RESUMEN
Indeterminate thyroid nodules include heterogeneous lesions that could benefit from a differential management. Our aim is to better define the management of the Bethesda System for Reporting Thyroid Cytopathology class III and IV nodules, by identifying cytological subcategories among Bethesda System for Reporting Thyroid Cytopathology class III associated with different clinical risk, by means of ultrasound, repeated FNAB, and BRAFV600E molecular analysis. We also evaluated the outcome of nodules not operated, over a 5-year follow-up. Out of 460 nodules (269 Bethesda System for Reporting Thyroid Cytopathology class III and 191 Bethesda System for Reporting Thyroid Cytopathology class IV), 344 were operated on surgical group and 116 followed-up conservatively (follow-up group). Bethesda System for Reporting Thyroid Cytopathology class III was divided into four subcategories on the basis of cytomorphological features (III-1, III-2, III-3, III-4). Clinical risk was defined on the basis of histological, cytological, and ultrasound data. Malignancy was higher in Bethesda System for Reporting Thyroid Cytopathology class III vs. Bethesda System for Reporting Thyroid Cytopathology class IV (34.4 vs. 26.2 %; p < 0.01). Papillary thyroid carcinoma was the most frequent cancer in each Bethesda System for Reporting Thyroid Cytopathology class (35 %). BRAFV600E diagnostic accuracy was 87 %. Repeated FNAB reclassified as benign nearly 40 % of nodules, selecting patients where surgery could be spared. Significant nodule growth occurred in 13.7 % of nodules, belonging mostly to Bethesda System for Reporting Thyroid Cytopathology class III-2 and Bethesda System for Reporting Thyroid Cytopathology class IV. Overall clinical risk was higher in Bethesda System for Reporting Thyroid Cytopathology III-1, III-4, and IV classes. We propose a differential management of Bethesda System for Reporting Thyroid Cytopathology III and IV classes and related subcategories: surgery may be indicated in Bethesda System for Reporting Thyroid Cytopathology class III-1, III-4, and IV; a conservative follow-up avoiding repeated FNAB may be appropriated in class III-3, while repeated FNAB may be useful in class III-2.
Asunto(s)
Carcinoma Papilar/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patología , Adulto , Biopsia con Aguja Fina , Carcinoma Papilar/diagnóstico por imagen , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Glándula Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico por imagen , Nódulo Tiroideo/diagnóstico por imagen , UltrasonografíaRESUMEN
BACKGROUND: A molecular profile including BRAF and RAS mutations as well as RET/PTC rearrangement evaluation has been proposed to provide an accurate presurgical assessment of thyroid nodules and to reduce the number of unnecessary diagnostic surgeries, sparing patients' health and saving healthcare resources. However, the application of such molecular analyses may provide different results among different centers and populations in real-life settings. Our aims were to evaluate the diagnostic utility of assessing the presence of BRAF and RAS mutations and RET/PTC1 and RET/PTC3 rearrangements in all cytological categories in an Italian group of thyroid nodule patients assessed prospectively, and to understand whether and which mutation testing might be helpful in cytologically indeterminate nodules. METHODS: A total of 911 patients were submitted to ultrasound and fine-needle aspiration biopsy examination. Cytological evaluation was performed in parallel with molecular testing and compared to pathological results in 940 thyroid nodules, including 140 indeterminate lesions. RESULTS: BRAF mutation testing provided the best contribution to cancer diagnosis, allowing the disease to be detected at an early stage, and identifying indeterminate nodules in which diagnostic lobectomy could be spared. On the contrary, RAS and RET/PTC analysis did not further increase diagnostic sensitivity for thyroid cancer. In addition, we found RET/PTC rearrangements in benign lesions, indicating that this molecular marker might not be useful for the detection of thyroid cancer. CONCLUSION: BRAF(V600E) mutation analysis is superior to RAS point mutations and evaluation of RET/PTC rearrangements in the diagnosis of thyroid cancer, even in indeterminate lesions.
