Publications by authors named "Manuel Sobrinho-Simões"

179 Publications

Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 Porto, Portugal.

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002-2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTp showed increased risk of structural disease (HR = 7.0, < 0.001) and DSM (HR = 10.1, = 0.001). Combined genotypes, BRAF/TERTp (HR = 6.8, = 0.003), BRAF/TERTp (HR = 3.2, = 0.056) and BRAF/TERTp (HR = 2.2, = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAF/TERTp (HR = 24.2, < 0.001) and BRAF/TERTp (HR = 11.5, = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTp regardless of BRAF status (BRAF/TERTp, log-rank < 0.001; BRAF/TERTp, log-rank < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients' outcome. BRAF/TERTp tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTp tumors were predisposed to recurrent structural disease and DSM.
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http://dx.doi.org/10.3390/cancers13092048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122921PMC
April 2021

Analyzing the Role of DICER1 Germline Variations in Papillary Thyroid Carcinoma.

Eur Thyroid J 2021 Feb 6;9(6):296-303. Epub 2020 Aug 6.

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

Introduction: DICER1 is a member of RNase III family that has a pivotal role in the biogenesis of microRNAs, being important for normal development. Dysregulation of DICER1 has been described in different human tumours; however, there is insufficient data on the risk of thyroid cancer in the presence of germline DICER1 variants, particularly when focusing on the background of papillary thyroid carcinoma (PTC). For this purpose, we ascertained the presence of DICER1 variants in 502 (PTC) cases available from The Cancer Genome Atlas (TCGA) research network in a well-characterized pathological context.

Material And Methods: in this study we analyzed 502 samples from 502 patients, described as PTC in the TCGA database. Tumour diagnoses were re-evaluated by 2 pathologists (S.C. and M.S.-S.) on slides available from the database, and clinicopathological and demographic data was examined. Data concerning germline and sporadic DICER1 gene variants as well as frequent mutations in the genes involved in thyroid carcinogenesis (e.g., and V600E) was retrieved from the database.

Results And Discussion: We report 1 new germline possibly pathogenic variant, besides 15 others already been identified in ClinVar. We found that the DICER1-positive PTC group more frequently includes PTC variants, namely the oncocytic, follicular, and aggressive (hobnail variant of PTC) variants. A previous association of DICER1 had been demonstrated, mainly with the follicular variant of PTC and follicular thyroid carcinomas. Tumours harbouring germline DICER1 mutations were more frequently "bilateral" and "encapsulated." The frequent association of DICER1 germline variants with other mutations associated with thyroid cancer can reflect an haploinsufficiency tumour suppressor gene function of DICER1, as suggested from the study of animal models.
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http://dx.doi.org/10.1159/000509183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923931PMC
February 2021

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;32(1):44-62. 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

S616-p-DRP1 associates with locally invasive behavior of follicular cell-derived thyroid carcinoma.

Endocrine 2021 Jul 20;73(1):85-97. Epub 2020 Nov 20.

Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.

Purpose: Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC).

Methods: Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals.

Results: DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028).

Conclusions: S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.
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http://dx.doi.org/10.1007/s12020-020-02546-4DOI Listing
July 2021

Clinicopathological Features as Prognostic Predictors of Poor Outcome in Papillary Thyroid Carcinoma.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

IPATIMUP-Instituto de Patologia e Imunologia Molecular, Universidade do Porto, 4200-135 Porto, Portugal.

