Publications by authors named "Catarina Eloy"

63 Publications

Molecular Pathology of Non-familial Follicular Epithelial-Derived Thyroid Cancer in Adults: From RAS/BRAF-like Tumor Designations to Molecular Risk Stratification.

Endocr Pathol 2021 Mar 2. Epub 2021 Mar 2.

i3S - Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, 4200-135, Porto, Portugal.

This review addresses the impact of molecular alterations on the diagnosis and prognosis of differentiated thyroid carcinoma (DTC), including papillary, follicular, and well-differentiated carcinoma NOS, as well as oncocytic neoplasms. The molecular characterization of DTC is based upon the well-established dichotomy of BRAF-like and RAS-like designations, together with a remaining third group, less homogeneous, composed of non-BRAF-/non-RAS-like tumors. The role of BRAF V600E mutation in risk stratification is discussed in the clinico-pathological context, namely, staging and invasive features of classic papillary thyroid carcinoma (PTC) and histopathological variants carrying an excellent prognosis (microPTC) or a guarded prognosis, including the aggressive variants tall cell and hobnail cell PTCs. In follicular patterned tumors, namely, follicular thyroid carcinoma (FTC), with or without oncocytic features, the most prevalent molecular alteration are RAS mutations that do not carry prognostic significance. The only genetic alteration that has been proven to play a role in risk stratification of PTC and FTC is TERT promoter (TERTp) mutation.
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http://dx.doi.org/10.1007/s12022-021-09666-1DOI Listing
March 2021

Digital Versus Optical Diagnosis of Follicular Patterned Thyroid Lesions.

Head Neck Pathol 2020 Oct 31. Epub 2020 Oct 31.

Institute of Molecular Pathology and Immunology, Ipatimup Diagnostics, University of Porto (IPATIMUP)/i3S, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.

Objectives: To study the concordance between pathologists in the diagnosis of follicular patterned thyroid lesions using both digital and conventional optical settings.

Material And Methods: Five pathologists reviewed 50 hematoxylin and eosin-stained slides of follicular patterned thyroid lesions using both digital (the D-Sight 2.0 scanner and navigator viewer) and conventional optical instruments with washout interval time.

Results: The mean concordance rate with the ground truth (GT) was similar between conventional optical and digital observation (83.2 and 85.2%, respectively). The most frequent reason for diagnostic discordance with GT on both systems was the evaluation of nuclear features (69.1% for conventional optical observation and 59.4% for digital observation). The intraobserver diagnostic concordance mean was 86.8%. Time for digital observation (mean time per case = 2.9 ± 0.8 min) was higher than that for conventional optical observation (mean time per case = 2.0 ± 0.7 min). Interobserver correlation of measurements was higher in the digital observation than the conventional optical observation.

Conclusion: Conventional optical and digital observation settings showed a comparable accuracy for the diagnosis of follicular patterned thyroid nodules, as well as substantial intraobserver agreement and a significant improvement in the reproducibility of the measurements that support the use of digital diagnosis in thyroid pathology. The origins underlying the variability of the diagnosis were the same in both conventional optical microscopy and digital pathology systems.
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http://dx.doi.org/10.1007/s12105-020-01243-yDOI Listing
October 2020

Artificial Intelligence Improves the Accuracy in Histologic Classification of Breast Lesions.

Am J Clin Pathol 2020 Oct 29. Epub 2020 Oct 29.

Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.

Objectives: This study evaluated the usefulness of artificial intelligence (AI) algorithms as tools in improving the accuracy of histologic classification of breast tissue.

Methods: Overall, 100 microscopic photographs (test A) and 152 regions of interest in whole-slide images (test B) of breast tissue were classified into 4 classes: normal, benign, carcinoma in situ (CIS), and invasive carcinoma. The accuracy of 4 pathologists and 3 pathology residents were evaluated without and with the assistance of algorithms.

Results: In test A, algorithm A had accuracy of 0.87, with the lowest accuracy in the benign class (0.72). The observers had average accuracy of 0.80, and most clinically relevant discordances occurred in distinguishing benign from CIS (7.1% of classifications). With the assistance of algorithm A, the observers significantly increased their average accuracy to 0.88. In test B, algorithm B had accuracy of 0.49, with the lowest accuracy in the CIS class (0.06). The observers had average accuracy of 0.86, and most clinically relevant discordances occurred in distinguishing benign from CIS (6.3% of classifications). With the assistance of algorithm B, the observers maintained their average accuracy.

Conclusions: AI tools can increase the classification accuracy of pathologists in the setting of breast lesions.
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http://dx.doi.org/10.1093/ajcp/aqaa151DOI 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

HER2 genomic heterogeneity is a frequent event in gastroesophageal adenocarcinoma and correlates with tumor morphology.

Pathol Res Pract 2020 Sep 29;216(9):153090. Epub 2020 Jun 29.

Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. Electronic address:

Aim: To characterize a cohort of gastro-esophageal adenocarcinomas (GEA) evaluated for HER2 gene amplification using bright field in situ hybridization (ISH) following the 2016 guidelines for GEA and correlating the results with clinico-pathological features. It was also aimed to evaluate the effect of applying the ISH criteria from the 2018 guidelines for breast cancer (BC) in the same GEA cases.

