria that might indicate the luminal phenotype of breast carcinoma in FNAC were mild/moderate cellularity, inconspicuous, present, and nonprominent nucleoli, and mild/moderate nuclear atypia.
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http://dx.doi.org/10.1159/000448835DOI Listing
January 2017

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors.

Cell Cycle 2016 07 27;15(14):1865-73. Epub 2016 May 27.

a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer. The majority of patients present advanced stage disease and has poor survival. Therefore, it is imperative to search for new biomarkers and new alternative and effective treatment options. Most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates. This phenotype is a hallmark of cancer, characterized by an increase in glucose consumption and production of high amounts of lactate. Consequently, cancer cells need to up-regulate many proteins and enzymes related with the glycolytic metabolism. Thus, the aim of this study was to characterize metabolic phenotype of oral cavity cancers (OCC) by assessing the expression pattern of monocarboxylate transporters (MCTs) 1, 2 and 4 and other proteins related with the glycolytic phenotype.

Material And Methods: We evaluated the immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX in 135 human samples of OCC and investigated the correlation with clinicopathological parameters and the possible association with prognosis.

Results: We observed that all proteins analyzed presented significantly higher plasma membrane expression in neoplastic compared to non-neoplastic samples. MCT4 was significantly associated with T-stage and advanced tumoral stage, while CD147 was significantly correlated with histologic differentiation. Interestingly, tumors expressing both MCT1 and MCT4 but negative for MCT2 were associated with shorter overall survival.

Conclusion: Overexpression of MCT1/4, CD147, GLUT1 and CAIX, supports previous findings of metabolic reprograming in OCC, warranting future studies to explore the hyper-glycolytic phenotype of these tumors. Importantly, MCT expression revealed to have a prognostic value in OCC survival.
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http://dx.doi.org/10.1080/15384101.2016.1188239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968907PMC
July 2016

Phyllodes tumours of the breast: a consensus review.

Histopathology 2016 Jan;68(1):5-21

Department of Pathology, Singapore General Hospital, Singapore.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.
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http://dx.doi.org/10.1111/his.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027876PMC
January 2016

Breast lesions of uncertain malignant nature and limited metastatic potential: proposals to improve their recognition and clinical management.

Histopathology 2016 Jan;68(1):45-56

Department of Histopathology, Nottingham City Hospital NHS Trust, Nottingham University, Nottingham, UK.

Breast lesions comprise a family of heterogeneous entities with variable patterns of presentation, morphology and clinical behaviour. The majority of breast lesions are classified traditionally into benign and malignant conditions and their behaviour can, in the vast majority of cases, be predicted with a reasonable degree of accuracy. However, there remain lesions which show borderline features and lie in a grey zone between benign and malignant, as their behaviour cannot be predicted reliably. Defined pathological categorization of such lesions is challenging, and for some entities is recognized to be subjective and include a range of diagnoses, and forms of terminology, which may trigger over- or undertreatment. The rarity of these lesions makes the acquisition of clinical evidence problematic and limits the development of a sufficient evidence base to support informed decision-making by clinicians and patients. Emerging molecular evidence is providing a greater understanding of the biology of these lesions, but this may or may not be reflected in their clinical behaviour. Herein we discuss some breast lesions that are associated with uncertainty regarding classification and behaviour, and hence management. These include biologically invasive malignant lesions associated with uncertain metastatic potential, such as low-grade adenosquamous carcinoma, low-grade fibromatosis-like spindle cell carcinoma and encapsulated papillary carcinoma. Other lesions of uncertain malignant nature remain, such as mammary cylindroma, atypical microglandular adenosis, mammary pleomorphic adenoma and infiltrating epitheliosis. The concept of categories of (1) breast lesions of uncertain malignant nature and (2) breast lesions of limited metastatic potential are proposed with details of which histological entities could be included in each category, and their management implications are discussed.
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http://dx.doi.org/10.1111/his.12861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987288PMC
January 2016

Targeting lactate transport suppresses in vivo breast tumour growth.

Oncotarget 2015 Aug;6(22):19177-89

Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus of Gualtar, Braga, Portugal.

Background: Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as "Warburg effect". Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment.

Results: The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth.

Conclusions: This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662483PMC
http://dx.doi.org/10.18632/oncotarget.3910DOI Listing
August 2015

Liquid-based cytology in fine-needle aspiration of breast lesions: a review.

Acta Cytol 2014 9;58(6):533-42. Epub 2014 Aug 9.

Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, and Department of Pathology, University Health Network, Toronto, Ont., Canada.

Objective: Fine-needle aspiration (FNA) is a safe and cost-effective technique for the diagnosis of breast lesions, especially when correlated with clinical and imaging studies. However, the success of breast FNA is highly dependent on the adequate preparation of cytological conventional smears (CS). The liquid-based cytology (LBC) technique consists of an automated method for preparing thin-layer cytological samples from cell suspensions collected in alcohol-based preservative. LBC is designed to improve CS by avoiding limiting factors such as obscuring material, air-drying and smearing artifacts.

Study Design: We performed a review of the published literature about LBC applied to breast FNA.

Results: LBC preparations of breast aspirates demonstrated better cellular preservation, less cell overlapping and elimination of blood and excessive inflammation compared to CS. Conversely, alterations in architecture and cell morphology as well as loss of myoepithelial cells and stromal elements have been described in LBC specimens, requiring training before applying this technique for diagnosis. Studies have shown a similar accuracy between LBC and CS for the diagnosis of breast lesions. LBC also permits the use of residual material for ancillary tests, which is an important advantage compared to CS.

Conclusions: LBC can be safely applied to breast FNA, showing a similar diagnostic accuracy to CS.
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http://dx.doi.org/10.1159/000362805DOI Listing
March 2015

Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization.

