Variante células altas de cáncer papilar de tiroides: reporte de casos / Tall cell variant of papillary thyroid cancer: case report

El cáncer papilar constituye aproximadamente el 80% de todos los casos de cáncer de tiroides y el 85% de los tumores diferenciados. La variante de células altas representa el 1,3 al 12% del cáncer papilar siendo la variante agresiva más común de estos tumores. Posee un comportamiento agresivo, con mayor incidencia de invasión extratiroidea, linfovascular y metástasis a distancia, responsables de tasas de recurrencia más altas y peor pronóstico. Los casos aquí reportados reflejan las características que hacen sospechar mayor agresividad tumoral, desde el diagnóstico. Describimos dos pacientes de sexo femenino, entre 40 y 50 años, con historia de corta evolución, cuya presentación fue con síntomas de compresión locorregional y adenopatías metastásicas en cuello. Con hallazgos ecográficos e intraoperatorios de relevancia en cuanto la agresividad tumoral que hicieron sospechar la presencia de una variante agresiva del cáncer papilar. La histopatología de la variante de células altas posee una base molecular diferente respecto al papilar clásico que le confiere mayor morbi-mortalidad, constituyendo un factor de pronóstico independiente para la recurrencia. El tratamiento quirúrgico es la tiroidectomía total con vaciamiento profiláctico de los ganglios linfáticos centrales y eventualmente vaciamiento lateral de cuello según valoración preoperatoria, con posterior ablación postoperatoria de restos tiroideos mediante yodo radiactivo.

Papillary cancer constitutes approximately 80% of all thyroid cancer cases and 85% of differentiated tumors. The tall cell variant represents 1.3 to 12% of papillary cancers, being the most common aggressive variant of these tumors. It has an aggressive behavior, showing a higher incidence of extrathyroid and lymphovascular invasion and distant metastasis, responsible for higher recurrence rates and a worse prognosis. The cases reported here reflect characteristics that make us suspect tumor aggressiveness. These are female patients, between 40 and 70 years old, with a history of short evolution. They present locoregional symptoms or metastatic adenopathies, with ultrasound and intraoperative findings of relevance in terms of tumor aggressiveness that led to the suspicion of the presence of an aggressive variant of papillary cancer. The histopathology of the tall cell variant has a different molecular basis that confers its own morbidity and mortality, being an independent prognostic factor for recurrence. Total thyroidectomy is recommended with prophylactic dissection of the central lymph nodes and eventually lateral neck dissection according to preoperative evaluation followed by postoperative ablation with radioactive iodine.

Metástasis cervical de cáncer papilar oculto de tiroides: reporte de casos / Cervical metastasis from occult papillary thyroid cancer: case report

El microcarcinoma papilar de tiroides es definido como un tumor de un cm o menos de diámetro mayor. La mayoría permanecen ocultos clínicamente, siendo un hallazgo en autopsias hasta en 36%. La presentación oculta ocurre hasta en un 10 a 26% de todas las neoplasias malignas de tiroides y se define como la presencia de ganglios metastásicos de carcinoma papilar de tiroides en ausencia de lesión primitiva tiroidea evidente durante la exploración clínica y ecográfica. El objetivo de este trabajo es el reporte de dos casos donde el diagnóstico de cáncer de tiroides se realizó a través de su presentación metastásica cervical, siendo el estudio anatomopatológico de la pieza de resección quirúrgica el que devela la presencia de un microcarcinoma papilar. Si bien el tratamiento del de estas lesiones es controversial, existen elementos que sellan la necesidad de resolución quirúrgica. En el debut metastásico ganglionar cervical, está indicada la tiroidectomía total con el vaciamiento ganglionar cervical radical modificado ipsilateral y central. El raidioyodo postquirúrgico será empleado en forma complementaria ante la persistencia, recurrencia o elementos de alto riesgo.