Materials And Methods: 159 GEA cases collected in a period of 59 months were evaluated for HER2 gene amplification by ISH according to GEA and BC guidelines. All cases were reviewed for histological type, grading and presence of signet ring cells.

Results: Most of the cases refereed to ISH were HER2 equivocal (57.9 %) by immunohistochemistry. According to the GEA guideline, 131 cases were HER2-negative (87.3 %) and 19 cases were HER2-positive (12.7 %). According to the BC guideline, 133 cases were HER2-negative (88.7 %) and 17 cases were HER2-positive (11.3 %), being statistically similar to the results obtained with the GEA guideline. HER2 genomic heterogeneity was detected in 31.6 % of the HER2-positive cases, almost exclusively in tubular adenocarcinoma. We observed a significant association between HER2 gene amplification and tubular adenocarcinomas, and absence of signet ring cells. The only case with HER2 gene amplification and presence of signet ring cells was a mixed carcinoma, where the signet ring cells represented the non-amplified component.

Conclusions: HER2 positivity rate was similar when applying the GEA or the BC guidelines. We also establish a tight association between morphology and HER2 gene amplification.
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http://dx.doi.org/10.1016/j.prp.2020.153090DOI Listing
September 2020

Pitfalls in Challenging Thyroid Tumors: Emphasis on Differential Diagnosis and Ancillary Biomarkers.

Endocr Pathol 2020 Sep 6;31(3):197-217. Epub 2020 Jul 6.

i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal.

Thyroid pathology encompasses a heterogenous group of clinicopathological entities including rare and diagnostically challenging neoplasms. The review is focused on morphological, immunohistochemical, and molecular features of rare thyroid neoplasms that can pose diagnostic problems. The tumors are organized based on growth patterns including thyroid neoplasms with predominantly papillary, follicular, solid, and spindle cell growth pattern, as well as neoplasms with distinct cytological characteristics. A special section is also dedicated to rare thyroid tumors with peculiar patterns including thyroid carcinoma with Ewing family tumor elements and intrathyroidal thymic-related neoplasms.
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http://dx.doi.org/10.1007/s12022-020-09638-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395918PMC
September 2020

Malignant teratoid tumor of the thyroid gland: an aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations-is the term "thyroblastoma" more appropriate?

Virchows Arch 2020 Dec 7;477(6):787-798. Epub 2020 Jun 7.

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

Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known "hotspot" pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that "blastoma" is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term "thyroblastoma" might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.
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http://dx.doi.org/10.1007/s00428-020-02853-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683491PMC
December 2020

[Tumors of the thyroid gland. Proposal for the management and study of samples from patients with thyroid neoplasms].

Rev Esp Patol 2020 Jan - Mar;53(1):27-36. Epub 2019 May 7.

IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Department of Pathology, Hospital de S. João, Porto, Portugal.

The recent changes in the classification and staging of thyroid tumors have arisen from the need to provide an adequate response to the exponential increase of thyroid cancer, which, however, has not been accompanied by an increase in mortality. These changes pretend to reduce overdiagnoses of malignancy, unnecessary treatment, side effects as well as cost for the health system. To this end, this article reviews recommendations for the management of thyroid surgical pathology samples with emphasis on the new terminology of the WHO classification. The basic criteria for the diagnosis of malignancy in well-differentiated thyroid carcinomas are reviewed and the criteria for NIFTP (non-invasive follicular tumor with papillary-like nuclear features) diagnosis are updated. Recommendations for the elaboration of the pathological report are also included.
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http://dx.doi.org/10.1016/j.patol.2019.03.003DOI Listing
May 2019

Repeating thyroid fine-needle aspiration before 3 months may render increased nondiagnostic results.

Clin Endocrinol (Oxf) 2019 12 11;91(6):899-900. Epub 2019 Sep 11.

Faculty of Medicine, University of Porto, Porto, Portugal.

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http://dx.doi.org/10.1111/cen.14080DOI Listing
December 2019

BACH: Grand challenge on breast cancer histology images.

Med Image Anal 2019 08 31;56:122-139. Epub 2019 May 31.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, Porto 4200-135, Portugal; Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Rua Alfredo Allen, 208, Porto 4200-135, Portugal. Electronic address:

Breast cancer is the most common invasive cancer in women, affecting more than 10% of women worldwide. Microscopic analysis of a biopsy remains one of the most important methods to diagnose the type of breast cancer. This requires specialized analysis by pathologists, in a task that i) is highly time- and cost-consuming and ii) often leads to nonconsensual results. The relevance and potential of automatic classification algorithms using hematoxylin-eosin stained histopathological images has already been demonstrated, but the reported results are still sub-optimal for clinical use. With the goal of advancing the state-of-the-art in automatic classification, the Grand Challenge on BreAst Cancer Histology images (BACH) was organized in conjunction with the 15th International Conference on Image Analysis and Recognition (ICIAR 2018). BACH aimed at the classification and localization of clinically relevant histopathological classes in microscopy and whole-slide images from a large annotated dataset, specifically compiled and made publicly available for the challenge. Following a positive response from the scientific community, a total of 64 submissions, out of 677 registrations, effectively entered the competition. The submitted algorithms improved the state-of-the-art in automatic classification of breast cancer with microscopy images to an accuracy of 87%. Convolutional neuronal networks were the most successful methodology in the BACH challenge. Detailed analysis of the collective results allowed the identification of remaining challenges in the field and recommendations for future developments. The BACH dataset remains publicly available as to promote further improvements to the field of automatic classification in digital pathology.
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http://dx.doi.org/10.1016/j.media.2019.05.010DOI Listing
August 2019

What to expect from the 2018 ASCO/CAP HER2 guideline in the reflex in situ hybridization test of immunohistochemically equivocal 2+ cases?

