Ecos da ETA 2017

  Grupo de Estudo da Tiroide da SPEDM
  com o apoio Merck, s.a.

Comunicações orais

Os temas das comunicações orais da manhã incluídas na ciência básica foram relacionados com o carcinoma da tiroide. Foram abordadas as mutações detetadas neste carcinoma, principalmente o papel do BRAF e do promotor TERT no carcinoma diferenciado da tiroide, assim como na metastização local e à distância.

Sobre este tema, foi apresentado pelo Prof. Doutor Miguel Melo, endocrinologista no CHUC e investigador no IPATIMUP, o trabalho Unrevealing metastatic dormancy in thyroid cancer: differences in the genotype between synchronous and metachronous metastases. O objetivo principal foi avaliar a concordância entre o genótipo dos tumores primários da tiroide e as metástases locais ou distantes, de acordo com o momento de deteção da lesão metastática (síncrona ou metácrona). O grupo de trabalho concluiu que alterações no BRAF são mais frequentes nas metástases locais e que existe uma concordância nessas alterações entre os genótipos do tumor primário e as metástases síncronas. As mutações no TERTp foram mais frequentes nas metástases à distância, com uma concordância estatística entre o tumor primário e as metástases metácronas, levantando a hipótese de que o TERTp pode estar envolvido na disseminação à distância e latência das metástases.

Foi também apresentado, sob a forma de comunicação oral, outro trabalho de investigação do IPATIMUP com o objetivo de avaliar o envolvimento da osteopontina no processo de mineralização dos tumores da tiroide derivados de células foliculares. O grupo de trabalho concluiu que o aumento da expressão da osteopontina está envolvido no processo de mineralização observado nos carcinomas papilares da tiroide.

Foram também apresentados vários trabalhos sobre o co-transportador sódio-iodo (NIS) e o seu papel no tratamento do carcinoma diferenciado da tiroide com iodo radioativo (IRA).

Salienta-se a apresentação de Sarah Umauer e colaboradores, da Universidade de Berlim, que mostrou o potencial terapêutico do NIS no carcinoma metastizado do cólon, mostrando diminuição do volume metastático e aumento da sobrevida dos ratinhos com o polímero sintético do gene NIS após terapêutica com IRA.

As comunicações orais da tarde do segundo dia abordaram os aspetos clínicos e diagnósticos do carcinoma da tiroide. A Dr.ª Lavinia Vija Racaru, da Universidade Paul Sebatier, em Toulouse, e seus colaboradores apresentaram um trabalho sobre a avaliação de metastização ganglionar no carcinoma medular da tiroide usando PET/CT com 18F-DOPA. Neste trabalho, o uso de 18F-DOPA PET/CT apresentou boa concordância com a CT cervical, tendo maior sensibilidade e especificidade que a ecografia cervical.

A sua boa sensibilidade e especificidade mesmo para valores de calcitonina < 150 pg/ml, tornam este exame uma arma diagnóstica promissora para a deteção precoce de recorrência ganglionar nos doentes com carcinoma medular da tiroide, cujos valores de calcitonina estão aumentados, embora os exames de diagnóstico convencionais não mostrem lesão estrutural.

Na sequência do discutido no simpósio satélite, em que muito se debateu sobre a eficácia de doses baixas de iodo radioativo no tratamento do carcinoma diferenciado a tiroide (CDT) e sobre os efeitos nefastos a longo prazo de altas doses de iodo, a Dr.ª Noemi Fralassi, da Universidade de Siena, apresentou um trabalho sobre o aumento da incidência de segundas neoplasias primárias em doentes com CDT.

Este trabalho retrospetivo incluiu 1023 doentes com DTC, sendo que 118 apresentaram segundas neoplasias, a maioria precedente ou síncrona com o carcinoma da tiroide (64,4%). A neoplasia mais comum foi o carcinoma da mama. A presença de uma segunda neoplasia foi significativamente superior em doentes com CDT do que na população geral, sendo sobreponível em doentes com outras neoplasias primárias.

Apesar da incidência de segundas neoplasias ser semelhante no conjunto dos doentes submetidos a tratamento com iodo radioativo e nos doentes não submetidos, verificou-se um aumento significativo naqueles submetidos a doses mais elevadas de iodo (> 300mCi).
OP-03-19
UNREVEALING METASTATIC DORMANCY IN THYROID CANCER: DIFFERENCES IN THE GENOTYPE BETWEEN SYNCHRONOUS AND METACHRONOUS METASTASES