Papillary thyroid microcarcinoma is defined as a tumor one cm or less in diameter. Most remain clinically hidden, being an autopsy finding in up to 36%. Occult presentation occurs in up to 10% to 26% of all thyroid malignancies and is defined as the presence of metastatic nodes from papillary thyroid carcinoma in the absence of a primitive thyroid lesion evident on clinical and ultrasound examination. The objective of this work is the report of two cases where the diagnosis of thyroid cancer was made through its cervical metastatic presentation, being the pathological study of the surgical resection specimen that reveals the presence of a papillary microcarcinoma. Although the treatment of these lesions is controversial, there are elements that seal the need for surgical resolution. In cervical lymph node metastatic debut, total thyroidectomy with modified ipsilateral and central radical cervical lymph node dissection is indicated. Post-surgical radiation iodine will be used in a complementary way in the event of persistence, recurrence or high-risk elements.

Respuesta al lenvatinib en una paciente pediátrica con insuficiencia respiratoria secundaria a carcinoma papilar de tiroides / Response to lenvatinib in a pediatric patient with respiratory failure associated with papillary thyroid carcinoma

El cáncer papilar de tiroides es el tumor tiroideo más común en la infancia. En estadios avanzados, puede presentarse con cuadro de insuficiencia respiratoria. El tratamiento de elección es la tiroidectomía total y iodo radiactivo. En tumores irresecables, se debería considerar terapia con inhibidores multicinasa.Niña de 10 años de edad derivada por insuficiencia respiratoria progresiva. Se realizó el diagnóstico de cáncer papilar de tiroides con metástasis pulmonares. Por presentar un tumor irresecable no pasible de cirugía, se indicó el uso compasivo de lenvatinib, que mostró una rápida y favorable respuesta clínica con resolución de la insuficiencia respiratoria al noveno día del tratamiento.El diagnóstico temprano de cáncer papilar de tiroides previene la grave morbilidad respiratoria ocasionada por diagnósticos tardíos. Podría considerarse el uso de lenvatinib como alternativa previa a las terapias de primera línea (cirugía e iodo radiactivo) en casos de enfermedad con gran compromiso local y a distancia.

Papillary thyroid cancer is the most common thyroid tumor in childhood. In advanced stages, it can present with respiratory failure. The treatment of choice is total thyroidectomy and radioactive iodine. In cases of unresectable tumors, therapy with multikinase inhibitors should be considered. A 10-year-old girl was referred for progressive respiratory failure. A diagnosis of papillary thyroid cancer with pulmonary metastases was made. Due to the presence of an unresectable tumor not subject to surgery, the compassionate use of lenvatinib was indicated, showing a rapid and favorable clinical response with resolution of respiratory failure on the ninth day.Early diagnosis of papillary thyroid cancer prevents severe respiratory morbidity caused by late diagnoses. The use of lenvatinib should be considered as a previous step towards first-line therapies (surgery and radioactive iodine) in cases with great local and distant involvement.

Comportamiento clínico-epidemiológico del cáncer de tiroides / Clinical epidemiological behavior of the thyroid cancer

RESUMEN Introducción: el cáncer de tiroides representa un 1% del total de todos los tipos de cáncer. Su incidencia parece aumentar un 4% cada año, y en la actualidad es el octavo cáncer más frecuente en mujeres. Objetivo: determinar el comportamiento clínico epidemiológico de los pacientes operados de cáncer de tiroides. Materiales y métodos: se realizó un estudio retrospectivo, observacional y descriptivo con todos los pacientes ingresados con cáncer tiroides en el servicio de Cirugía General del Hospital Universitario Comandante "Faustino Pérez Hernández", en el período desde enero del 1993 a diciembre de 2018. Se empleó un modelo recolector de datos con las variables de interés para el estudio y los datos se presentaron en tablas de frecuencia, números y porciento. Resultados: el cáncer de tiroides fue más frecuente en el grupo etario de 31 a 50 años, predomino el sexo femenino, la variedad histológica papilar fue la más frecuente, el lóbulo derecho fue el más afectado. Conclusiones: el cáncer de tiroides es más frecuente en pacientes relativamente jóvenes y del sexo femenino, a forma clínica de nódulo solitario con función tiroidea normal y el carcinoma papilar la variedad más frecuente (AU).