Virchows Arch 2019 Sep 5;475(3):303-311. Epub 2019 Apr 5.

Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal.

To evaluate the effect of the 2018 ASCO/CAP guideline in the identification of HER2-positive breast carcinomas (BC) in reflex in situ hybridization (ISH) test. A total of 592 primary invasive BC cases from before and after the publication of the updated ASCO/CAP guideline were evaluated for HER2 amplification by silver ISH according to the 2013 and 2018 guidelines. Cases were mostly (95%) HER2 equivocal by immunohistochemistry (IHC), not centrally reviewed. Other reasons for referring cases were IHC confirmation, IHC discordancy (either between needle-core-biopsy (NCB) and surgical excision specimen (SES) or between different laboratories) and IHC result unexpected for histopathologic features. Cases evaluated with the 2013 guideline (1st cohort) were 14.6% HER2-positive, decreasing significantly after the reclassification with the 2018 guideline due to the exclusion of group 2 cases without HER2 protein overexpression. Cases studied after the implementation of the 2018 guideline (2nd cohort) were 8.7% HER2-positive, a frequency that was not significantly different from the reclassification of the 1st cohort with the 2018 guideline. All cases referred for IHC confirmation had the expected ISH result. Cases with IHC discordancy between NCB and SES were ISH concordant. Only one out of 14 cases with an IHC score 3+ and classified as histological grade 1 or with a Ki67 below 10% was classified as ISH HER2-positive. The 2018 ASCO/CAP guideline resulted in a decrease of HER2-positive cases in reflex ISH test, selecting less patients for anti-HER2-targeted therapy.
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http://dx.doi.org/10.1007/s00428-019-02567-zDOI Listing
September 2019

OPNa Overexpression Is Associated with Matrix Calcification in Thyroid Cancer Cell Lines.

Int J Mol Sci 2018 Sep 30;19(10). Epub 2018 Sep 30.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia and dystrophic calcification, including psammoma bodies (PB). This work aimed to investigate total OPN (tOPN) and OPN-SV expression and their association with the presence of PB in the PTC classical variants (cPTC), as well as the involvement of OPN-SV in matrix calcification of TC cell lines. We found that cPTC samples presenting PB showed higher OPN expression levels. In TC cell lines, OPNa overexpression promotes higher matrix calcification and collagen synthesis when compared to that of clones overexpressing OPNb or OPNc. In response to OPN knockdown, calcification was inhibited, paralleled with the downregulation of calcification markers. In conclusion, our data evidenced that OPN expression is associated with the presence of PB in cPTC samples. Among the OPN-SV, OPNa is the main contributor to matrix calcification in tested TC cells, providing clues to a better understanding on the biology and ethiopathogenesis of the calcification process in TC cells.
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http://dx.doi.org/10.3390/ijms19102990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213506PMC
September 2018

Cribriform-morular variant of thyroid carcinoma: a neoplasm with distinctive phenotype associated with the activation of the WNT/β-catenin pathway.

Mod Pathol 2018 08 21;31(8):1168-1179. Epub 2018 May 21.

i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal.

Cribriform-morular variant of thyroid carcinoma is classically associated with familial adenomatous polyposis but, it can also occur as a sporadic neoplasm. This neoplasm is much more frequently observed in women than in men (ratio of 61:1). In familial adenomatous polyposis patients, tumors are generally multifocal and/or bilateral (multinodular appearance), whereas in the sporadic cases tumors tend to occur as single nodules. The tumors are well delimited, and characteristically show a blending of follicular, cribriform, papillary, trabecular, solid, and morular patterns. Neoplastic cells are tall or cuboidal with the occasional nuclear features of classic papillary thyroid carcinoma. The morules include cells with peculiar nuclear clearing and show positivity for CDX2 and CD10. Angioinvasion and capsular invasion have been described in about 30 and 40% of cases, respectively, with lymph node metastases in less than 10% of patients and distant metastases in 6%. Although this tumor has good prognosis, neuroendocrine and/or poor differentiation have been associated with aggressive behavior. Tumor cells can be focally positive or negative for thyroglobulin, but are always positive for TTF-1, estrogen and progesterone receptors, and negative for calcitonin and cytokeratin 20. Nuclear and cytoplasmic staining for β-catenin is the hallmark of this tumor type; this feature plays a role in fine needle aspiration biopsy. Cribriform-morular variant of thyroid carcinoma has a peculiar endodermal (intestinal-like) type phenotype, activation of the WNT/β-catenin signaling pathway, and belongs to the non-BRAF-non-RAS subtype of the molecular classification of thyroid tumors. Elevated expression of estrogen and progesterone receptors and activation of the WNT/β-catenin pathway may prove useful as putative therapeutic targets in cases that do not respond to conventional therapy. Clinicians should be alerted to the possibility of familial adenomatous polyposis when a diagnosis of cribriform-morular variant of thyroid carcinoma is made. Instead of being considered as a variant of papillary thyroid carcinoma its designation as cribriform-morular thyroid carcinoma seems more appropriate.
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http://dx.doi.org/10.1038/s41379-018-0070-2DOI Listing
August 2018

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and mRNA Expression.