Adriana Gaspar da Rocha1,Miguel Melo2, Rui Batista3, João Vinagre4, José Manuel Cameselle-Teijeiro5, Valeriano Leite6, Francisco Carrilho7, Manuel Sobrinho-Simões8, Paula Soares9
1Instituto de Investigação e Inovação Em Saúde (I3s), Institute of Pathology and Immunology of the University of Porto (Ipatimup), Public Health Unit, Aces Baixo Mondego, Coimbra, Portugal, 2Instituto de Investigação e Inovação Em Saúde (I3s), Institute of Pathology and Immunology of the University of Porto (Ipatimup), Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal, 3Instituto de Investigação e Inovação Em Saúde (I3s), Institute of Pathology and Immunology of the University of Porto (Ipatimup), Medical Faculty, University of Porto, Porto, Portugal, 4Instituto de Investigação e Inovação Em Saúde (I3s), Institute of Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal, 5Department of Pathology, Clinical University Hospital, Sergas, Medical Faculty, University of Santiago de Compostela, Santiago de Compostela, Spain, 6Unit for Investigation of Molecular Pathobiology, Portuguese Institute of Oncology – Lisbon Center, Department of Endocrinology, Portuguese Institute of Oncology – Lisbon Center, Department of Endocrinology, Portuguese Institute of Oncology – Lisbon Center, Lisbon, Portugal, 7Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal, 8Department of Pathology and Oncology, Medical Faculty, University of Porto, Department of Pathology, Hospital S. João, Institute of Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal, 9Instituto de Investigação e Inovação Em Saúde (I3s), Institute of Pathology and Immunology of the University of Porto (Ipatimup), Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto, Portugal

Introduction: Thyroid cancer is a model in which metastatic dormancy is a frequent phenomenon. The concordance of genotype between primary tumours and metastases may be influenced by the time elapsed between the initial diagnosis and the clinical emergence of metastatic lesions.

Objective: We aimed to evaluate the concordance of genotype between primary thyroid tumours, local and distant metastases, according to the time of detection of the metastatic lesion (synchronous or metachronous).

Material and Methods: We studied 230 pairs of primary thyroid tumours and metastatic lesions, including 190 local and 40 distant metastases. BRAF and TERT promoter (TERTp) mutation analysis was performed in both thyroid tumours and metastatic lesions.

Results: We found the following mutation frequency in primary thyroid tumours, local metastases and distant metastases, respectively: BRAF 42.5%, 38.5%, and 25.0%; TERTp 11.3%, 7.3%, and 37.5%. For BRAF, the concordance of genotype between primary tumours and metastatic tissue was higher for synchronous lesions (kappa=0.379; p<0.001) than for metachronous lesions (kappa=0.117; p=0.463). The latter holds true whether the analysis was performed only in local metastases (synchronous lesions: kappa=0.379; p<0.001; metachronous lesions: kappa=-0.055; p=0.820) or in distant metastases (synchronous lesions: kappa=0.64; p=0.004; metachronous lesions: kappa=-0.112; p=0.540). For TERTp, the concordance of genotype between primary tumours and metastatic tissue was similar and statistically significant for synchronous (kappa=0.195; p<0.001) and for metachronous lesions (kappa=0.159; p=0.016). However, we found heterogeneity between local metastases (higher concordance in synchronous lesions) and distant metastases (higher concordance in metachronous lesions).

Conclusions: In the natural history of metastatic thyroid tumours, BRAF and TERTp mutations seem to play different roles. BRAF may be involved in more frequent local and synchronous metastases. TERTp mutations may be one of the major factors involved in distant dissemination and metastatic dormancy.
OP-03-16
INVESTIGATION OF THE ROLE OF OSTEOPONTIN IN CALCIFICATION AND MATRIX DEPOSITION IN THYROID CANCER

Luciana Ferreira1, Raquel T. Lima2, Andreia Machado Silva3, Ana Pestana4, Catarina Tavares4, Elisabete Rios5, Catarina Eloy6, Manuel Sobrinho-Simões7, Etel Gimba8, Paula Soares2
1Instituto Nacional de Câncer - Inca, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rio de Janeiro, Brazil, 2I3s-Instituto de Investigação e Inovação Em Saúde, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Medical Faculty, University of Porto, Porto, Portugal, 3I3s- Instituto de Investigação e Inovação Em Saúde, Ineb – Instituto de Engenharia Biomédica, Icbas – Instituto de Ciências Biomédicas Abel Salazar Da Universidade Do Porto, Porto, Portugal, 4I3s-Instituto de Investigação e Inovação Em Saúde, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal, 5Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Medical Faculty, University of Porto, Department of Pathology, Hospital de S. João, Porto, Portugal, 6Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal, 7I3s-Instituto de Investigação e Inovação Em Saúde, Universidade Do Porto, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Department of Pathology, Hospital de S. João, Porto, Portugal,8Instituto Nacional de Câncer-Inca, Universidade Federal Fluminense-Uff, Rio de Janeiro, Brazil

Background: Osteopontin (OPN) and its three spliced variants (OPN-SV:
OPNa, OPNb and OPNc) are overexpressed in several tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC) which is the most common variety of thyroid cancer (TC) being the histologic type which often presents desmoplasia (collagen deposition) and dystrophic calcification, including a fairly typical feature, the psammoma bodies (PB). The aim of this study was to investigate the role of OPN-SV expression in the calcification and in classical variant of PTC (cPTC).