ABSTRACT Introduction: Thyroid cancer represents 1% of the total of all kinds of cancer. Its incidence seems to increase 4% every year, and at the present time it is the eighth more frequent cancer in women. Objective: to determine the clinical epidemiological behaviour of the patients who underwent thyroid cancer surgery. Materials and methods: a retrospective, observational and descriptive study was carried out in all the patients who were admitted in the service of General Surgery of the University Hospital "Comandante Faustino Pérez Hernández" with thyroid cancer, in the period from January 1993 to December 2018. A data collector model was used with the variables of interest for the study and the data were presented by charts of frequency, numbers and percent. Results: thyroid cancer was more frequent in the age group of 31 to 50 years; the female sex prevailed; the most frequent variety was the histological papillary one, and the right lobe was the most affected. Conclusions: thyroid cancer is more frequent in relatively young, female patients; the clinical form of solitary nodule with normal thyroid function and papillary carcinoma the most frequent variety (AU).

Resultado de los medios diagnósticos en pacientes operados de cáncer de tiroides. Hospital Universitario Comandante "Faustino Pérez Hernández". Matanzas / Outcomes of the diagnostic means in patients undergoing thyroid cancer surgery. University Hospital "Comandante Faustino Pérez Hernández". Matanzas

RESUMEN Introducción: el cáncer de tiroides representa un 1% del total de todos los tipos de cáncer. Su incidencia parece aumentar un 4% cada año, y en la actualidad es el octavo cáncer más frecuente en mujeres. Se utilizan medios diagnósticos para definir que paciente operar y la estrategia terapéutica a seguir. Objetivo: evaluar el resultado de los medios diagnósticos en los pacientes operados de cáncer de tiroides. Materiales y métodos: se realizó un estudio descriptivo, retrospectivo y observacional que incluye todos los pacientes operados de cáncer tiroides en el servicio de Cirugía General del Hospital Universitario "Comandante Faustino Pérez Hernández", en el período desde enero de 1993 a diciembre del 2018. Se confeccionó una planilla pararecopilar la información para el estudio de la base de datos y los resultados se presentaron en tablas de frecuencia, números y porciento. Resultados: el cáncer de tiroides fue más frecuente en el grupo etario de 31 a 50 años, predomino el sexo femenino, la variedad histológica papilar fue la más frecuente, el ultrasonido y la citología con aguja fina aportan resultados favorables para definir la estirpe biológica de los tumores del tiroides, no comportándose de igual forma la biopsia por congelación. Conclusiones: el cáncer de tiroides es más frecuente en pacientes relativamente jóvenes, del sexo femenino y de variedad papilar. El ultrasonido y la citología con aguja fina aportan criterios beneficiosos para definir conducta terapéutica (AU).

SUMMARY Introduction: thyroid cancer represents 1% of the total of all kinds of cancer. Its incidence seems to increase 4% every year, and at the present time it is the eighth more frequent cancer in women. Diagnostic means are used to determine what patient undergoes a surgery and the therapeutic strategy to follow. Objective: to evaluate the results of the diagnostic means used in patients who undergo a thyroid cancer surgery. Materials and methods: a retrospective, descriptive, observational study was carried out including all patients who underwent a surgery of thyroid cancer in the service of General Surgery of the University Hospital ¨Comandante Faustino Perez Hernandez¨ in the period from January 1993 to December 2018. A form was elaborated to collect the information for the study of the database; the results were presented in charts of frequency, numbers and percentages. Results: the thyroid cancer was more frequent in the age group of 31 to 50 years; the female sex prevailed; the most frequent variety was the histological papillary one; ultrasound and fine needle cytology yield favourable results to define the biological stock of the thyroid cancers unlike the behaviour of the biopsy by freezing. Conclusions: thyroid cancer of the papillary variety is more frequent in relatively young, female patients. Ultrasound and fine needle cytology yield beneficial criteria to define the therapeutic behaviour (AU).

Importance of ELABELA in the differential diagnosis of benign and malignant lesions of the thyroid gland