Asunto(s)
Reordenamiento Génico , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/diagnóstico , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patologíaRESUMEN
BACKGROUND: Prospective uncontrolled study to investigate in papillary thyroid carcinoma (PTC) patients: (1) Distribution of lymph node metastases within the neck compartments, (2) factors predicting lymph nodes metastases, and (3) disease recurrence after thyroidectomy associated with radio-guided selective compartment neck dissection (RSCND). METHODS: We studied 345 consecutive PTC patients operated on between February 2004 and October 2011 at the S. Anna University Hospital, Ferrara (Italy). Patients with cervical lymph node metastases on preoperative ultrasonography and fine needle aspiration cytology were excluded. All patients underwent total thyroidectomy associated with SLN identification followed by RSCND in the SLN compartment, without SLN frozen section. RESULTS: In patients with lymph node metastases, metastatic nodes were not in the central neck compartment in 22.6% of the cases. The presence of infiltrating or multifocal PTC was a predicting factor for lymph nodes metastases. The median follow-up was 35.5 months. RSCND was associated with a false-negative rate of 1.1%, a persistent disease rate of 0.6%, and a recurrent disease rate of 0.9%. The permanent dysphonia rate was 1.3%. CONCLUSION: RSCND associated with total thyroidectomy may improve: (1) the locoregional lymph node staging, and (2) the identification of the site of lymphatic drainage within the neck compartments. Thus, considering the high false-negative rate of sentinel lymph node biopsy (SLNB), a radio-guided technique in PTC patients may guide the lymphadenectomy (ie, RSCND) to increase the metastatic yield and improve staging of the disease rather than avoid prophylactic lymphadenectomy (ie, SLNB).
Asunto(s)
Carcinoma/cirugía , Linfocintigrafia/métodos , Disección del Cuello/métodos , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Adulto , Anciano , Carcinoma/diagnóstico por imagen , Carcinoma/patología , Carcinoma Papilar , Reacciones Falso Negativas , Femenino , Estudios de Seguimiento , Secciones por Congelación , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Cuello , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Estudios Prospectivos , Biopsia del Ganglio Linfático Centinela , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/patología , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Hashimoto's thyroiditis (HT) is the most common of all thyroid diseases and is characterized by abundant lymphocyte infiltrate and thyroid impairment, caused by various cell- and antibody-mediated immune processes. Viral infections have been suggested as possible environmental triggers, but conclusive data are not available. We analyzed the presence and transcriptional state of human herpesvirus 6 (HHV-6) in thyroid fine needle aspirates (FNA) and peripheral blood mononuclear cells (PBMCs) from 34 HT patients and 28 controls, showing that HHV-6 DNA prevalence (82% vs. 10%, p≤0.001) and viral load were significantly increased in FNA from HT patients, and thyrocytes from HT FNA displayed a 100-fold higher HHV-6 DNA load compared to infiltrating lymphocytes. In addition, while HHV-6 was strictly latent in positive samples from controls, a low grade acute infection was detected in HT samples. HHV-6 variant characterization was carried out in 10 HT FNA samples, determining that all specimens harbored HHV-6 Variant A.The tropism of HHV-6 for thyroid cells was verified by infection of Nthy-ori3-1, a thyroid follicular epithelial cell line, showing that thyrocytes are permissive to HHV-6 replication, which induces de novo expression of HLA class II antigens. Furthermore, HHV-6-infected Nthy-ori3-1 cells become targets for NK-mediated killing, NK cells from HT patients show a significantly more efficient killing of HHV-6 infected thyroid cells than healthy controls, and HT patients have increased T-cell responses to HHV-6 U94 protein, associated to viral latency. These observations suggest a potential role for HHV-6 (possibly variant A) in the development or triggering of HT.