Methods: Total OPN and OPN-SV expression was analyzed by immunohistochemistry and real time PCR in a series of 48 cPTC cases and three diffuse sclerosing PTCs. The association of OPN expression and the presence of PB as well as between PB in cPTC and the clinicopathological features of the tumors were evaluated. TPC-1 and c643 TC cell lines overexpressing OPN-SV were tested for the ability to promote calcification and to synthesize collagen in vitro.

Results: Overexpression of OPNa transcripts was significantly associated with the presence of PB in cPTC samples. The presence of PB in cPTC was associated with younger patients and lymph node metastasis. Moreover, OPNa overexpression displayed a strong capacity to promote calcification and substantial collagen synthesis in thyroid cancer cell lines.

Conclusion: Our data suggest that OPNa plays a role in the formation of calcification often associated with cPTC. Basic research on the interactions between OPNa overexpression by tumor cells and the surrounding microenvironment can give clues for a better understanding of cPTC biology and phenotype.
P2-04-92
NIVOLUMAB-ASSOCIATED THYROID DYSFUNCTION

Rita Silva1, Joana Oliveira1, César Esteves1, Gabriela Fernandes2, Cláudia Caeiro3, Lúcia Águas3, Joana Queirós1, Davide Carvalho1
1Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, E.P.E., Porto, Portugal, 2Department of Pulmonology, Centro Hospitalar São João, E.P.E., Porto, Portugal, 3Department of Medical Oncology, Centro Hospitalar São João, E.P.E., Porto, Portugal, Porto, Portugal

Background: Nivolumab is a monoclonal antibody specific for human programmed cell death protein-1 (PD-1), a checkpoint molecule highly expressed in several malignancies. Besides its benefits as an immunotherapeutic

strategy for cancer, it may exhibit endocrine side effects.

Case Reports: We report 3 cases of thyroid dysfunction during nivolumab treatment. Two males (70 and 64 years old) and one female (56 years old) were diftreated with nivolumab for metastatic clear cell renal carcinoma, lung adenocarcinoma and esophageal melanoma, respectively. No patient had previous thyroid disease or familial thyroid pathology. A few months after starting treatment, the patients developed thyrotoxicosis with suppressed thyroid-stimulating hormone (TSH) and normal (2 patients) or high (1 patient) free thyroxine (FT4) and free triiodothyronine (FT3). All patients had positive thyroglobulin antibody (TgAb) and/or positive peroxidase antibody (TPOAb) and negative TSH-receptor antibodies (TRAb). In one patient treatment with methimazole was instituted for 3.5 months, leading to symptom improvement and with no recurrence after antithyroid drug withdrawal. The other patients had spontaneous remission of thyrotoxicosis within 1-2 months and then developed hypothyroidism, leading to the diagnosis of nivolumab-associated thyroiditis and treatment with levothyroxine. Currently all patient maintain normal thyroid function.

Conclusion: Our cases highlight thyroid dysfunction due to a possible immune-mediated mechanism and the importance to test for thyroid function at baseline and during nivolumab treatment. No patient has discontinued nivolumab owing to thyroid dysfunction, but symptoms, evolution and treatment may differ among patients. Since the number of patients treated with nivolumab is expected to increase, health providers must be aware of endocrine disorders that may be associated with immunomodulatory therapies for a timely diagnosis and correct treatment.
P2-04-93
THYROTOXIC HYPOKALEMIC PERIODIC PARALYSIS AS PRESENTATION OF GRAVES‘ DISEASE IN A CAUCASIAN MALE PATIENT

Joao Sergio Neves1, Luís Teles2, Sofia Castro Oliveira3, Pedro Souteiro3, Ana Varela3, Ana Isabel Oliveira3, Celestino Neves4, Paula Freitas4, Davide Carvalho4
1Endocrinology, São João Hospital, Departamento de Fisiologia, Fmup, Porto, Portugal, 2Serviço de Medicina Interna. Centro Hospitalar Entre Douro e Vouga, Santa Maria Da Feira, Portugal, 3Department of Endocrinology, Diabetes and Metabolism, São João Hospital Center. Faculty of Medicine of Porto University, Porto, Portugal, 4Department of Endocrinology, Diabetes and Metabolism, São João Hospital Center. Faculty of Medicine of Porto University, Instituto de Investigação e Inovação Em Saúde Da Universidade Do Porto, Porto, Portugal

Introduction: Thyrotoxic hypokalemic periodic paralysis is a rare manifestation of Graves’ disease. This manifestation presents a significantly higher frequency in Asiatic patients, being rare in Caucasian patients.