J Transl Med 2014 May 9;12:118. Epub 2014 May 9.

Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Portugal.

Background: Soft tissue sarcomas (STSs) are a group of neoplasms, which, despite current therapeutic advances, still confer a poor outcome to half of the patients. As other solid tumors, STSs exhibit high glucose consumption rates, associated with worse prognosis and therapeutic response. As highly glycolytic tumors, we hypothesized that sarcomas should present an increased expression of lactate transporters (MCTs).

Methods: Immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 was assessed in a series of 86 STSs and the expression profiles were associated with patients' clinical-pathological parameters.

Results: MCT1, MCT4 and CD147 were mainly observed in the plasma membrane of cancer cells (around 60% for MCTs and 40% for CD147), while MCT2 was conspicuously found in the cytoplasm (94.2%). Importantly, we observed MCT1 nuclear expression (32.6%). MCT1 and MCT4, alone or co-expressed with CD147 in the plasma membrane, were associated with poor prognostic variables including high tumor grade, disease progression and shorter overall survival. Conversely, we found MCT1 nuclear expression to be associated with low grade tumors and longer overall survival.

Conclusions: The present work represents the first report of MCTs characterization in STSs. We showed the original finding of MCT1 expression in the nucleus. Importantly, opposite biological roles should be behind the dual sub-cellular localization of MCT1, as plasma membrane expression of MCT1 is associated with worse patients' prognosis, while nuclear expression is associated with better prognosis.
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http://dx.doi.org/10.1186/1479-5876-12-118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036386PMC
May 2014

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines.

Endocr Relat Cancer 2014 Feb 16;21(1):27-38. Epub 2013 Dec 16.

School of Health Sciences, Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, Braga, Portugal ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal Medical Faculty, University of Porto, Porto, Portugal Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada Department of Pathology, University Health Network, Toronto, Canada Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, Sao Paulo, Brazil.

The tumour microenvironment is known to be acidic due to high glycolytic rates of tumour cells. Monocarboxylate transporters (MCTs) play a role in extracellular acidification, which is widely known to be involved in tumour progression. Recently, we have described the upregulation of MCT1 in breast carcinomas and its association with poor prognostic variables. Thus, we aimed to evaluate the effect of lactate transport inhibition in human breast cancer cell lines. The effects of α-cyano-4-hydroxycinnamate, quercetin and lonidamine on cell viability, metabolism, proliferation, apoptosis, migration and invasion were assessed in a panel of different breast cancer cell lines. MCT1, MCT4 and CD147 were differently expressed among the breast cancer cell lines and, as expected, different sensitivities were observed for the three inhibitors. Interestingly, in the most sensitive cell lines, lactate transport inhibition induced a decrease in cell proliferation, migration and invasion, as well as an increase in cell death. Results were validated by silencing MCT1 expression using siRNA. The results obtained here support targeting of lactate transport as a strategy to treat breast cancer, with a special emphasis on the basal-like subtype, which so far does not have a specific molecular therapy.
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http://dx.doi.org/10.1530/ERC-13-0132DOI Listing
February 2014

Marluce Bibbo retires as editor-in-chief of Acta Cytologica.

Acta Cytol 2013 12;57(4):314-5. Epub 2013 Jul 12.

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http://dx.doi.org/10.1159/000353790DOI Listing
October 2013

Lobular neoplasia of the breast revisited with emphasis on the role of E-cadherin immunohistochemistry.

Am J Surg Pathol 2013 Jul;37(7):e1-11

Department of Pathology, Magee-Women's Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Lobular neoplasia (LN) is a term that encompasses both lobular carcinoma in situ and atypical lobular hyperplasia. These lesions have been shown to constitute both risk indicators and nonobligate precursors of invasive breast cancer, they are relatively uncommon, and are most often identified in specimens taken for other reasons. Their incidence has increased in the last 2 decades, and novel variants, including a pleomorphic type, have been described. Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions. The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex. This review provides an update on recent clinicopathologic and molecular data on LN and invasive lobular carcinoma and a discussion about the use and limitations of IHC with E-cadherin in diagnostic breast pathology.
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http://dx.doi.org/10.1097/PAS.0b013e3182918a2bDOI Listing
July 2013

The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90β.

Genes Dev 2013 Apr;27(7):805-17

Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

Matrix metalloproteinases (MMPs) are crucial mediators in sculpting tissue architecture and are required for many physiological and pathological processes. MMP3 has been shown to regulate branching morphogenesis in the mammary gland. Ectopic expression of proteolytically active MMP3 in mouse mammary epithelia triggers supernumerary lateral branching and, eventually, tumors. Using a three-dimensional collagen-I (Col-1) gel assay that simulates epithelial invasion and branching, we show that it is the hemopexin domain that directs these processes. Using three different engineered constructs containing a variation on MMP3 structural domains, we confirmed the importance of the hemopexin domain also in primary organoids of the mammary gland. A proteomic screen of MMP3-binding partners surprisingly revealed that the intracellular chaperone heat-shock protein 90 β (HSP90β) is present extracellularly, and its interaction with the hemopexin domain of MMP3 is critical for invasion. Blocking of HSP90β with inhibitory antibodies added to the medium abolished invasion and branching. These findings shift the focus from the proteolytic activity of MMP3 as the central player to its hemopexin domain and add a new dimension to HSP90β's functions by revealing a hitherto undescribed mechanism of MMP3 regulation. Our data also may shed light on the failure of strategies to use MMP inhibitors in cancer treatment and other related disorders.
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http://dx.doi.org/10.1101/gad.211383.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639420PMC
April 2013