ABSTRACT Objective: This study investigated whether ELABELA plays a role in the differential diagnosis of benign and malignant lesions of the thyroid gland. Subjects and methods: Of the 87 patients included in the study, 12 had undergone surgery for benign thyroid diseases, 30 had papillary thyroid cancer without invasion and/or lymph node metastasis in the surrounding tissues in the pathology report, and 45 had papillary thyroid cancer with invasion and/or lymph node metastasis in the surrounding tissues. Results: In the macrocarcinoma group, the proportion of patients with severe ELABELA staining (61.1%) was higher than that in the adenoma (50%) and microcarcinoma (23.8%) groups, while the proportion of those with mild to moderate staining was lower (p < 0.001). In the microcarcinoma group, the proportion of patients with severe staining was lower than that in the adenoma group, while the proportion of those with mild to moderate staining was higher (p < 0.001). In papillary thyroid carcinomas, the rates of moderate and severe staining in the classical variant, mild staining in the follicular variant, severe staining in the classical + follicular variant, and severe staining in the oncocytic variant were higher. Conclusion: To the best of our knowledge, this study is the first to be conducted on this subject. In this study, ELABELA was not found to be significant in the differential diagnosis of benign and malignant lesions of the thyroid gland. In papillary thyroid carcinomas, severe ELABELA staining patterns were more common in macrocarcinoma patients than in microcarcinoma patients.

La densidad óptica nuclear como indicador diagnóstico en el carcinoma papilar de tiroides / Nuclear optical density as a diagnostic indicator in papillary thyroid carcinoma

Introducción: El carcinoma papilar de tiroides es la causa más frecuente de cáncer de naturaleza endocrina. Constituye la variante histológica de mejor pronóstico, sin embargo, en ocasiones es motivo de importantes dudas diagnósticas con otras variantes de evolución tórpida, lo que dificulta que un mayor número de pacientes se beneficie con un tratamiento individualizado y conservador. Por esta razón, se desarrollan estudios en los que cada vez más se añaden procedimientos morfométricos y densitométricos, los que permiten disminuir la subjetividad en el diagnóstico histopatológico. Objetivo: Determinar la densidad óptica nuclear en el carcinoma papilar de tiroides. Método: Se realizó un estudio morfométrico de serie de casos con 12 pacientes con carcinoma papilar de tiroides, atendidos en el Hospital Provincial Universitario Vladimir Ilich Lenin. Se seleccionaron 36 campos y se midieron 965 núcleos celulares, lo que constituyó la muestra del estudio. Se determinó la densidad óptica nuclear como indicador morfométrico del carcinoma papilar de tiroides. Resultados: El valor de la densidad óptica nuclear fue 1,14, considerado bajo. Conclusiones: Se determinó la densidad óptica nuclear del carcinoma papilar de tiroides en los casos estudiados, lo que puede contribuir a su diagnóstico histopatológico(AU)

Background: Papillary thyroid carcinoma is the most frequent cause of endocrine cancer. It is an histological variant with the best prognosis, however, sometimes it is a reason for significant diagnostic doubts with other variants of torpid evolution, which makes it difficult for a greater number of patients to benefit from an individualized and conservative treatment. For this reason, studies are developed in which more and more morphometric and densitometric procedures are added, which allow reducing the subjectivity in the histopathological diagnosis and could represent a tool of great value. Objective: To determine the nuclear optical density in papillary thyroid carcinoma. Method: A morphometric study of a series of cases was carried out with 12 patients with this histopathological diagnosis, attended at the Vladimir Ilich Lenin University Provincial Hospital. We chose 36 fields and 965 cell nuclei were measured, which constituted the study sample. Nuclear optical density was determined as a morphometric indicator of papillary thyroid carcinoma. Results: The value of nuclear optical density was 1, 14. It is considered low. Conclusion: Nuclear optical density of papillary thyroid carcinoma was determined in the studied cases that may contribute to histopathological diagnosis(AU)

The Difference in Thyroid Stimulating Hormone Levels between Differentiated Carcinoma and Benign Enlargement

Abstract Introduction Papillary and follicular thyroid carcinoma are common head and neck cancers. This cancer expresses a thyroid stimulating hormone (TSH) receptor that plays a role as a cancer stimulant substance. This hormone has a diagnostic value in the management of thyroid carcinoma. Objective The present study aimed to determine the difference in TSH levels between differentiated thyroid carcinoma and benign thyroid enlargement. Methods The present research design was a case-control study. The subjects were patients with thyroid enlargement who underwent thyroidectomies at the Dr. Sardjito General Hospital, Yogyakarta, Indonesia. Thyroid stimulating hormone levels were mea- sured before the thyroidectomies. The inclusion criteria for the case group were: 1) differentiated thyroid carcinoma, and 2) complete data; while the inclusion criteria for the control group were: 1) benign thyroid enlargement, and 2) complete data. The exclusion criteria for both groups were: 1) patients suffering from thyroid hormone disorders requiring therapy before thyroidectomy surgery, 2) patients receiving thyroid suppression therapy before the thyroidectomy was performed, and 3) patients suffering from severe chronic diseases such as renal insufficiency, and severe liver disease. Results There were 40 post-thyroidectomy case group patients and 40 post-thyroidect- omy control group patients. There were statistically significant differences in TSH levels between the groups with differentiated thyroid carcinoma and benign thyroid enlargement (p = 0.001; odds ratio [OR] = 8.42; 95% confidence interval [CI]: 3.19-36.50). Conclusion Based on these results, it can be concluded that there were significant differences in TSH levels between the groups with differentiated thyroid carcinoma and benign thyroid enlargement.