Papillary thyroid cancer (PTC) has an indolent nature and usually excellent prognosis. Some PTC clinicopathological features may contribute to the development of aggressive metastatic disease. In this work, we want to evaluate PTC clinicopathological features that are presurgical prognostic predictors of patients' outcomes and find which indicators are more adequate for tailoring surgical procedures and follow-up. We studied a series of 241 PTC patients submitted to surgery. All patients' files and histological tumor samples were reviewed. The 8th edition AJCC/UICC (American Joint Committee on Cancer/Union for International Cancer) Controlstaging system and the 2015 American Thyroid Association risk stratification system were used. Total thyroidectomy was performed in 228 patients, lymphadenectomy in 28 patients. Gross extrathyroidal extension (ETE) was present in 10 patients and 31 tumor resection margins were incomplete. Cervical lymph node metastases (LNMs) were present in 34 patients and distant metastases at diagnosis in four patients. In multivariate analysis, male gender (OR = 15.4, = 0.015), venous invasion (OR = 16.7, = 0.022), and lateral compartment LNM (OR = 26.7, = 0.004) were predictors of mortality; psammoma bodies (PBs) (OR = 4.5, = 0.008), lymph vessel invasion (OR = 6.9, < 0.001), and gross ETE (OR = 16.1, = 0.001) were predictors of structural disease status; male gender (OR = 2.9, = 0.011), lymph vessel invasion (OR = 2.8, = 0.006), and incomplete resection margins (OR = 4.6, < 0.001) were predictors of recurrent/persistent disease. Our study supports that the factors helping to tailor patient's surgery are male gender, presence of PBs, gross ETE, and lateral compartment LNM. Together with pathological factors, lymph vessel invasion, venous invasion, necrosis, and incomplete surgical resection, should be taken into consideration regarding treatment and follow-up of patients.
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http://dx.doi.org/10.3390/cancers12113186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693726PMC
October 2020

Molecular Aspects of Thyroid Calcification.

Int J Mol Sci 2020 Oct 19;21(20). Epub 2020 Oct 19.

Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, Porto 4200-319, Portugal.

In thyroid cancer, calcification is mainly present in classical papillary thyroid carcinoma (PTC) and in medullary thyroid carcinoma (MTC), despite being described in benign lesions and in other subtypes of thyroid carcinomas. Thyroid calcifications are classified according to their diameter and location. At ultrasonography, microcalcifications appear as hyperechoic spots ≤ 1 mm in diameter and can be named as stromal calcification, bone formation, or psammoma bodies (PBs), whereas calcifications > 1 mm are macrocalcifications. The mechanism of their formation is still poorly understood. Microcalcifications are generally accepted as a reliable indicator of malignancy as they mostly represent PBs. In order to progress in terms of the understanding of the mechanisms behind calcification occurring in thyroid tumors in general, and in PTC in particular, we decided to use histopathology as the basis of the possible cellular and molecular mechanisms of calcification formation in thyroid cancer. We explored the involvement of molecules such as runt-related transcription factor-2 (Runx-2), osteonectin/secreted protein acidic and rich in cysteine (SPARC), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteopontin (OPN) in the formation of calcification. The present review offers a novel insight into the mechanisms underlying the development of calcification in thyroid cancer.
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http://dx.doi.org/10.3390/ijms21207718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589718PMC
October 2020

Comprehensive Assessment of mRNA Expression across a Large Cohort of Benign and Malignant Thyroid Tumours.

Cancers (Basel) 2020 Jul 9;12(7). Epub 2020 Jul 9.

Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal.

The presence of promoter (p) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of p mutations and mRNA expression in these settings. In this series, p mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. p mutations and mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas mRNA expression in the benign tumours is associated with the presence of thyroiditis.
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http://dx.doi.org/10.3390/cancers12071846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408963PMC
July 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

Poorly differentiated thyroid carcinoma with pleomorphic giant cells-a case report.

Virchows Arch 2020 Oct 1;477(4):597-601. Epub 2020 Apr 1.

Pathology Department, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.