Int J Mol Sci 2018 May 13;19(5). Epub 2018 May 13.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto 4099-002, Portugal.

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase mRNA levels, whereas Torin2 caused a ~6 fold increase in mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of mRNA expression.
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http://dx.doi.org/10.3390/ijms19051448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983778PMC
May 2018

Genomic and transcriptomic characterization of the mitochondrial-rich oncocytic phenotype on a thyroid carcinoma background.

Mitochondrion 2019 05 6;46:123-133. Epub 2018 Apr 6.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Electronic address:

We conducted the first systematic omics study of the oncocytic phenotype in 488 papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas. Oncocytic phenotype is secondary to PTC, being unrelated to several pathologic scores. The nuclear genome had low impact on this phenotype (except in specific copy number variation), which was mostly driven by the significant accumulation of mitochondrial DNA non-synonymous and frameshift mutations at high heteroplasmy levels. Energy and mitochondrial-related pathways were significantly enriched in oncocytic tumors that also displayed increased levels of expression for genes involved in autophagy and fusion of mitochondria. Our in vitro tests confirmed that autophagy is increased and functional while mitophagy is decreased in these tumors.
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http://dx.doi.org/10.1016/j.mito.2018.04.001DOI Listing
May 2019

Automatic classification of tissue malignancy for breast carcinoma diagnosis.

Comput Biol Med 2018 05 8;96:41-51. Epub 2018 Mar 8.

Institute of Biomedical Engineering (INEB), University of Porto, Porto, Portugal; Institute for Research and Innovation in Health Sciences (i3S), Porto, Portugal.

Breast cancer is the second leading cause of cancer death among women. Its early diagnosis is extremely important to prevent avoidable deaths. However, malignancy assessment of tissue biopsies is complex and dependent on observer subjectivity. Moreover, hematoxylin and eosin (H&E)-stained histological images exhibit a highly variable appearance, even within the same malignancy level. In this paper, we propose a computer-aided diagnosis (CAD) tool for automated malignancy assessment of breast tissue samples based on the processing of histological images. We provide four malignancy levels as the output of the system: normal, benign, in situ and invasive. The method is based on the calculation of three sets of features related to nuclei, colour regions and textures considering local characteristics and global image properties. By taking advantage of well-established image processing techniques, we build a feature vector for each image that serves as an input to an SVM (Support Vector Machine) classifier with a quadratic kernel. The method has been rigorously evaluated, first with a 5-fold cross-validation within an initial set of 120 images, second with an external set of 30 different images and third with images with artefacts included. Accuracy levels range from 75.8% when the 5-fold cross-validation was performed to 75% with the external set of new images and 61.11% when the extremely difficult images were added to the classification experiment. The experimental results indicate that the proposed method is capable of distinguishing between four malignancy levels with high accuracy. Our results are close to those obtained with recent deep learning-based methods. Moreover, it performs better than other state-of-the-art methods based on feature extraction, and it can help improve the CAD of breast cancer.
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http://dx.doi.org/10.1016/j.compbiomed.2018.03.003DOI Listing
May 2018

CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension.

BMC Cancer 2018 01 10;18(1):68. Epub 2018 Jan 10.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.

Background: The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis.

Methods: We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers.

Results: We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC.

Conclusions: We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.
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http://dx.doi.org/10.1186/s12885-017-3948-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763897PMC
January 2018

NIS expression in thyroid tumors, relation with prognosis clinicopathological and molecular features.

Endocr Connect 2018 Jan;7(1):78-90

Instituto de Investigação e Inovação em Saúde (i3S)Porto, Portugal

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring V600E mutation. Analysis of expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring , and/or promoter (p) mutations presented significantly less expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for , and p mutations. mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving , and p. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features.
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http://dx.doi.org/10.1530/EC-17-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754505PMC
January 2018

Calcitonin receptor expression in medullary thyroid carcinoma.

PeerJ 2017 13;5:e3778. Epub 2017 Sep 13.

Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.

Background: Calcitonin expression is a well-established marker for medullary thyroid carcinoma (MTC); yet the role of calcitonin receptor (CTR), its seven-transmembrane G-protein coupled receptor, remains to be established in C-cells derived thyroid tumors. The aim of this work was to investigate CTR expression in MTC and to correlate such expression with clinicopathological features in order to evaluate its possible role as a prognostic indicator of disease aggressiveness and outcome.

Methods: Calcitonin receptor expression was analyzed in a series of 75 MTCs by immunohistochemistry, and by qPCR mRNA quantification in specimens from four patients. Statistical tests were used to evaluate the correlation between CTR expression and the clinicopathological and molecular characteristics of patients and tumors.

Results: Calcitonin receptor expression was detected in 62 out of 75 samples (82.7%), whereas 13 of the 75 samples (17.3%) were completely negative. CTR expression was significantly associated with expression of cytoplasmatic phosphatase and tensin homologue deleted on chromosome 10 and osteopontin, as well as with wild type genes and absence of tumor stroma, suggesting that CTR expression do not associate with clinicopathological signs of worse prognosis.

