Impact of Proto-Oncogene Mutation Detection in Cytological Specimens from Thyroid Nodules Improves the Diagnostic Accuracy of Cytology

Cantara, Silvia; Capezzone, Marco; Marchisotta, Stefania; Capuano, Serena; Busonero, Giulia; Toti, Paolo; Santo, Andrea Di; Caruso, Giuseppe; Carli, Anton Ferdinando; Brilli, Lucia; Montanaro, Annalisa; Pacini, Furio

doi:10.1210/jc.2009-2103

Cited by 292 publications

(257 citation statements)

References 17 publications

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“…10,12 Moreover, we detected 10/48 mutated samples (21%) with a higher incidence of RAS variants in comparison with previous reports in Thy 3 patients. 10,16 In addition to establishing the evident advantages of HRM prescreening in terms of time and economic improvement, this pilot study confirmed the accuracy of the proposed method. Complete concordance was found between the standard protocol, based on sequencing of all samples, and the HRM-based screening.…”

Section: Discussionsupporting

confidence: 56%

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

Mancini

Pinzani

Pupilli

et al. 2012

The Journal of Molecular Diagnostics

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Thyroid cancer is the most common malignancy of the endocrine system, accounting for approximately 1% of all malignancies in Western countries. 1 The incidence of thyroid cancer has increased 2.6-fold in the last 30 years. This change is attributed not only to an increment in papillary thyroid carcinoma, 2 but also to more wisely conducted medical surveillance and improvements in diagnostic tools. 3 The large majority of thyroid nodules, as discovered with the use of new diagnostic imaging techniques, are asymptomatic and benign. In this context, diagnostic studies are becoming essential to identify the small fraction of thyroid nodules that harbor malignant disease and to predict when surgery is indicated. Fine-needle aspiration biopsy (FNAB) has emerged over the past 30 years as an accurate and cost-effective procedure for the preoperative screening of thyroid nodules, representing the gold standard for differential diagnosis of benign and malignant nodules. 4 Under recent guidelines, 5,6 cytological smears are classified in five categories for the diagnostic report: Thy 1, nondiagnostic; Thy 2, benign or negative for malignant cells; Thy 3, all follicular lesions (including atypia/ follicular lesion of undetermined significance and follicular neoplasm or suspicious for follicular neoplasm); Thy 4, suspicious; and Thy 5, diagnostic for malignancy.Although the overall accuracy of FNAB is considered excellent, approximately 30% of cytological aspirates do not allow definitive diagnosis of malignancy, because of intrinsic and unavoidable characteristics of samples. 7 The major limitations of FNAB procedures are linked to inadequate and indeterminate specimens and, in that sense, are also linked respectively to the nondiagnostic or follicular lesions categories. 8,9 Thus, a clinical need emerges for the characterization of aspirates with suspicious features but with unsatisfactory cellularity, to allow accurate distinction of benign from malignant forms of follicular lesions.Several somatic mutations have been identified in thyroid cancer, stimulating the search for genetic alterations in FNAB that could increase the diagnostic accuracy of traditional cytology. Numerous studies have demonstrated that identification of specific mutations in cytological specimens can assist in the diagnosis by FNAB and in the clinical decision to excise the nodule and to intensify the follow-up. 10 -16 In most cases, genetic alterations are represented by activating mutations of oncogenes that are mutually exclusive and linked to distinct histological subtypes, with a demonstrated pathogenic role in thyroid cell transformation as effectors of the RAS/RAF/ MAPK signaling cascade.The presence of BRAF mutations, a frequent alteration in papillary carcinoma (PTC), evolves into an unregulated activation of the intracellular MAPK pathway that can promote tumorigenesis and tumor progression. The main mutation of BRAF, identified exclusively in PTC, affects

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Section: Discussionsupporting

confidence: 56%

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

Mancini

Pinzani

Pupilli

et al. 2012

The Journal of Molecular Diagnostics

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“…Recent studies have demonstrated the feasibility of mutations detection in clinical FNAB samples, extensively BRAF and RAS mutations, and the improvement of accuracy of FNAB especially in indeterminate cytology. Detection of other molecular markers such as as RET/PTC and PAX8/PPARg mutations does not contribute substantially to cancer diagnosis and in addition, they are technically more difficult to study (18).…”

Section: Discussionmentioning

confidence: 99%

Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma

Danilovic

Lima

Domingues

et al. 2014

European Journal of Endocrinology

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Objective: The p.V600E BRAF and RAS mutations are found in 30-80% of differentiated thyroid carcinoma (DTC). BRAF mutation has been associated with poor prognosis. This study investigated the role of molecular studies in preoperative diagnosis of DTC and the association of p.V600E mutation with prognostic factors. Design: Prospective study. Methods: A total of 202 patients with cytological diagnosis of Bethesda III-VI underwent preoperative molecular studies and subsequent thyroidectomy. p.V600E and RAS mutations were studied in the cytology smears, using real-time PCR genotyping technique. The BRAF mutation (BRAF C or BRAF K ) was correlated with histological and clinical findings. Results: Molecular study of 172 nodules with Bethesda III-V cytology improved negative predictive value and accuracy of Bethesda III and IV diagnosis. BRAF mutation was present in 65% of 94 DTC and p.Q61R NRAS in one. Except for age, BRAF C and BRAF K did not differ in sex, tumor size, histological subtype, multifocality, vascular invasion, extrathyroidal extension, or prognostic staging. Among papillary carcinomas, lymph node (LN) metastasis was diagnosed in 23% BRAF C and 37% BRAF K . Distant metastasis occurred in four BRAF K . Recurrent or persistent disease was more frequent in BRAF K (26.7 vs 3.3% BRAF C , PZ0.002) along follow-up of 29.8G10 months. BRAF C patients without LN metastasis by pre-operative evaluation submitted to thyroidectomy with central neck dissection (CND) had more frequent LN metastasis (45 vs 5% no CND, PZ0.002), but no difference in clinical outcome was observed. Conclusions: Pre-operative identification of BRAF mutation improved cytological diagnosis of DTC, but it was not associated with poor prognostic factors. Prophylactic CND did not guarantee better outcome in BRAF C patients.

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“…Most studies demonstrated that the sensitivity of molecular assays has improved by combined detection of BRAF and RET/PTC. An increased sensitivity from about 42.3-69% to 56.4-78% has been reported [196][197][198].…”

Section: Molecular Targets In Histopathological Diagnosis and Classifmentioning

confidence: 90%

“…TRK rearrangements may also be added to this panel. Presence of BRAF, RAS, RET/PTC, PAX8-PPAR␥ and TRK in FNAB samples correlated with malignancy in 97% of cases [196,197,212]. Therefore, detection of any mutation of this panel is a strong predictor for thyroid cancer.…”

Section: Molecular Targets In Histopathological Diagnosis and Classifmentioning

confidence: 98%

An update on molecular biology of thyroid cancers

Ömür

Baran

2014

Critical Reviews in Oncology/Hematology

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Impact of Proto-Oncogene Mutation Detection in Cytological Specimens from Thyroid Nodules Improves the Diagnostic Accuracy of Cytology

Abstract: Our findings demonstrate that molecular analysis of cytological specimens is feasible and that its results in combination with cytology improves the diagnostic performance of traditional cytology.

Cited by 292 publications

References 17 publications

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma

An update on molecular biology of thyroid cancers

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