DISCUSSION
Our study shows that thyroid nodules with BRAF V600E mutations are
strongly associated with Bethesda categories V and VI, whereas nodules
with a RAS or EIF1AX mutation, copy number alteration or GEP are more
commonly associated with Bethesda categories III and IV. Certain
mutations within dominant thyroid nodules, specifically those with a
BRAF V600E, TERT or RET mutation, were associated with thyroid cancer
subtypes known to be more aggressive. An increasing number of studies
have concluded that molecular testing of thyroid nodules has a
significant diagnostic as well as prognostic value and can help improve
management of patients. [19-25] Other studies, however, question the
clinical utility and cost-benefit analysis of molecular testing.
[20,24] The Afirma Gene Expression Classifier (Afirma®, Veracyte,
Inc., South San Francisco, CA) measures mRNA transcript levels of 142
genes and has shown to have a high sensitivity of 91% and a moderate
specificity of 68%. [18,22] ThyGeNEXT (ThyGeNEXT®, Interpace
Diagnostics, PDI Inc, Parsippany, NJ) and ThyroSeq v3 (ThyroSeq® joint
partnership between UPMC and CBLPath, Pittsburgh, PA) are two
comprehensive tests, designed to improve the overall accuracy of
molecular testing, with sensitivity of 89% and 94% and specificity of
85% and 82%, respectively. [20,24] The data regarding the clinical
utility of molecular testing in patients with a Bethesda V and VI
thyroid nodules remains unclear. [24-28] The value in molecular
testing for such thyroid nodules lies not in the fact that this tool can
predict malignancy. Further characterizing Bethesda V and VI thyroid
nodules with molecular testing can identify patients with higher-risk
disease (ex. presence of BRAF V600E, TERT) and may offer clinicians
better perioperative patient counselling and prognostication.
The American Association of Endocrine Surgeons 2020 guidelines strongly
recommend molecular testing as a diagnostic adjunct for cytologically
indeterminate thyroid nodules if the information gained will affect
clinical care. [20] Molecular testing may help clinicians with the
management of thyroid nodules by identifying the nature of indeterminate
lesions with mutations highly specific for malignancy such as BRAF
V600E, RET or TERT, leading to improved diagnostic accuracy and
potential reduction in the number of completion thyroidectomies
performed. [22-24] Moreover, the extent of surgery performed on
patients with a cytologic diagnosis of Bethesda
category V or VI is related to the
risk of recurrence and determined by the tumor size, radiographic
features, presence of adenopathy and contralateral thyroid disease.
[20] In this study, 44% of patients with a Bethesda category V or
VI nodule harboured a BRAF V600E mutation. Given the relatively high
prevalence of this mutation in Bethesda V/VI lesions, identifying this
mutation can stratify patients into a distinct higher risk group.
[8-15,22] Preoperative
knowledge of a BRAF V600E mutation can help clinicians recognize
patients with high risk thyroid nodule and potentially offer
personalized patient counselling and treatment planning, even in nodules
of smaller size. In the four patients with a less than 2 cm Bethesda
III/IV thyroid nodule, identification of a BRAF V600E mutation
preoperatively allowed for a total thyroidectomy with elective neck
dissection to be performed. All 4 patients showed aggressive thyroid
cancer features: 2 with central neck metastasis and 2 with solid or tall
cell variants of papillary thyroid cancer.
The management of patients with thyroid nodules that are indeterminate
on cytology often consists of a diagnostic lobectomy or active
surveillance based on clinical factors including the nodule’s size,
enlargement on ultrasound, suspicious ultrasound features, clinical and
family history, history of radiation exposure, and patient’s
preferences. [5,20, 25] Yip et al. show that molecular testing of
thyroid nodules can also be useful in defining the extent of surgery for
patients with low risk mutations to thyroid lobectomy. [24]
Understanding that RAS-type mutations, which are shown to have a
favorable prognosis when isolated, are commonly associated with Bethesda
III and IV suggests that patients with an isolated RAS mutation may
potentially be more conservatively treated with lobectomy. [25] The
current results show that BRAF V600E mutations have been identified in
4.1% of indeterminate nodules which highlights the need for molecular
testing to identify nodules of higher risk of malignancy. In this
context, it may be warranted for the thyroid specialist to consider
mutation testing analysis for specific higher-risk mutations such as
BRAF V600E, TERT or RET as a means to preoperatively risk stratify
patients. That being said, 128
patients did not have an identified molecular mutation with 64.6%
proving to be malignant. In this subgroup of patients, only 12.6% of
patients showed evidence of aggressive variants of thyroid cancer or
central neck metastasis and is significantly lower in prevalence
compared to patients with an identified molecular mutation. Additional
understanding of thyroid carcinogenesis, presence of co-mutations and
heterogeneity of nodules is needed to better allow clinicians to predict
risk of malignancy and tumor aggressivity. [25]
Certain limitations to this study are related to the retrospective
design and inclusion of patients undergoing molecular testing and
thyroidectomy. By doing so, the overall prevalence of malignancy was
elevated due to the selection of cases with more suspicious disease.
Also, the indication for molecular profile testing was at the surgeon’s
discretion. Expenses related to molecular profile testing of thyroid
nodules is currently not covered in the Quebec health system; this may
introduce a selection bias for patients who have the financial means to
access it. Lastly, validation with
larger prospectively collected data is needed to generalize results.
That being said, the number of patients included and analyzed in this
study offers a measure of diagnostic precision and clinical utility of
using molecular test for thyroid nodules.