Discussion: Calcitonin receptor expression appears to be associated in MTC with more differentiated status of the neoplastic cells.
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http://dx.doi.org/10.7717/peerj.3778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600720PMC
September 2017

[Fine-needle Aspiration of Thyroid Nodules: Is it Worth Repeating?]

Acta Med Port 2017 Jun 30;30(6):472-478. Epub 2017 Jun 30.

IPATIMUP Diagnósticos. Instituto de Patologia e Imunologia Molecular. Universidade do Porto. Porto. Portugal; Departamento de Patologia. Faculdade de Medicina. Universidade do Porto. Porto. Portugal.

Introduction: The fine-needle aspiration has a significant role in assessing the malignancy risk of thyroid nodules. There is uncertainty regarding the value of repeat fine-needle aspiration in benign nodules. This study aims to evaluate the concordance of results in consecutive fine-needle aspiration and to study the relevance of repetition in benign results.

Material And Methods: Retrospective study of the 4800 thyroid nodules fine-needle aspiration held in Instituto de Patologia e Imunologia Molecular da Universidade do Porto between January 1, 2014 and May 2, 2016. Of the initial sample, we selected the repeated fine-needle aspiration on the same nodule.

Results: The first fine-needle aspiration result of the 309 nodules underwent revaluation was non-diagnostic in 103 (33.3%), benign in 120 (38.8%) and atypia/follicular lesion of undetermined significance in 86 (27.8%). The agreement between the first and second fine-needle aspiration was significantly higher in cases with an initial benign result (benign: 85.8%, non-diagnostic: 27.2% and atypia/follicular lesion of undetermined significance: 17.4%, p < 0.005). The fine-needle aspiration repeating motifs in initially benign nodules (n = 78) were repetition suggestion in 58, nodule growth in 17 and suspicious ultrasonographic features in 3.

Discussion: The fine-needle aspiration repetition in nodules with initial non-diagnostic and atypia/follicular lesion of undetermined significance result changed the initial diagnosis in a significant proportion of patients, modifying their therapeutic approach. The high concordance of results in initially benign nodules makes fine-needle aspiration repetition not cost-effective in most cases.

Conclusion: The fine-needle aspiration should be repeated when the initial cytology result is non-diagnostic or atypia/follicular lesion of undetermined significance.
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http://dx.doi.org/10.20344/amp.8215DOI Listing
June 2017

Accounting for tissue heterogeneity in infrared spectroscopic imaging for accurate diagnosis of thyroid carcinoma subtypes.

Vib Spectrosc 2017 Jul 16;91:77-82. Epub 2016 Sep 16.

Department of Pathology, University of Illinois at Chicago, 840 S Wood St. 130 CSN, Chicago, IL 60612, USA.

Fourier transform infrared (FT-IR) microscopy was used to image tissue samples from twenty patients diagnosed with thyroid carcinoma. The spectral data were then used to differentiate between follicular thyroid carcinoma and follicular variant of papillary thyroid carcinoma using principle component analysis coupled with linear discriminant analysis and a Naïve Bayesian classifier operating on a set of computed spectral metrics. Classification of patients' disease type was accomplished by using average spectra from a wide region containing follicular cells, colloid, and fibrosis; however, classification of disease state at the pixel level was only possible when the extracted spectra were limited to follicular epithelial cells in the samples, excluding the relatively uninformative areas of fibrosis. The results demonstrate the potential of FT-IR microscopy as a tool to assist in the difficult diagnosis of these subtypes of thyroid cancer, and also highlights the importance of selectively and separately analyzing spectral information from different features of a tissue of interest.
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http://dx.doi.org/10.1016/j.vibspec.2016.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542415PMC
July 2017

Classification of breast cancer histology images using Convolutional Neural Networks.

PLoS One 2017 1;12(6):e0177544. Epub 2017 Jun 1.

Faculdade de Engenharia da Universidade do Porto (FEUP), R. Dr. Roberto Frias s/n, 4200-465 Porto, Portugal.

Breast cancer is one of the main causes of cancer death worldwide. The diagnosis of biopsy tissue with hematoxylin and eosin stained images is non-trivial and specialists often disagree on the final diagnosis. Computer-aided Diagnosis systems contribute to reduce the cost and increase the efficiency of this process. Conventional classification approaches rely on feature extraction methods designed for a specific problem based on field-knowledge. To overcome the many difficulties of the feature-based approaches, deep learning methods are becoming important alternatives. A method for the classification of hematoxylin and eosin stained breast biopsy images using Convolutional Neural Networks (CNNs) is proposed. Images are classified in four classes, normal tissue, benign lesion, in situ carcinoma and invasive carcinoma, and in two classes, carcinoma and non-carcinoma. The architecture of the network is designed to retrieve information at different scales, including both nuclei and overall tissue organization. This design allows the extension of the proposed system to whole-slide histology images. The features extracted by the CNN are also used for training a Support Vector Machine classifier. Accuracies of 77.8% for four class and 83.3% for carcinoma/non-carcinoma are achieved. The sensitivity of our method for cancer cases is 95.6%.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177544PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453426PMC
September 2017

Counting invasive breast cancer cells in the HER2 silver in-situ hybridization test: how many cells are enough?