Poorly differentiated thyroid carcinoma (PDTC) refers to a malignant tumour that displays an intermediate prognosis between well-differentiated carcinomas and anaplastic thyroid carcinomas (ATC). In the thyroid, pleomorphic giant cells are observed in ATC or in some non-neoplastic thyroid diseases. We described the case of a 43-year-old woman with a 34-mm nodule in her thyroid right lobe. Microscopic examination revealed an encapsulated tumour with a main solid growth pattern and extensive capsular invasion. Multiple images of angioinvasion were observed. There was neither necrosis nor inflammation. Most of the tumour cells were medium-sized and intermingled with pleomorphic giant tumour cells with bizarre features. The immunoprofile (keratins +, TTF1+, Pax 8+) proved their thyroid origin. By NGS, no molecular alteration was identified. The patient was treated by surgery and radioiodine therapy and she has no recurrence after a follow-up of 24 months. Our case meets all the histological criteria of the Turin proposal for PDTC but with pleomorphic giant cells and is very different from ATC according to clinical, histological and immunohistochemical features. Pleomorphic tumour giant cells in thyroid carcinomas could be present in PDTC and do not always represent dedifferentiation and more aggressive carcinoma, thyroid neoplasm.
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http://dx.doi.org/10.1007/s00428-020-02807-7DOI Listing
October 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
March 2021

Cancer incidence after childhood irradiation for tinea capitis in a Portuguese cohort.

Br J Radiol 2020 Jan 11;93(1105):20180677. Epub 2019 Nov 11.

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

Objectives: Our aim was to compare cancer incidence in a cohort exposed in childhood (1950-63) to a therapeutic dose of radiation in the North of Portugal and followed-up until the end of 2012, with the incidence rates for the same age and sex in the general population.

Methods: A population-based North Region cancer registry (RORENO) was used to assess which members of the cohort developed cancer. The association between radiation exposure and overall and specific cancer sites was evaluated using standardised incidence ratios (SIR).

Results: Over the full follow-up period, 3357 individuals of the 5356 original tinea capitis (TC) cohort (63%) were retrieved in the RORENO, and 399 new cancer cases were identified, representing an increased risk of 49% when compared with the general population (SIR = 1.49; 95% CI: 1.35-1.64). The risk was slightly higher in males than in females (SIR = 1.65; 95% CI: 1.43-1.89 SIR = 1.35; CI = 1.17-1.55). The risk was slightly higher in the individuals exposed to a higher radiation dose (SIR = 1.78; 95% CI: 1.22-2.51 for ≥630 R SIR = 1.46; 95% CI: 1.31-1.62 for 325-475 R). In females, there was an excess cancer risk in all cancers with the higher radiation dose (SIR = 2.00; 95% CI: 1.21-3.13 for ≥630 R SIR = 1.30; 95% CI: 1.11-1.51 for 325-475 R) which was not observed in males, and for combined dose categories significantly raised SIRs for thyroid and head and neck cancer, suggesting a possible higher radiosensitivity of females. An increased risk was also observed for some cancers located far from the irradiated area.

Conclusions: The results suggest an association between radiation exposure and later increased cancer risk for cancers located near the radiation exposed area, mainly thyroid, and head and neck cancers. Further studies are necessary to disentangle possible non-radiation causes for distant cancers increased risk.

Advances In Knowledge: This paper shows a possible association between childhood X-ray epilation and increased risk of cancer which was not previously investigated in the Portuguese TC cohort.
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http://dx.doi.org/10.1259/bjr.20180677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948089PMC
January 2020

Interaction of Genetic Variations in and Modulates the Risk of Hashimoto's Thyroiditis.

Thyroid 2019 09;29(9):1302-1315

Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by , is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in on the risk of developing HT. In a case-control candidate gene association study, functional SNPs in the promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene , encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. and SNPs were genotyped using TaqMan assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells. When all three SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43,  = 0.072). Among subjects harboring only major alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the minor allele. Conversely, in subjects heterozygous or homozygous for the risk allele, the presence of an minor allele significantly increased HT risk by 2.8-fold ( = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling. The promoter genotype interacts with the promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways.
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http://dx.doi.org/10.1089/thy.2018.0480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760180PMC
September 2019

European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium.

Thyroid 2019 01 7;29(1):7-26. Epub 2019 Jan 7.

