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OBJECTIVE: The association between Papillary Thyroid Carcinoma (PTC) and coexistent Hashimoto's Thyroiditis (HT) was controversial. The purpose of this study was to evaluate the presence of HT exerts any influence on the aggressiveness of PTC, and to establish a nomogram for predicting the possibility of aggressiveness in PTC. METHODS: 373 consecutive PTC patients with/without coexistent HT from January 2017 to December 2020 were retrospective reviewed. Patients' clinicopathologic and sonographic characteristics were collected for univariate and multivariate analyses. A nomogram was established based on the risk factors for aggressiveness in PTC. RESULTS: Male (pâ¯=â¯0.001), tumor size >1.0â¯cm (pâ¯=â¯0.046) and lymph node metastasis (pâ¯=â¯0.018) were negatively associated with PTC coexisted with HT, while it was significantly positively associated with the frequence of multifocality (pâ¯=â¯0.010). Univariate and multivariate analyses suggested that age ≥55 years (pâ¯=â¯0.000), male (pâ¯=â¯0.027), HT (pâ¯=â¯0.017), tumor size >1.0â¯cm (pâ¯=â¯0.015), multifocality (pâ¯=â¯0.041), distance to capsular ≤0â¯cm (pâ¯=â¯0.050) and blood flow (Grade I: pâ¯=â¯0.044) were independent risk factors for predicting the aggressiveness in PTC. A nomogram according to these predictors was further developed and validated. The receiver operating characteristic curve (AUCâ¯=â¯0.734 and 0.809 for training and validation cohorts, respectively) and decision curve analyses indicated that the nomogram model was clinically useful. The calibration curve revealed that the nomogram exhibited an excellent consistency. CONCLUSIONS: In this study, the coexistent HT might play a protective role in preventing the proliferation of PTC. Dispensable aggressive treatment may be reduced in PTC by pre-operative identification of sonographic and clinical characteristics and incorporating with the predicted nomogram model.
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Doença de Hashimoto , Nomogramas , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Ultrassonografia , Humanos , Masculino , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnóstico por imagem , Doença de Hashimoto/patologia , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Adulto , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/complicações , Fatores de Risco , Idoso , Adulto Jovem , Metástase Linfática/diagnóstico por imagemRESUMO
Background: Papillary thyroid carcinoma has become increasingly prevalent over the years. Avoiding unnecessary treatments and the risk of complications is essential, as well as understanding the mechanisms of tumor progression and the conditions that indicate a worse prognosis. Assessment of the tumor microenvironment can allow us understand how the immune system organizes itself to contain neoplastic progression. Methods: We compared characteristics related to the lymphocytic subpopulations in the thyroid tumor microenvironment and lymph nodes in two groups, with and without lymph node metastatic involvement. Results: Of the 400 cases followed up at a thyroid cancer reference service, 32 were selected, of which, 13 cases did not present lymph node metastasis (N0 group) and 19 had lymph node involvement (N1 group). Clinical data were collected, and immunohistochemical reactions were performed for markers CD4, CD8, FoxP3, CD25, and CD20 in lymph nodes and peritumoral infiltrate. We found that the N1 group had larger tumor sizes, higher risk staging, higher frequency of extrathyroidal extension, shorter disease-free times, and higher expression of CD4+ T lymphocytes in lymph nodes; however, there was no difference in the expression of other markers or in the pattern of lymphocyte distribution in the lymph node. Conclusion: In cervical lymph nodes, the higher frequency of CD4+ T lymphocytes is related to the presence of metastasis. However, there were no differences in lymphocytic subpopulations in the thyroid tumor microenvironment. The absence of changes in unaffected lymph nodes could not predict any tumor behavior.