Histopathology 2017 Aug 26;71(2):247-257. Epub 2017 Apr 26.

Department of Pathology, Ipatimup Diagnostics, Ipatimup, Porto, Portugal.

Aim: To evaluate the intraobserver and interobserver reproducibility of the HER2 in-situ hybridization (ISH) test in breast cancer by measuring the impact of counting different numbers of invasive cancer cells.

Methods And Results: A cohort of 101 primary invasive breast cancer cases were evaluated for HER2 gene amplification by silver ISH, and the concordance among four observers with different levels of experience, counting different numbers of invasive cancer cells, was determined. The evaluation of the samples included scoring 20 nuclei, in three different areas. The cases were scored twice, with a washout interval of at least 2 weeks. We observed an increase in the intraobserver concordance rate between the first and second evaluations with an increase in cell count. A count of 60 invasive cells was needed to obtain a concordance rate near 95% and an agreement rate greater than 0.80 by all observers. The interobserver concordance rate of the HER2 test also increased with the increase in cell count, reaching at least a 90% concordance rate with a count of 60 invasive cells. The median variability of both the HER2/CEP17 ratio and the average HER2 copy number between different evaluations decreased with the increase in cell count, being statistically higher in HER2-positive cases.

Conclusions: The minimal cell number recommended in current guidelines should be raised to at least 40, and preferably 60, invasive cells. Moreover, cases with amplification levels close to the threshold should be subjected to a dual count from an experienced observer.
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http://dx.doi.org/10.1111/his.13208DOI Listing
August 2017

Hobnail Variant of Papillary Thyroid Carcinoma: Clinicopathologic and Molecular Evidence of Progression to Undifferentiated Carcinoma in 2 Cases.

Am J Surg Pathol 2017 Jun;41(6):854-860

*Department of Anatomic Pathology, Clinical University Hospital, Servicio Gallego de Salud (SERGAS), Health Research Institute of Santiago de Compostela (IDIS) †Department of Anatomic Pathology, Medical Faculty, University of Santiago de Compostela, Santiago de Compostela ‡Department of Anatomic Pathology, Hospital HM Puerta del Sur, Móstoles, Madrid, Spain §Institute of Research and Innovation in Health (i3S), University of Porto ∥Institute of Molecular Pathology and Immunology of the University of Porto ¶Medical Faculty, University of Porto #Department of Pathology, Hospital de S. João, Porto, Portugal.

The hobnail variant (HV) of papillary thyroid carcinoma (PTC) is an unusual entity recently proposed as an aggressive variant of PTC. We describe the pathologic and molecular features of 2 cases of HV of PTC. Both tumors presented in stage III (pT3 pN1a M0). The first case was diagnosed in a 62-year-old man, whereas the second was in a 53-year-old woman. Both patients were treated with total thyroidectomy and radioactive iodine. The primary tumors showed a hobnail/micropapillary pattern in ≥50% of the neoplasm, and positivity for TTF-1, TTF-2, thyroglobulin (TG), cyclin D1, and p53. The Ki-67 index was 4.6% and 5%, respectively. In case 1, the tumor disclosed BRAFV600E and TERT C228T (124:G>A) promoter gene mutation, negativity for NRAS, HRAS, and KRAS mutations, and negativity for RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. After 11 years the patient died with cervical lymph node, bone, and liver metastases. In the liver metastasis, the tumor displayed columnar cell PTC areas (positive for TTF-1, TG, and BRAFV600E) merging with undifferentiated carcinoma (UC) areas (positive for TTF-1 and BRAFV600E; negative for TG). In case 2, the patient died 6 years after treatment with local recurrence and disseminated metastases to the lung, pleura, bone, and liver. The tumor recurrence showed a UC component (positive for cyclin D1 and p53; negative for TTF-1 and TG) with a residual HV of PTC (positive for cyclin D1, p53, TTF-1, and TG). No BRAF, TERT, NRAS, HRAS, nor KRAS mutations were detected in the primary tumor or recurrence in case 2. Our findings suggest that p53-positive HV is a very aggressive form of PTC prone to progression to UC.
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http://dx.doi.org/10.1097/PAS.0000000000000793DOI Listing
June 2017

TERT promoter mutations: a genetic signature of benign and malignant thyroid tumours occurring in the context of tinea capitis irradiation.

Eur J Endocrinol 2017 Jan 19;176(1):49-55. Epub 2016 Oct 19.

IPATIMUP - Institute of Molecular Pathology and Immunology of the University of PortoPorto, Portugal.

Objective: The aim of this study is to evaluate the frequency and molecular characteristics of TERTp mutations in thyroid adenomas and carcinomas occurring in the low-dose radiation exposure tinea capitis setting.

Design And Methods: Twenty-seven patients with 34 well-differentiated thyroid carcinomas and 28 patients with 29 follicular adenomas diagnosed in a Portuguese tinea capitis cohort were studied. Blood samples were obtained from all the patients. Screening for TERTp mutations was performed by PCR amplification followed by Sanger sequencing. A series of 33 sporadic thyroid adenomas was used as control.