18 Department of Endocrinology and Metabolism, Endocrine Tumor Center at WTZ, Essen University Hospital, Essen, Germany.

Background: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions.

Summary: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions.

Conclusions: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes.
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http://dx.doi.org/10.1089/thy.2017.0129DOI Listing
January 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

TERTp mutation is associated with a shorter progression free survival in patients with aggressive histology subtypes of follicular-cell derived thyroid carcinoma.

Endocrine 2018 09 15;61(3):489-498. Epub 2018 Jun 15.

Programa de Pós Graduação em Endocrinologia da Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Purpose: Evaluate the impact of TERTp mutation on the outcomes after initial treatment of 45 patients with thyroid carcinomas derived from follicular cells (TCDFC) with aggressive histology, in which the role of this mutation is not yet well defined.

Methods: Analysis of the presence of TERTp (-124C > T and -146C > T), BRAF (V600E), and NRAS (Q 61R) mutations by Sanger sequencing and analysis of their correlation with the patient's outcomes.

Results: Forty-five patients with aggressive histopathologic variants were included in the study. Of these, 68.9% had aggressive variants of papillary thyroid cancer (PTC), 22.2% had poorly differentiated thyroid carcinoma (PDTC)/insular carcinoma, and 8.9% had invasive follicular thyroid cancer (FTC) with Hurthle cell features (Hurthle cell carcinoma). Lymph node metastases were present in 46.7% and distant metastases in 54.6%. The response to the initial therapy was excellent in 45.5% and structurally incomplete in 50%. During the follow-up period (median of 56 months; 5-360 months), 47.7% presented with disease progression and 17.8% experienced disease-related death. In 53.3% of the cases at least one molecular alteration (TERTp in 33.4%, BRAF in 24.5%, RAS in 8.9%) was detected. In the multivariate analysis, TERTp mutation was the factor associated with the highest risk (6 times) of having structural disease after initial therapy (p = 0.01), followed by vascular invasion (p = 0.02), gross extrathyroidal extension (ETE) (p = 0.02) and distant metastasis (p = 0.04). Regarding mutational status, only TERTp mutation was associated with disease progression, and diminished disease progression-free survival (PFS). The presence of distant metastasis, vascular invasion and gross ETE were significantly associated with the risk of disease progression.

Conclusions: TERTp mutation appears be an indicator of both persistence and progression of structural disease after initial therapy in aggressive variants of TCDFC, and associates with a shorter progression free survival regardless of the therapy employed.
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http://dx.doi.org/10.1007/s12020-018-1642-0DOI Listing
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

Telomere Maintenance Mechanisms in Cancer.

Genes (Basel) 2018 May 3;9(5). Epub 2018 May 3.

Cancer Signaling and Metabolism Group, Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135 Porto, Portugal.

Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the promoter (), amplification of the genes and , polymorphic variants of the gene and of its promoter, rearrangements of the gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of mutations, and amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.
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http://dx.doi.org/10.3390/genes9050241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977181PMC
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

Age-Associated Mortality Risk in Papillary Thyroid Cancer: Does BRAF Make a Real Difference?

J Clin Oncol 2018 05 23;36(14):1455-1456. Epub 2018 Mar 23.

Miguel Melo, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto; Centro Hospitalar e Universitário de Coimbra, University of Coimbra, Coimbra, Portugal; Adriana Gaspar da Rocha, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto; ACeS Baixo Mondego, Coimbra, Portugal; Gustavo Cancela e Penna, Federal University of Minas Gerais; Hospital Mater Dei, Belo Horizonte, Minas Gerais; Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Manuel Sobrinho-Simões, Instituto de Investigação e Inovação em Saúde, University of Porto, Hospital S. João, Porto, Portugal; and Paula Soares, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.

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http://dx.doi.org/10.1200/JCO.2018.77.8571DOI Listing
May 2018

Multinodular Goiter Progression Toward Malignancy in a Case of DICER1 Syndrome: Histologic and Molecular Alterations.