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In solid tumors, hypereosinophilia is a rare phenomenon and is mainly associated with mucin-secreting carcinomas. Thyroid tumors associated with neutrophilia and/or eosinophilia have been described exclusively in patients with anaplastic thyroid cancer. Eosinophilia associated with papillary thyroid cancer is extremely rare and there are very few cases currently described. It has been suggested that three cytokines, namely interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte-macrophage colony-stimulating factor (GM-CSF), may act as a peptide potential eosinophilic. To date, only three patients with differentiated thyroid cancer associated with eosinophilia have been reported, two of the papillary type and one of the medullary type. A 48-year-old patient consulted in 2022 due to bilateral cervical lymphadenopathy of 3 years' duration associated with wasting syndrome and hypereosinophilia. PET CT was requested, which showed hypermetabolic focus in the right thyroid lobe and lymph node, lung, bone, and liver metastases; Thyroid ultrasound showing a nodule of high suspicion of malignancy and a conglomerate of lymphadenopathy in the right lobe with positive needle wash for thyroglobulin. Hypereosinophilia was evaluated with initial leukocytosis values of GB 30,310/mm3 (10,608/mm3 of eosinophils) to maximum values of GB 77,090/mm3 (eosinophils 20,814/mm3). It was interpreted as paraneoplastic syndrome and corticosteroid therapy was started at immunosuppressive doses without response. Our observations presented in this article are in line with most studies reflecting that paraneoplastic hypereosinophilia is characterized by more advanced disease and poor prognosis.
En los tumores sólidos la hipereosinofilia es un fenómeno raro y se asocia principalmente con carcinomas secretores de mucina. Los tumores tiroideos asociados a neutrofilia y/o eosinofilia se han descrito exclusivamente en pacientes con cáncer anaplásico de tiroides. La eosinofilia asociada con cáncer papilar de tiroides es extremadamente rara y se encuentran muy pocos casos descriptos actualmente. Se ha sugerido que tres citocinas, a saber, la interleucina-3 (IL-3), la interleucina-5 (IL-5) y el factor estimulante de colonias de granulocitos y macrófagos (GM-CSF), pueden actuar como un péptido eosinofílico potencial. Hasta el momento solo se han reportado tres pacientes con cáncer diferenciado de tiroides asociados a eosinofilia, dos de tipo papilar y uno de tipo medular. Paciente de 48 años consultó en el año 2022 por adenopatías cervicales bilaterales de 3 años de evolución asociado a síndrome consuntivo e hipereosinofilia. Se solicitó PET CT que evidenció foco hipermetabólico en lóbulo tiroideo derecho y metástasis ganglionares, pulmonares, óseas y hepáticas; ecografía tiroidea que evidencia en lóbulo derecho nódulo de alta sospecha de malignidad y conglomerado de adenopatías con lavado de aguja positivo para tiroglobulina. Evaluada la hipereosinofilia con valores iniciales de leucocitosis de GB 30310/mm3 (10608/mm3 de eosinófilos) hasta valores máximos de GB 77090/mm3 (eosinófilos 20814/mm3) se interpretó como síndrome paraneoplásico y se inició corticoterapia en dosis inmunosupresoras sin respuesta. Nuestras observaciones presentadas en este artículo están en línea con la mayoría de los estudios que reflejan que la hipereosinofilia paraneoplásica se caracteriza por una enfermedad más avanzada y un mal pronóstico.