Results: TERTp mutations were detected in six of the 28 patients with adenoma (21.4%) and in four of the 27 patients with carcinoma (14.8%). Three tumours (two carcinomas and one adenoma) had the tandem mutation -124/-125 GG>AA (30.0%), whereas the remaining seven had the -124G > A. The 20.7% frequency of TERTp mutations in adenomas contrasts with the absence of mutations in the adenomas from the control group and from most series on record, whereas the one found in carcinomas (11.8%) is similar to those reported in the literature for sporadic carcinomas.

Conclusion: TERTp mutations, including the tandem mutation -124/-125 GG>AA not described previously in thyroid tumours, appear to represent a genetic signature for thyroid tumours in patients submitted to low-dose X-ray irradiation. The high frequency of TERTp mutations in the adenomas of our cohort contrasts with their absence in sporadically occurring, as well as in adenomas of the Chernobyl series.
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http://dx.doi.org/10.1530/EJE-16-0740DOI Listing
January 2017

pmTOR is a marker of aggressiveness in papillary thyroid carcinomas.

Surgery 2016 12 26;160(6):1582-1590. Epub 2016 Aug 26.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), University of Porto, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), University of Porto, Porto, Portugal; Medical Faculty, University of Porto, Porto, Portugal; Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal. Electronic address:

Background: Activation of the mTOR pathway has been observed in thyroid cancer, but the biologic consequences regarding tumor behavior and patient prognosis remain poorly explored.

Methods: We aimed to evaluate the associations of the mTOR pathway with clinicopathologic and molecular features and prognosis through the immunocharacterization of pmTOR and pS6 expression (as readouts of the pathway) in a series of 191 papillary thyroid carcinomas.

Results: pmTOR expression was associated with distant metastases (P = .05) and persistence of disease (P = .05). Cases with greater expression of pmTOR were submitted to more I treatments (r[102] = 0.2; P = .02) and a greater cumulative dose of radioactive iodine (r[100] = 0.3; P = .01). Positive pmTOR expression showed to be an independent risk factor for distant metastases (odds ratio = 18.2; 95% confidence interval 2.1-157.9; P = .01). In contrast, pS6 expression was associated with absence of extrathyroid extension (P = .001), well-defined tumor margins (P = .05), and wild-type BRAF status (P = .01). There was no correlation between the expression of pmTOR and pS6 expression (r[140] = 0.1; P = .3).

Conclusion: pmTOR expression is an indicator of aggressive, metastatic papillary thyroid carcinoma, being possibly implicated in refractoriness to therapy, while pS6 expression is associated with less aggressive pathologic features. Further studies are needed to understand better the biologic consequences of activation of the mTOR pathway in the behavior of thyroid cancer, namely the contribution of other pmTOR downstream effectors.
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http://dx.doi.org/10.1016/j.surg.2016.06.050DOI Listing
December 2016

Osteopontin-a splice variant is overexpressed in papillary thyroid carcinoma and modulates invasive behavior.

Oncotarget 2016 Aug;7(32):52003-52016

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

Osteopontin (OPN) is a matricellular protein overexpressed in cancer cells and modulates tumorigenesis and metastasis, including in thyroid cancer (TC). The contribution of each OPN splice variant (OPN-SV), named OPNa, OPNb and OPNc, in TC is currently unknown. This study evaluates the expression of total OPN (tOPN) and OPN-SV in TC tissues and cell lines, their correlation with clinicopathological, molecular features and their functional roles. We showed that tOPN and OPNa are overexpressed in classic papillary thyroid carcinoma (cPTC) in relation to adjacent thyroid, adenoma and follicular variant of papillary thyroid carcinoma (fvPTC) tissues. In cPTC, OPNa overexpression is associated with larger tumor size, vascular invasion, extrathyroid extension and BRAFV600E mutation. We found that TC cell lines overexpressing OPNa exhibited increased proliferation, migration, motility and in vivo invasion. Conditioned medium secreted from cells overexpressing OPNa induce MMP2 and MMP9 metalloproteinases activity. In summary, we described the expression pattern of OPN-SV in cPTC samples and the key role of OPNa expression on activating TC tumor progression features. Our findings highlight OPNa variant as TC biomarker, besides being a putative target for cPTC therapeutic approaches.
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http://dx.doi.org/10.18632/oncotarget.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239531PMC
August 2016

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma.

Eur J Endocrinol 2016 Apr 25;174(4):551-61. Epub 2016 Jan 25.

Instituto de Investigação e Inovacão em SaúdeUniversidade do Porto, 4200-135 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRua Dr Roberto Frias, s/n, 4200-465 Porto, PortugalMedical FacultyUniversity of Porto, Al. Professor Hernâni Monteiro, P-4200 Porto, PortugalUnidade de Investigação em Patobiologia Molecular (UIPM)Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Professor Lima Basto, 1099-023 Lisboa, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Avenue. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Professor Hernâni Monteiro, P-4200 Porto, PortugalResearch CoordinationNational Institute of Cancer, Rio de Janeiro 22743-051, BrazilNatural Sciences DepartmentHealth and Humanities Institute, Fluminense Federal University, Rio das Ostras, Rio de Janeiro 28895-532, Brazil Instituto de Investigação e Inovacão em SaúdeUniversidade do Porto, 4200-135 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRua Dr Roberto Frias, s/n, 4200-465 Porto, PortugalMedical FacultyUniversity of Porto, Al. Professor Hernâni Monteiro, P-4200 Porto, PortugalUnidade de Investigação em Patobiologia Molecular (UIPM)Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Professor Lima Basto, 1099-023 Lisboa, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Avenue. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Professor Hernâni Monteiro, P-4200 Porto, PortugalResearch CoordinationNational Institute of Cancer, Rio de Janeiro 22743-051, BrazilNatural Sciences DepartmentHealth and Humanities Institute, Fluminense Federal University, Rio das Ostras, Rio de Janeiro 28895-532, Brazil Instituto de Investigação e In