Am J Clin Pathol 2018 Mar;149(5):379-386

Department of Pathology Pediatric Department, Centro Hospitalar São João, Porto, Portugal.

Objectives: Multinodular goiter (MNG) and well-differentiated thyroid carcinoma (WDTC) are emerging phenotypes of DICER1 syndrome.

Methods: Histologic and molecular findings of botryoid-type embryonal rhabdomyosarcoma (bERMS) and thyroid nodules from a 12-year-old DICER1 mutation carrier (p.Arg1060Ilefs*7) were investigated, providing interesting clues for understanding thyroid carcinogenesis.

Results: The patient had bERMS at age 7 years. The thyroid was enlarged and multinodular (61 g). Histologically, some nodules were classified as adenomatous and others as tumors with "intermediate" nuclei. One displayed vascular invasion and was classified as WDTC not otherwise specified (NOS). Somatic DICER1 mutations were identified in bERMS, two tumors with "intermediate" nuclei and WDTC. No somatic DICER1 mutations were found in adenomatous nodules. No molecular alterations were detected in BRAF600, NRAS61, HRAS12/61, KRAS12/61, TERT promoter, RET/PTC1, RET/PTC3, and PAX8/PPARγ.

Conclusions: The findings obtained from this single case support the assumption that DICER1 syndrome-related WDTC NOS may develop on a background of MNG, via a stepwise process, involving DICER1 somatic mutations and additional molecular events, distinct from the classic pathways of papillary/follicular carcinoma.
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http://dx.doi.org/10.1093/ajcp/aqy004DOI Listing
March 2018

Dynamin-Related Protein 1 at the Crossroads of Cancer.

Genes (Basel) 2018 Feb 21;9(2). Epub 2018 Feb 21.

Cancer Signaling & Metabolism Group, Instituto de Investigação e Inovação em Saúde (Institute for Research and Innovation in Health Sciences) (I3S), University of Porto, Porto 4200-135, Portugal.

Mitochondrial dynamics are known to have an important role in so-called age-related diseases, including cancer. Mitochondria is an organelle involved in many key cellular functions and responds to physiologic or stress stimuli by adapting its structure and function. Perhaps the most important structural changes involve mitochondrial dynamics (fission and fusion), which occur in normal cells as well as in cells under dysregulation, such as cancer cells. Dynamin-related protein 1 (DRP1), a member of the dynamin family of guanosine triphosphatases (GTPases), is the key component of mitochondrial fission machinery. Dynamin-related protein 1 is associated with different cell processes such as apoptosis, mitochondrial biogenesis, mitophagy, metabolism, and cell proliferation, differentiation, and transformation. The role of DRP1 in tumorigenesis may seem to be paradoxical, since mitochondrial fission is a key mediator of two very different processes, cellular apoptosis and cell mitosis. Dynamin-related protein 1 has been associated with the development of distinct human cancers, including changes in mitochondrial energetics and cellular metabolism, cell proliferation, and stem cell maintenance, invasion, and promotion of metastases. However, the underlying mechanism for this association is still being explored. Herein, we review the published knowledge on the role of DRP1 in cancer, exploring its interaction with different biological processes in the tumorigenesis context.
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http://dx.doi.org/10.3390/genes9020115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852611PMC
February 2018

Is Low-Dose Radiation Exposure a Risk Factor for Atherosclerotic Disease?

Radiat Res 2018 04 20;189(4):418-424. Epub 2018 Feb 20.