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Síndromes Paraneoplásicas , Neoplasias da Glândula Tireoide , Humanos , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/patologia , Síndromes Paraneoplásicas/etiologia , Síndrome Hipereosinofílica/complicações , Masculino , Feminino , Carcinoma Papilar/complicações , Eosinofilia/complicaçõesRESUMO
Objective: After initial treatment, up to 30% of patients with papillary thyroid cancer (PTC) have incomplete response, mainly cervical lymph node (LN) disease. Previous studies have suggested that active surveillance (AS) is a possible option for these patients. Our aim was to report the results of AS in patients with PTC and cervical LN disease. Materials and methods: In this retrospective observational study, we included adult patients treated and followed for PTC, who presented with cervical LN disease and were managed with AS. Growth was defined as an increase ≥ 3mm in either diameter. Results: We included 32 patients: 27 (84.4%) women, age of 39 ± 14 years, all initially treated with total thyroidectomy, and 22 (69%) with therapeutic neck dissection. Cervical LN disease was diagnosed 1 year (0.3-12.6) after initial management, with a diameter of 9.0 mm (6.0-19.0). After a median AS of 4.3 years (0.6-14.1), 4 (12.5%) patients had LNgrowth: 2 (50%) of whom were surgically removed, 1 (25%) was effectively treated with radiotherapy, and 1 (25%) had a scheduled surgery. Tg increase was the only predictive factor of LN growth evaluated as both the delta Tg (p < 0.0366) and percentage of Tg change (p < 0.0140). None of the included patients died, had local complications due to LN growth or salvage therapy, or developed distant metastases during follow-up. Conclusion: In selected patients with PTC and suspicious cervical LNs diagnosed after initial treatment, AS is a feasible and safe strategy as it allows effective identification and treatment of the minority of patients who progress.
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Linfonodos , Metástase Linfática , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Tireoidectomia , Conduta Expectante , Humanos , Feminino , Masculino , Adulto , Estudos Retrospectivos , Tireoidectomia/métodos , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/patologia , Linfonodos/patologia , Estudos de Viabilidade , Pescoço/cirurgia , Carcinoma Papilar/cirurgia , Carcinoma Papilar/patologia , Esvaziamento Cervical/métodos , Adulto JovemRESUMO
Introducción: El cáncer de tiroides es una enfermedad frecuente en el mundo, con mayor prevalencia del tipo diferenciado. El diagnóstico temprano y manejo pertinente, individualizado y adaptable puede mejorar su pronóstico. Objetivo: Generar recomendaciones basadas en evidencia sobre el tratamiento y seguimiento de personas adultas con cáncer diferenciado de tiroides (CDT). Metodología: Guía de práctica clínica (GPC) a partir de revisión sistemática de literatura (RSL) y consenso de expertos clínicos. El grupo desarrollador definió el alcance y cuatro preguntas que se resolvieron a través de revisión de evidencia de GPC existentes, RSL, estudios primarios publicadas en español o inglés en diferentes fuentes de información desde 2013. Las preguntas de investigación fueron: 1. ¿Cuáles son las indicaciones de la vigilancia activa?, ¿cómo realizarla?, ¿cuándo y con que periodicidad realizarla? 2. ¿Cuál es el tratamiento y su indicación en pacientes con nódulos tiroideos sospechosos de cáncer? 3. ¿Cómo y cuándo realizar seguimiento de pacientes con CDT de acuerdo con el riesgo dinámico? 4. ¿Cuál es el manejo actual de los pacientes iodo refractarios? Se propusieron recomendaciones basadas en la evidencia, y analizadas y discutidas por el colectivo experto en sesiones asincrónicas. Se evalúo la calidad de la evidencia y las recomendaciones fueron gradadas en fuerte o condicional y a favor o en contra a partir del análisis de la calidad de la evidencia, contexto de implementación (disponibilidad e implementación) y la experticia clínica. En el presente documento se desarrollada la primera pregunta, referente a vigilancia activa. Resultados: 86 recomendaciones fueron propuestas y acordadas por el grupo desarrollador, categorizadas en tratamiento y seguimiento para resolver las preguntas planteadas. 10 de las recomendaciones corresponden a vigilancia activa y se incluyen en el presente documento. Recomendaciones claves incluyen, brindar información completa y oportuna a pacientes, conformación de equipos multidisciplinarios, análisis individualizado del paciente para la decisión de tratamiento, estadificación rutinaria de riesgo dinámico para evaluar la respuesta al tratamiento y ajustarlo, minimización de procedimientos fútiles o que aportan poco a la supervivencia y calidad de vida de los pacientes. Conclusión: Se presentan recomendaciones que esperan incidir en la estandarización de la práctica clínica cotidiana de pacientes con CDT y mejores resultados en salud.