Asunto(s)
Enfermedad de Hashimoto/etiología , Enfermedad de Hashimoto/virología , Herpesvirus Humano 6/patogenicidad , Infecciones por Roseolovirus/virología , Glándula Tiroides/patología , Biopsia con Aguja Fina , Línea Celular , ADN Viral , Células Epiteliales/virología , Enfermedad de Hashimoto/inmunología , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/inmunología , Herpesvirus Humano 6/aislamiento & purificación , Antígenos de Histocompatibilidad Clase II/biosíntesis , Humanos , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/virología , Glándula Tiroides/virología , Carga ViralRESUMEN
CONTEXT: Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the most reliable nonsurgical test for distinguishing benign from malignant thyroid nodules. However, there is no consensus on which nodules should undergo FNAB. AIMS: The aims of this study were to evaluate the utility of US-guided FNAB in the diagnostic assessment of nodules with or without clinical/US features suggestive for malignancy and to investigate the additional contribution of BRAF V600E mutation analysis in the detection of differentiated thyroid cancer. DESIGN AND METHODS: Thyroid cytoaspirates from 2421 nodules at least 4 mm in diameter were performed in 1856 patients who underwent cytological evaluation and biomolecular analysis. RESULTS: Cytology showed high positive predictive value and specificity for the diagnosis of malignant lesions. BRAF V600E mutation was found in 115 samples, 80 of which were also cytologically diagnosed as papillary thyroid cancer. BRAF mutation analysis significantly enhanced the diagnostic value of cytology, increasing FNAB diagnostic sensitivity for malignant nodules by approximately 28%. Micro PTC (63% of diagnosed papillary thyroid carcinoma) showed a high prevalence of multifocality, extrathyroidal extension, and lymph node metastases, underlining the malignant potential of thyroid microcarcinomas. Each investigated US/clinical characteristic of suspected malignancy correlated with the presence of a thyroid cancer in thyroid nodules with diameter of at least 4 mm. CONCLUSIONS: These data indicate that nodules of at least 4 mm may underlie a thyroid cancer independently of US/clinical characteristics of suspected malignancy, suggesting the need to perform FNAB. The diagnostic sensitivity for thyroid cancer is significantly increased by BRAF V600E mutation analysis, indicating that the screening for BRAF mutation in FNAB samples has a relevant diagnostic potential.
Asunto(s)
Análisis Mutacional de ADN , Detección Precoz del Cáncer/métodos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/diagnóstico , Nódulo Tiroideo/patología , Ultrasonografía Intervencional , Adulto , Sustitución de Aminoácidos/genética , Biopsia con Aguja Fina/métodos , Carcinoma , Carcinoma Papilar , Técnicas Citológicas , Femenino , Ácido Glutámico/genética , Humanos , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Mutación Missense , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteínas Proto-Oncogénicas B-raf/análisis , Estudios Retrospectivos , Sensibilidad y Especificidad , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/diagnóstico por imagen , Nódulo Tiroideo/genética , Ultrasonografía Intervencional/métodos , Ultrasonografía Intervencional/estadística & datos numéricos , Valina/genéticaRESUMEN
OBJECTIVE: Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid cancers, presenting the V600E activating BRAF mutation in 29-83% of cases. The aim of our study is to analyze the influence of BRAF mutation analysis on the diagnostic accuracy of fine-needle aspiration biopsy (FNAB) in patients with suspected PTC. DESIGN AND METHODS: Thyroid cytoaspirates from 469 nodules (size: 1.1+/-0.8 cm) with ultrasonographic features suspicious of malignant lesion, performed in 374 patients, were submitted to cytological evaluation and to biomolecular analysis, carried out after somatic DNA isolation, specific PCR amplification, and subsequent automated direct sequencing. All PCR fragments were also processed by specific enzyme restriction analysis. RESULTS: BRAF V600E mutation was found in 48 samples, 41 of which were also cytologically diagnosed as PTC, with histologic confirmation after thyroidectomy. Total thyroidectomy was perfomed also in seven patients with negative cytology but positive BRAF mutation, with histological confirmation of PTC in all. Among the 429 BRAF-negative samples, 407 had negative cytology for PTC, while 22 were diagnosed as suspected PTC and underwent total thyroidectomy with histological diagnosis of PTC in 17 and benign lesion in five. The prevalence of BRAF V600E mutation among histologically diagnosed PTC patients was 64%. Biomolecular analysis significantly increased cytology sensitivity for PTC from 77.3 to 86.7% (P<0.01). CONCLUSIONS: These data indicate that BRAF V600E mutation analysis can significantly improve FNAB diagnostic accuracy. However, biomolecular analysis is complementary to cytology, which should always be performed.
