ABSTRACT
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.
Subject(s)
DNA Mutational Analysis , Early Detection of Cancer/methods , Proto-Oncogene Proteins B-raf/genetics , Thyroid Neoplasms/diagnosis , Thyroid Nodule/pathology , Ultrasonography, Interventional , Adult , Amino Acid Substitution/genetics , Biopsy, Fine-Needle/methods , Carcinoma , Carcinoma, Papillary , Cytological Techniques , Female , Glutamic Acid/genetics , Humans , Male , Middle Aged , Molecular Diagnostic Techniques , Mutation, Missense , Predictive Value of Tests , Prospective Studies , Proto-Oncogene Proteins B-raf/analysis , Retrospective Studies , Sensitivity and Specificity , Thyroid Cancer, Papillary , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Nodule/diagnostic imaging , Thyroid Nodule/genetics , Ultrasonography, Interventional/methods , Ultrasonography, Interventional/statistics & numerical data , Valine/geneticsABSTRACT
BACKGROUND: In this study, the authors conducted a comparative quantitative evaluation of the proliferation markers ProEx C (an aberrant S-phase induction marker, human papillomavirus E6-E7 correlated) and MIB-1 in squamous intraepithelial lesions (SIL) to identify a biomolecular profile informative for the diagnosis of high-grade SIL/cervical intraepithelial neoplasia 3 or greater that was complementary to the morphologic Papanicolaou (Pap) test ("biomolecular Pap test"). METHODS: After the cytologic diagnosis, reflex immunocytochemistry was carried out on 76 unstained SurePath cell samples (20 routine samples that were negative for intraepithelial lesion or malignancy and 56 positive samples that were selected with matching histology). Both a morphometric analysis with a software imaging analysis system and a quantitative analysis of atypical squamous clusters were performed. RESULTS: The quantitative evaluation revealed an excellent, direct correlation between the 2 markers, although ProEx C was more selective and more informative for the progression of low- and moderate-grade lesions, because it only revealed cells in aberrant S-phase cell cycle. The quantitative morphometric analysis revealed the increased presence of atypical, positive clusters and the percentage of positive cells within, both paralleling the severity of the lesions. The threshold of a 3% ProEx C-positive nuclear area was useful for splitting lesions into groups with a low risk or high risk of progression. CONCLUSIONS: Both ProEx C and MIB-1 were valid proliferation markers in cytologic preparations, and nuclear positivity was quantified successfully by using computer-assisted analysis. The analysis of atypical clusters may be a valuable tool in the diagnosis of SIL. The presence of atypical clusters and their positivity for proliferation markers are good first-glance indicators of lesion grade.