Introduction: Thyroid cancer is a common disease in the world, with a higher prevalence of the differentiated type. Early diagnosis individualized and adaptive management can improve prognosis. Objective: Generate evidence-based recommendations on the treatment and follow-up of adults with differentiated thyroid carcinoma (DTC). Methodology: Clinical practice guideline (CPG) based on systematic literature review (RSL) and consensus of clinical experts. The development group defined the range and four questions that were resolved through a review of evidence from existing CPGs, RSLs, primary studies published in Spanish or English in various sources of information since 2013. The research questions were: 1. What are the indications for active surveillance? How to carry it out? When and how often to carry it out? 2. What is the treatment and its indication in patients with thyroid nodules suspicious for cancer? 3. How and when to follow up patients with CDT according to dynamic risk? 4. What is the current management of iodine refractory patients? Evidence-based recommendations analyzed and discussed by the expert group in asynchronous sessions were proposed. The quality of the evidence was evaluated, and the recommendations were graded as strong or conditional and in favor or against based on the analysis of the quality of the evidence, implementation context (availability and implementation) and clinical expertise. In this document, is developed the first question, referring to active surveillance. Results: 86 recommendations were proposed and agreed upon by the development group, categorized into treatment and follow-up to solve the questions raised. 10 of the recommendations correspond to active surveillance and are included in this document. Key recommendations include providing complete and timely information to patients, develop of multidisciplinary teams, individualized patient analysis for treatment decisions, routine dynamic risk staging to evaluate response to treatment and adjust it, minimization of futile procedures or that contribute little to the survival and quality of life of patients. Conclusion: Recommendations are presented that longs to influence the standardization of the daily clinical practice of patients with DTC and better health outcomes.
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Objective: Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification). Subjects and methods: We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy. Results: After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-riskto high-risk patients with postoperative s-Tg > 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification. Conclusion: The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based ondynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.
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Recidiva Local de Neoplasia , Tireoglobulina , Neoplasias da Glândula Tireoide , Humanos , Radioisótopos do Iodo , Recidiva Local de Neoplasia/diagnóstico , Estudos Retrospectivos , Medição de Risco , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
BACKGROUND: Despite the increasing recognition of PD-L1 as predictor of immunotherapeutic response in various malignancies, its role and prognostic significance in thyroid cancer remain underexplored and subject to debate. This study begins to address this gap by comprehensively analyzing PD-L1 expression in papillary thyroid carcinoma (PTC) and investigating its correlation with key clinicopathological variables. METHODS: We conducted immunohistochemistry (IHC) to assess PD-L1 expression in whole-tissue sections from 121 primary papillary thyroid carcinoma (PTC) cases. We then analyzed the correlations between PD-L1 expression and various clinicopathological variables. RESULTS: PD-L1 expression was detected in 33.1% of papillary thyroid carcinomas (PTCs), predominantly exhibiting weak to moderate intensity. Notably, this study found no significant correlation between PD-L1 expression and various clinicopathological variables. The lack of association with traditional factors such as age, sex, histological subtype, and tumor size suggests the complex and multifaceted nature of PD-L1 regulation in PTC. Multivariate logistic regression analysis identified chronic lymphocytic thyroiditis with oncocytic metaplasia as the sole independent predictor of PD-L1 expression (P = 0.014), underlining the potential influence of the tumor microenvironment on immune checkpoint expression in PTC. CONCLUSIONS: Our study underscores the intricate interplay between chronic lymphocytic thyroiditis with oncocytic metaplasia and PD-L1 expression in papillary thyroid carcinoma. The observed link suggests a potential avenue for therapeutic intervention using anti-PD-1/PD-L1 therapies in surgery-refractory PTC. Understanding the dynamics of immune checkpoint regulation in the context of the tumor microenvironment is crucial for devising effective treatment strategies. Future research endeavors should delve deeper into the molecular mechanisms underlying this interaction and explore its implications for patient outcomes. As the field of immunotherapy continues to evolve, our findings contribute valuable insights into the complex immunological landscape of thyroid cancer.