Asunto(s)
Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Análisis Mutacional de ADN , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Biopsia con Aguja Fina , Carcinoma Papilar/patología , Análisis Mutacional de ADN/métodos , Femenino , Ácido Glutámico/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Sensibilidad y Especificidad , Neoplasias de la Tiroides/patología , Valina/genética , Adulto JovenRESUMEN
OBJECTIVE: To compare characteristics and outcomes of differentiated thyroid cancers < or =10 mm with those 11-20 mm in diameter. DESIGN: Retrospective chart review of 426 patients with thyroid carcinoma < or =20 mm diagnosed and treated between 1990 and 2004 in one university clinic. MAIN OUTCOMES: Lymph node metastases were more frequent at diagnosis in 11-20 mm than in < or =10 mm cancers (p < 0.001). The prevalence of distant metastases did not differ between < or =10 mm and 11-20 mm cancers. One hundred and thirty-three patients (73%) with tumors 11-20 mm were disease free 2 years after 131I treatment, and no recurrence has been observed over 2-14 years of follow-up. Forty-one patients (22%) with cancers 11-20 mm (N1 or M1) required 2-4 years to become disease free. Neck lymph node recurrence was observed in nine patients (4.9%) 4 months to 14 years after surgery and (131)I therapy. Four patients (1.6%) with cancers < or =10 mm in diameter had cancer recurrence (p = 0.05 compared to the 11-20 mm cancers). Based on the presence of distant metastases at diagnosis and recurrence of disease during follow-up, cancers 11-20 mm in diameter seemed more aggressive than those < or =10 mm (p < 0.05). CONCLUSION: Cancers 11-20 mm seem more aggressive than those < or =10 mm.
Asunto(s)
Carcinoma Papilar/secundario , Neoplasias Pulmonares/secundario , Metástasis Linfática/patología , Neoplasias del Mediastino/secundario , Neoplasias de la Tiroides/patología , Adulto , Carcinoma Papilar/epidemiología , Carcinoma Papilar/radioterapia , Diferenciación Celular , Femenino , Estudios de Seguimiento , Humanos , Radioisótopos de Yodo/uso terapéutico , Neoplasias Pulmonares/epidemiología , Masculino , Neoplasias del Mediastino/epidemiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Prevalencia , Estudios Retrospectivos , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/radioterapiaRESUMEN
CONTEXT: The recognition of thyroid microcarcinoma has increased due to the widespread use of ultrasound-guided fine-needle aspiration biopsies. OBJECTIVE: The objective of this study was to describe histological and clinical characteristics of papillary thyroid microcarcinoma (PTMC) less than or equal to 1 cm. DESIGN: This study was a retrospective cohort. SETTING: This study was conducted at a university hospital endocrine clinic. PATIENTS: Over a 9-yr period, 243 consecutive patients with PTMC were studied. RESULTS: PTMC was an incidental finding at surgery in 21.4% of the PTMC cases. There were no differences in the clinical characteristics between those with incidental PTMC and those with suspected thyroid carcinoma. None of the patients with a cancer less than 8 mm had distant metastases, whereas distant metastases were observed in patients with cancers >/= 8 mm (P = 0.05). Disease-related mortality was not observed. CONCLUSIONS: PTMC is prevalent in the population. Among patients with PTMC, tumor size more than 8 mm is associated with more aggressive disease.
Asunto(s)
Carcinoma Papilar/patología , Neoplasias de la Tiroides/patología , Biopsia con Aguja , Carcinoma Papilar/terapia , Humanos , Radioisótopos de Yodo/uso terapéutico , Metástasis Linfática , Estudios Retrospectivos , Neoplasias de la Tiroides/terapia , TiroidectomíaRESUMEN
BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.