Molecular markers in the diagnosis of thyroid nodules

Abstract

SUMMARYAn indeterminate thyroid nodule cytology result occurs about every sixth fine-needle aspiration. These indeterminate nodules harbor a 24% risk of malignancy (ROM); too high to ignore, but driving surgery where most nodules are benign. Molecular diagnostics have emerged to ideally avoid surgery when appropriate, and to trigger the correct therapeutic surgery when indicated, as opposed to an incomplete diagnostic surgery. No current molecular test offers both high sensitivity and high specificity. A molecular diagnostic test with high sensitivity (e.g. Afirma Gene Expression Classifier sensitivity 90%) offers a high Negative Predictive Value when the ROM is relatively low, such as < 30%. Only such tests can "rule-out" cancer. In this setting, a molecularly benign result suggests the same ROM as that of operated cytologically benign nodules (~6%). Thus, clinical observation can replace diagnostic surgery; increasing quality of life and decreasing medical costs. However, its low specificity cannot "rule-in" cancer as a suspicious result has a Positive Predictive Value (PPV) of ~40%, perhaps too low to routinely reflex to definitive cancer surgery. Conversely, high specificity tests (BRAF, RAS, PPAR/PAX-8, RET/PTC, PTEN) offer high PPV results, and only these tests can "rule-in" cancer. Here a positive molecular result warrants definitive therapeutic surgery. However, their low sensitivity cannot "rule-out" cancer and a negative molecular result cannot dissuade diagnostic surgery; limiting their cost-effectiveness. Whether or not there is a useful and cost-effective role to sequentially combine these approaches, or to modify existing approaches, is under investigation. Arq Bras Endocrinol Metab. 2013;57(2):89-97 Keywords Biopsy, fine-needle; DNA mutational analysis; gene expression; genomics; molecular diagnostic techniques SUMáRioResultados indeterminados na citologia de um nódulo tireoidiano ocorrem em cerca de um a cada seis punções aspirativas por agulha fina. Esses nódulos indeterminados apresentam risco de malignidade (RM) de cerca de 24%, um valor alto demais para ser ignorado e que leva à cirurgia em casos em que a maioria dos nódulos é benigna. O diagnóstico molecular é uma forma ideal de se evitar a cirurgia quando apropriado e de se levar ao correto procedimento cirúrgico terapêutico quando indicado, em oposição à cirurgia diagnóstica incompleta. Atualmente, não existem testes moleculares com alta sensibilidade e especificidade. Um teste molecular de alta sensibilidade (por exemplo, a sensibilidade do teste Afirma Gene Expression Classifier é de 90%) tem um alto Valor Preditivo Negativo quando o RM é relativamente baixo, por exemplo, < 30%. Apenas esses testes podem "excluir" o câncer. Nesse contexto, um resultado molecular benigno sugere o mesmo RM de nódulos com resultado benigno na citologia e operados (~6%). Assim, a observação clínica pode substituir a cirurgia diagnóstica, aumentando a qualidade de vida e diminuindo os custos médicos. Entretanto, a baixa especificidade não pode "incluir" o cân...

Tiroid kanserinde moleküler etyolojik faktörler

“…Tiroid kanserinde olası moleküler genetik etyolojik sebepleri, şu şekilde sınıflandırmak mümkündür: [23][24][25]. Diğer taraftan literatürde BRAF mutasyonu bulunan tiroid kanserlerinin prognozunun daha kötü olduğundan ve kemoterapi cevabını olumsuz etkilediğinden bahseden çok sayıda yayın bulunmaktadır.…”

Comparative analysis of the new guidelines and consensuses for the management of hypothyroidism, thyroid nodules, and differentiated thyroid cancer

“…The use of those biomarkers may become a safe and inexpensive alternative to surgery (15), but further evaluation is needed. Their use needs to be individually assessed, and cost-effectiveness should also be considered (16). Also, in cases of follicular lesion or of atypia or indeterminate significance, FDG-PET is not recommended by the SBEM panel; the ATA panel does not have a position on that issue.…”

Molecular Markers: From Diagnosis to Prognosis in 2013

“…The use of a panel of DNA/RNA mutation/rearrangement tests, studied by the microarray technique and validated by a large multicenter study, is starting to be used commercially; it is known as the Afirma gene expression classifier (AGEC) [43 •• ]. This test has been considered to be a good tool for ''ruling out'' malignant tumors when associated with a negative result [17]. On the other hand, the best test to ''rule in'' the suspicion of a malignant thyroid tumor is the association of the expression of mutated BRAF, RAS and RET/PTC and PAX8/PPARG translocations [44 •• ].…”

“…This study was a landmark and was used as the basis to format the four-gene classifier test (miR-Inform, Asuragen Inc., Austin, TX, USA), with the intention to ''rule in'' highly suspicious molecular profile nodules for WDTC with Bethesda III FNAB results [17]. The number of detected mutations observed in this FNAB category is low (11.3 %) [44 •• ], but it is in accordance with the low risk of malignancy observed in this FNAB category as well [36].…”

“…This geneexpression classifier (Veracyte Afirma GEC) was able to detect 92 % of malignancies with 52 % specificity. In contrast to the 74 % rate of diagnostic surgery for the group with undetermined FNAB results, in the Afirma GEC-negative group, the frequency of surgery dropped to 7.6 % [17]. This molecular classifier is intended to ''rule out'' unsuspected molecular cases from surgical treatment, opening the opportunity for a watch-and-wait approach [10 • ] (Fig.…”