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Doença de Hashimoto , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/patologia , Doença de Hashimoto/complicações , Antígeno B7-H1 , Neoplasias da Glândula Tireoide/patologia , Metaplasia , Microambiente TumoralRESUMO
Objective: As the most prevalent type of thyroid malignancy, papillary thyroid carcinoma (PTC) accounts for over 80% of all thyroid cancers. Circular RNAs (circRNAs) have been found to regulate multiple cancers, including PTC. Materials and methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to analyse RNA and protein levels. Fluorescence in situ hybridization (FISH) was used to detect the distribution of the target genes. Functional experiments and animal experiments were implemented to analyse the biological functions of target genes in vitro and in vivo. Luciferase reporter, RNA pulldown, RNA binding protein immunoprecipitation (RIP) and mRNA stability assays were used to probe the underlying mechanisms. Results: CircSEMA6Awas found to be upregulated in PTC tissues and cells, and its circular structure was verified. CircSEMA6A promotes PTC cell migration and invasion. Moreover, circSEMA6A functions as a competing endogenous RNA (ceRNA) to upregulate proline rich and Gla domain 4 (PRRG4) expression by sponging microRNA-520h (miR-520h). CircSEMA6A recruits ELAV1 to stabilize PRRG4 mRNA and drives PTC progression via PRRG4. Conclusion: CircSEMA6A upregulates PRRG4 by targeting miR-520h and recruiting ELAVL1 to affect the invasion and migration of PTC cells, offering insight into the molecular mechanisms of PTC.
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MicroRNAs , Neoplasias da Glândula Tireoide , Animais , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Hibridização in Situ Fluorescente , Proliferação de Células/genética , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: ZEB1, a core transcription factor involved in epithelial-mesenchymal transition (EMT), is associated with aggressive cancer cell behavior, treatment resistance, and poor prognosis across various tumor types. Similarly, the expression and activity of CD73, an ectonucleotidase implicated in adenosine generation, is an important marker of tumor malignancy. Growing evidence suggests that EMT and the adenosinergic pathway are intricately linked and play a pivotal role in cancer development. Therefore, this study focuses on exploring the correlations between CD73 and ZEB1, considering their impact on tumor progression. METHODS: We employed CRISPR/Cas9 technology to silence CD73 expression in cell lines derived from papillary thyroid carcinoma. These same cells underwent lentiviral transduction of a reporter of ZEB1 non-coding RNA regulation. We conducted studies on cell migration using scratch assays and analyses of cellular speed and polarity. Additionally, we examined ZEB1 reporter expression through flow cytometry and immunocytochemistry, complemented by Western blot analysis for protein quantification. For further insights, we applied gene signatures representing different EMT states in an RNA-seq expression analysis of papillary thyroid carcinoma samples from The Cancer Genome Atlas. RESULTS: Silencing CD73 expression led to a reduction in ZEB1 non-coding RNA regulation reporter expression in a papillary thyroid carcinoma-derived cell line. Additionally, it also mitigated ZEB1 protein expression. Moreover, the expression of CD73 and ZEB1 was correlated with alterations in cell morphology characteristics crucial for cell migration, promoting an increase in cell polarity index and cell migration speed. RNA-seq analysis revealed higher expression of NT5E (CD73) in samples with BRAF mutations, accompanied by a prevalence of partial-EMT/hybrid state signature expression. CONCLUSIONS: Collectively, our findings suggest an association between CD73 expression and/or activity and the post-transcriptional regulation of ZEB1 by non-coding RNA, indicating a reduction in its absence. Further investigations are warranted to elucidate the relationship between CD73 and ZEB1, with the potential for targeting them as therapeutic alternatives for cancer treatment in the near future.