Background: Osteopontin (OPN) or secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and has been shown to be involved in tumourigenesis and metastasis in many malignancies, including follicular cell-derived thyroid carcinomas. Its role in C-cell-derived thyroid lesions and tumours remains to be established.

Objective: The objective of this study is to clarify the role of OPN expression in the development of medullary thyroid carcinoma (MTC).

Methods: OPN expression was analysed in a series of 116 MTCs by immunohistochemistry and by qPCR mRNA quantification of the 3 OPN isoforms (OPNa, OPNb and OPNc) in six cases from which fresh frozen tissue was available. Statistical tests were used to evaluate the relationship of OPN expression and the clinicopathological and molecular characteristics of patients and tumours.

Results: OPN expression was detected in 91 of 116 (78.4%) of the MTC. We also observed high OPN expression in C-cell hyperplasia as well as in C-cells scattered in the thyroid parenchyma adjacent to the tumours. OPN expression was significantly associated with smaller tumour size, PTEN nuclear expression and RAS status, and suggestively associated with non-invasive tumours. OPNa isoform was expressed significantly at higher levels in tumours than in non-tumour samples. OPNb and OPNc presented similar levels of expression in all samples. Furthermore, OPNa isoform overexpression was significantly associated with reduced growth and viability in the MTC-derived cell line (TT).

Conclusion: The expression of OPN in normal C-cells and C-cell hyperplasia suggests that OPN is a differentiation marker of C-cells, rather than a marker of biological aggressiveness in this setting. At variance with other cancers, OPN expression is associated with good prognostic features in MTC.
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http://dx.doi.org/10.1530/EJE-15-0577DOI Listing
April 2016

Early cardiac changes induced by a hypercaloric Western-type diet in "subclinical" obesity.

Am J Physiol Heart Circ Physiol 2016 Mar 22;310(6):H655-66. Epub 2016 Jan 22.

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Universidade do Porto, Porto, Portugal; Department of Cardiothoracic Surgery, Centro Hospitalar São João, Porto, Portugal.

"Obesity cardiomyopathy" effects have been widely described; however, the specific contribution of metabolic changes and altered adipokine secretion are still uncharacterized. Moreover, a diagnosis based on body mass index might not be the most accurate to identify increased adiposity and its outcomes. In this study, we aimed to determine the impact of a Western-type diet [hypercaloric diet (HCD)] ingestion on biventricular structure and function, as well as the metabolic and endocrine changes that occur before the establishment of overt obesity. Wistar rats were fed for 6 wk with a regular diet or HCD. At the end of the protocol, metabolic tests, cardiac structure, and functional evaluation were performed, and blood and tissue samples collected to perform histological, molecular biology, and functional studies. The animals that ingested the HCD presented increased adiposity and larger adipocyte cross-sectional area, but similar body weight compared with the regular diet group. At the cardiac level, HCD induced biventricular cardiomyocyte hypertrophy, fibrosis, increased stiffness, and impaired relaxation. Galectin-3 plasma expression was likewise elevated in the same animals. The nutritional modulation also altered the secretory pattern of the adipose tissue, originating a proinflammatory systemic environment. In this study, we observed that before "clinical" overweight or frank obesity is established, the ingestion of a HCD-induced cardiac remodeling manifests by increased biventricular stiffness and diastolic dysfunction. The mechanism triggering the cardiac alterations appears to be the proinflammatory environment promoted by the adipose tissue dysfunction. Furthermore, galectin-3, a profibrotic molecule, might be a potential biomarker for the myocardial alterations promoted by the HCD before overweight or obesity.
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http://dx.doi.org/10.1152/ajpheart.00684.2015DOI Listing
March 2016

Poorly Differentiated and Undifferentiated Thyroid Carcinomas.

Turk Patoloji Derg 2015 ;31 Suppl 1:48-59

Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology, Porto, Portugal.

Thyroid cancer is the most common endocrine malignancy and its incidence goes on increasing worldwide. The majority of thyroid tumours comprise well-differentiated (papillary and follicular) thyroid carcinomas that usually carry an excellent prognosis, while a minority progress to poorly differentiated carcinoma (PDTC) and, ultimately, to the highly aggressive and lethal undifferentiated carcinoma (UTC). Recently, some major advances have been made on the histologic and imunohistochemical identification, as well as on the molecular characterization of PDTC and UTC. In this review we summarize the most recent immunohistochemical and molecular findings in PDTC and UTC, giving a particular emphasis to the diagnostic and prognostic meaning of the genetic alterations.
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http://dx.doi.org/10.5146/tjpath.2015.01314DOI Listing
March 2016