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

Nontargeted late effects of radiation include an increased risk of cardiovascular disease, although this is still debatable in the context of low-dose radiation. Tinea capitis patients treated in childhood with X rays to induce scalp epilation received a low dose of radiation to their carotids. To better clarify this issue, we evaluated carotid atherosclerosis in a cohort of such patients treated in 1950-1963 in Portugal. A group of 454 individuals randomly chosen from previously observed Portuguese tinea capitis patients and a control group mainly composed of their spouses (n = 280) were enrolled. Cardiovascular risk factors such as waist circumference, body mass index, blood pressure and tobacco consumption, as well as biochemical measurements were obtained. Ultrasound imaging of carotid arteries for intima media thickness and stenosis evaluation were performed according to a standardized protocol. In comparison to the control group, the irradiated cohort members were significantly older, more frequently never smokers, hypertensive, and presented higher glycated hemoglobin and alkaline phosphatase levels. In addition, the irradiated cohort showed a higher frequency of carotid stenosis ≥30% than the nonirradiated group (13.9% vs. 10.7%), although this was not significant ( P = 0.20). Stenosis was ≥50% in 2.9% of the irradiated group and 0.4% of the nonirradiated group ( P = 0.02). Likewise, the frequency of intima media thickness ≥1 mm was significantly higher in the irradiated group (16.8% vs. 10.7%; P = 0.02). Multivariate analysis, including other cardiovascular risk factors, showed that exposure to low-dose radiation increased the risk of carotid stenosis by ≥50% [odds ratio (OR) = 8.85; P = 0.04] and intima media thickness by ≥1 mm (OR = 1.82; P = 0.02). These findings confirm that low-dose exposure is a risk factor of carotid atherosclerotic disease.
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http://dx.doi.org/10.1667/RR14942.1DOI Listing
April 2018

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): impact on the reclassification of thyroid nodules.

Endocr Relat Cancer 2018 04 9;25(4):R247-R258. Epub 2018 Feb 9.

Department of Pathology, Centro Hospitalar S. João, Porto, Portugal.

The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled 'Other encapsulated follicular-patterned thyroid tumours', in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word 'carcinoma' from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with 'very low malignant potential'. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because mutations and rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features.
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http://dx.doi.org/10.1530/ERC-17-0513DOI Listing
April 2018

New WHO classification of thyroid tumors: a pragmatic categorization of thyroid gland neoplasms.

Endocrinol Diabetes Nutr (Engl Ed) 2018 Mar 7;65(3):133-135. Epub 2018 Feb 7.

Department of Pathology, Medical Faculty, University of Porto, Porto, Portugal; Department of Pathology, Hospital São João, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.

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http://dx.doi.org/10.1016/j.endinu.2017.11.012DOI Listing
March 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

Inhibitory Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) in Thyroid Cancer.

Horm Cancer 2017 12 18;8(5-6):314-324. Epub 2017 Sep 18.

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

Growth hormone-releasing hormone (GHRH) is a peptide hormone secreted by the hypothalamus that regulates the synthesis and secretion of growth hormone (GH) in the pituitary. The extra-hypothalamic GHRH and its cognate receptors (GHRHR and splice variants) play a mitogenic role by stimulating cell proliferation and preventing apoptotic cell death. It is well established that GHRH antagonists inhibit the growth, tumorigenicity, and metastasis of various human malignancies. In this work, we studied the effect of two new GHRH antagonists, MIA602 and MIA690, on thyroid cancer. We studied the effect of MIA602 and MIA690 on thyroid cancer in vitro, using human thyroid cancer cell lines, and in vivo, using chicken embryo chorioallantoic membrane (CAM) assays. We found that mRNA for GHRH and GHRH receptor is expressed in thyroid cell lines and in samples of thyroid tumors. Immunohistochemistry confirmed the expression of GHRHR protein in specimens of thyroid tumor. We observed that GHRH antagonists inhibited the growth and increased apoptosis of thyroid cancer cells. In vivo, the antagonists inhibited growth and angiogenesis of engrafted thyroid tumors. Our results suggest that GHRH expression may play a role in growth of thyroid cancer and that GHRH antagonists can be a therapeutic option for thyroid cancer patients.
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http://dx.doi.org/10.1007/s12672-017-0307-4DOI Listing
December 2017