Neoplasia folicular tiroidea no invasiva con características nucleares de tipo papilar (Noninvasive follicular thyroid neoplasm with papillary-like nuclear features o NIFTP): en qué estamos hoy, a propósito de un caso / Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): we are we today, about a case

Es bien conocido que ha existido en las últimas décadas un incremento en los casos de cáncer diferenciado de tiroides, especialmente los microcarcinomas. Diversos factores han contribuido a pesquisar pequeños cánceres como el aumento de la disponibilidad de exámenes imagenológicos. Estos pequeños cánceres tiroideos pueden tener un comportamiento no agresivo y no producir letalidad; esto es lo que se conoce como sobrediagnóstico. Esto último tiene implicancias tanto médicas como económicas por terapias agresivas. Así, desde el año 2015, un grupo de expertos cambia la nomenclatura en anatomía patológica del carcinoma papilar tiroideo variante folicular encapsulado (NIEFVPTC de sus siglas en inglés) por Neoplasia folicular tiroidea no invasiva con características nucleares de tipo papilar (NIFTP de sus siglas en inglés). Este cambio se basó en un estudio de Nikiforov donde los NIEFVPTC no tenían efectos adversos ni mortalidad en su seguimiento. Así, la intención inicial del cambio de nomenclatura es eliminar la palabra cáncer y evitar los sobretratamientos innecesarios. Presentamos un caso clínico de una paciente que se sometió a cirugía por un nódulo tiroideo clasificado Bethesda III donde la biopsia definitiva posterior a cirugía evidenció que se trataba de un NIFTP. A raíz de este caso analizamos la literatura hasta la fecha de esta nueva entidad y hacemos un repaso histórico de los carcinomas papilares tiroideos variante folicular. Además, desarrollamos nuevas interrogantes que se plantean desde este nuevo diagnóstico anatomopatológico, de cómo sospecharlo previo a una cirugía, cuál es la cirugía de elección, y cómo debiera ser el seguimiento una vez diagnosticado.

It is well known that there has been an increase in cases of differentiated thyroid cancer in recent decades, especially microcarcinomas. Several factors have contributed to diagnose small cancers such as the increased availability of imaging tests. These small thyroid cancers can have a non-aggressive behavior and not cause lethality, this is what is known as overdiagnosis. The latter has medical as well as economic implications for aggressive therapies. Thus, since 2015, a group of experts has changed the nomenclature in pathological anatomy of encapsulated variant papillary thyroid carcinoma (NIEFVPTC) for non-invasive thyroid follicular neoplasia with papillary nuclear characteristics (NIFTP). This change was based on a Nikiforov study where the NIEFVPTC had no adverse effects or mortality in their follow-up; thus, the initial intention of the nomenclature change is to eliminate the word cancer and avoid unnecessary over-treatments. We present a clinical case of a patient who underwent surgery for a thyroid nodule classified Bethesda III where the definitive biopsy after surgery showed that it was a NIFTP. Following this case, we analyze the literature to date of this new entity and make a historical review of the follicular variant papillary thyroid carcinomas. In addition, we develop new questions that arise from this new pathological diagnosis, how to suspect it prior to surgery, what is the surgery of choice, and what should the follow-up once diagnosed.

Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules

ABSTRACT Objectives: This observational study analyzed telomerase reverse transcriptase (pTERT) mutations in 45 fine-needle aspiration (FNA) specimens obtained from thyroid nodules followed by postoperatively confirmation of papillary thyroid cancer (PTC) diagnosis, examining their relationship with clinicopathologic aspects and the BRAFV600E mutation. Subjects and methods: Clinical information was collected from patients who presented to Ribeirao Preto University Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between January 2010 to October 2012. Tests included a DNA-based somatic detection of BRAFV600E and pTERT mutations. Results: We found coexistence of pTERTC228T and BRAFV600E mutations in 8.9% (4/45) of thyroid nodules. All nodules positive for pTERT mutations were BRAFV600E positives. There was a significant association between pTERTC228T/BRAFV600E with older age and advanced stage compared with the group negative for either mutation. Conclusions: This series provides evidence that FNA is a reliable method for preoperative diagnosis of high-risk thyroid nodules. pTERTC228T/BRAFV600E mutations could be a marker of poor prognosis. Its use as a personalized molecular medicine tool to individualize treatment decisions and follow-up design needs to be further studied.

Aggressive papillary thyroid carcinoma in a child with type 2 congenital generalized lipodystrophy

SUMMARY Thyroid carcinoma (TC) is rare in children, particularly in those aged < 10 years. Several studies have demonstrated a correlation between neoplasms and hyperinsulinemia and insulin resistance, which are often associated with a higher risk for and/or aggressiveness of the neoplasm. Congenital generalized lipodystrophy (CGL) with autosomal recessive inheritance is a rare disease and is characterized by the lack of adipose tissue, severe insulin resistance, and early metabolic disturbances. Here, we reported a rare case of a type 2 CGL in a girl who presented with a papillary TC (PTC) at the age of 7 years. She had no family history of TC or previous exposure to ionizing radiation. She had a generalized lack of subcutaneous fat, including the palmar and plantar regions, muscle hypertrophy, intense acanthosis nigricans, hepatomegaly, hypertriglyceridemia, severe insulin resistance, and hypoleptinemia. A genetic analysis revealed a mutation in the BSCL2 gene (p.Thr109Asnfs* 5). Ultrasound revealed a hypoechoic solid nodule measuring 1.8 × 1.0 × 1.0 cm, and fine needle aspiration biopsy suggested malignancy. Total thyroidectomy was performed, and a histopathological examination confirmed PTC with vascular invasion and parathyroid lymph node metastasis (pT3N1Mx stage). This is the first report to describe a case of differentiated TC in a child with CGL. Severe insulin resistance that is generally observed in patients with CGL early in life, especially in those with type 2 CGL, may be associated with this uncommon presentation of aggressive PTC during childhood.

Identification of key genes and miRNAs markers of papillary thyroid cancer

OBJECTIVE: In this study, crucial genes and microRNAs (miRNAs) associated with the progression, staging, and prognosis of papillary thyroid cancer (PTC) were identified. METHODS: Four PTC datasets, including our own mRNA-sequencing (mRNA-seq) dataset and three public datasets downloaded from Gene Expression Omnibus and The Cancer Genome Atlas, were used to analyze differentially expressed genes (DEGs) and miRNAs (DEMs) between PTC tumor tissues and paired normal tissues (control). Gene ontology (GO) terms and pathways associated with these DEGs were identified, and protein-protein interactions (PPIs) were analyzed. Additionally, an miRNA-mRNA regulatory network was constructed and the functions of DEMs were explored. Finally, miRNAs/mRNAs associated with tumor staging and prognosis were identified. The expression levels of several key genes and miRNAs were validated by qRT-PCR. RESULTS: Numerous DEGs and DEMs were identified between tumor and control groups in four datasets. The DEGs were significantly enriched in cell adhesion and cancer-related GO terms and pathways. In the constructed PPI network, ITGA2, FN1, ICAM1, TIMP1 and CDH2 were hub proteins. In the miRNA-mRNA negative regulatory networks, miR-204-5p regulated the largest number of target genes, such as TNFRSF12A. miR-146b, miR-204, miR-7-2, and FN1 were associated with tumor stage in PTC, and TNFRSF12A and CLDN1 were related to prognosis. CONCLUSIONS: Our results suggested the important roles of ITGA2, FN1, ICAM1, TIMP1 and CDH2 in the progression of PTC. miR-204-5p, miR-7-2, and miR-146b are potential biomarkers for PTC staging and FN1, CLDN1, and TNFRSF12A may serve as markers of prognosis in PTC.