Case Description: A 25-year old Caucasian male was evaluated in our emergency department due to decreased muscular strength after waking up with an associated fall. No consciousness loss or muscular pain was observed. The patient reported a similar episode two weeks before that occurred during rest after physical activity. In the two months before, the patient lost 10kg and presented frequent palpitations, tremor, hyperhidrosis and insomnia. The history of Graves’ disease in mother and sister was the most relevant finding from the personal and family history. On the initial examination, the patient was tachycardic (110bpm) with normal blood pressure (136/80mmHg), decreased muscular strength without other neurologic abnormalities. At initial analytic evaluation, a severe hypokalemia (1.9mEq/L) and a mild hypomagnesemia (1.35mEq/L) were shown without other relevant findings. An evaluation of thyroid function revealed a TSH <0.001µUI/mL and a free T4 of 2.75ng/dL and a diagnosis of thyrotoxic hypokalemic periodic paralysis was established. The patient was supplement with potassium and magnesium and started treatment with methimazole and bisoprolol. During the first three days of stay in the hospital, two more episodes of sudden decrease of muscular strength were observed. No more episodes of muscular strength loss were observed since then. The presence of positive TRAB antibodies (4.5U/L) confirmed the diagnosis of Graves’ disease. The patient was discharged with methimazole and propranolol.

Conclusions: The authors presented a case of thyrotoxic hypokalemic periodic paralysis as presentation of Graves’ disease in a caucasian male patient. Although is it a rare manifestation in non-asiatic patients, the presence of sudden decreased muscular strength with additional clinical findings suggestive of hyperthyroidism must prompt evaluation of thyroid function.
P2-05-103
PARATHYROID HORMONE WASHOUT (PTHW) IN ULTRASOUND-GUIDED FINE NEEDLE ASPIRATION CYTOLOGY (US-FNA) FOR DIFFERENTIAL DIAGNOSES AND MANAGEMENT OF THYROID AND PARATHYROID NODULES

Maria de Lurdes Godinho de Matos1, Joanna Prokop1, Miguel Vasques1, Conceição Godinho2, Isaura Rodrigues2, Paula Tavares3, José Coutinho3, Ana Maria Agapito1
1Hospital Curry Cabral, Endocrinology, Lisboa, Portugal, 2Hospital Curry Cabral, Laboratory, Lisboa, Portugal, 3Hospital Curry Cabral, Surgery, Lisboa, Portugal

Introduction: To distinguish between thyroid and parathyroid nodules remains difficult in many cases, despite of image or cytological exams. PTH washout in US-FNA of cervical nodules has been performed to differential diagnoses of thyroid and parathyroid nodules and to locate parathyroid nodules in primary hyperparathyroidism proposed to surgery.

Aims: To study the diagnostic value of PTH washout in US-FNA for differential diagnoses and management of thyroid and parathyroid nodules.

Methods: This study was performed between 2012 and 2017, in patients with one or more nodules suspected of parathyroid origin after neck ultrasound. The cohort was characterized for clinical presentation, hormone assay, ultrasonography, Sestamibi scan, 4D CTscan and cytological diagnosis. After US-FNA, the needle used was washed in 1ml of normal saline and intact PTH was determinate by chemiluminescent immunoassay; PTHw defined as positive if superior to serum PTH. PTHw results were compared with histological diagnoses.

Results: We studied 59 patients (13,6% men), mean age 60yr (37-86yr), with nodules suspected to be parathyroid origin, mean size 2.1cm (0.98-5cm). Primary hyperparathyroidism diagnosed in 20 patients (33.9%). Eighty lesions were submitted to US-FNA. Cytological results: non diagnostic (47), thyroid (30) and parathyroid (3); PTHw positive in 12 cases with a mean value 2542.7 pg/ml (59.2–6000 pg/ml). Surgery was performed in 25 patients (42.3%).

Histological results: 20 parathyroids (17 adenoma/2 hyperplasia/1 malignant) and 10 thyroids (4 benign /1 microPTC/4 PTC/ 1 microFTC). Positive correlation between PTHw and histology in 9 patients (45%), for a specificity of 100%, a sensitivity of 45%, false negative 55% and no false positive.

Conclusions: These results confirmed the diagnostic value of an elevated. PTHw for differential diagnosis and management of thyroid and parathyroid nodules. There was a strong positive correlation between high levels of PTHw and parathyroid lesions. This diagnostic technique may allow for targeted surgical approach.

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