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BRAF in primary and recurrent papillary thyroid cancers: The relationship with 131I and 2-[18F]fluoro-2-deoxy-D-glucose uptake ability

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BRAF V600E is a potential marker of poor prognosis in papillary thyroid cancers (PTC). In a previous report, we showed that recurrent PTC with no radioiodine ((131)I) uptake are frequently associated with BRAF mutations, a low expression of thyroid-related genes and a high expression of glucose type-1 transporter gene. The aim of the present study was to assess BRAF status in a large series of recurrent PTC patients, considering paired primary and recurrent cancers. The BRAF genotype was correlated with the ability to concentrate (131)I and/or 2-[(18)F]fluoro-2-deoxi-d-glucose ((18)F-FDG) in the recurrent cancers, serum markers of recurrence, and patient outcome. We studied 50 PTC patients with recurrent cervical disease submitted to a re-intervention, followed up in median for 9 years. BRAF analysis was conducted by direct sequencing and mutant allele-specific PCR amplification. In 18 cases, molecular analysis was also assessed in the primary cancer. Out of 50 patients, 30 underwent (18)F-FDG-positron emission tomography-computed tomography. BRAF V600E-positive recurrent patients were found (131)I-negative in 94% of cases (P<0.001); 73% of the cancers carrying BRAF V600E were both (131)I-negative and (18)F-FDG positive. In paired primary and recurrent PTC, BRAF V600E was observed in 79% of the primary cancers and 84% of their recurrences. Three patients with (131)I-negative and BRAF V600E-positive recurrent cancers deceased during follow-up. BRAF mutations are more common in thyroid recurrences with no (131)I uptake than in (131)I-positive cases. They are correlated with the ability to concentrate (18)F-FDG, and they can appear, albeit rarely, as a de novo event in the course of PTC recurrences.
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CLINICAL STUDY
BRAF in primary and recurrent papillary thyroid cancers:
the relationship with
131
I and 2-[
18
F]fluoro-2-deoxy-D-glucose
uptake ability
Susi Barollo
1
, Gianmaria Pennelli
2
, Federica Vianello
1,3
, Sara Watutantrige Fernando
4
, Isabella Negro
4
,
Isabella Merante Boschin
5
, Maria Rosa Pelizzo
5
, Massimo Rugge
2
, Franco Mantero
4
, Davide Nacamulli
4
,
Maria Elisa Girelli
4
, Benedetto Busnardo
4
and Caterina Mian
4
1
Istituto Oncologico Veneto – IRCCS, 35128 Padova, Italy,
2
II Pathology Unit, Department of Medical and Diagnostic Sciences, 35121 Padova, Italy,
3
Radiotherapy Department, Istituto Oncologico Veneto – IRCCS, 35128 Padova, Italy,
4
Endocrinology Unit and
5
Special Surgery Unit, Department of
Medical and Surgical Sciences, University of Padua, Via Ospedale n.105, 35128 Padova, Italy
(Correspondence should be addressed to C Mian; Email: caterina.mian@unipd.it)
Abstract
Objective:BRAF V600E is a potential marker of poor prognosis in papillary thyroid cancers (PTC). In a
previous report, we showed that recurrent PTC with no radioiodine (
131
I) uptake are frequently
associated with BRAF mutations, a low expression of thyroid-related genes and a high expression of
glucose type-1 transporter gene.
Aim: The aim of the present study was to assess BRAF status in a large series of recurrent PTC patients,
considering paired primary and recur rent cancers. The BRAF genotype was correlated with the ability
to concentrate
131
I and/or 2-[
18
F]fluoro-2-deoxi-D-glucose (
18
F-FDG) in the recurrent cancers, serum
markers of recurrence, and patient outcome.
Design and methods: We studied 50 PTC patients with recurrent cervical disease submitted to a
re-intervention, followed up in median for 9 years. BRAF analysis was conducted by direct sequencing
and mutant allele-specific PCR amplification. In 18 cases, molecular analysis was also assessed in the
primary cancer. Out of 50 patients, 30 underwent
18
F-FDG-positron emission tomography–computed
tomography.
Results:BRAF V600E-positive recurrent patients were found
131
I-negative in 94% of cases (P!0.001);
73% of the cancers carrying BRAF V600E were both
131
I-negative and
18
F-FDG positive. In paired
primary and recurrent PTC, BRAF V600E was observed in 79% of the primary cancers and 84% of
their recurrences. Three patients with
131
I-negative and BRAF V600E-positive recurrent cancers
deceased during follow-up.
Conclusions:BRAF mutations are more common in thyroid recurrences with no
131
I uptake than in
131
I-positive cases. They are correlated with the ability to concentrate
18
F-FDG, and they can appear,
albeit rarely, as a de novo event in the course of PTC recurrences.
European Journal of Endocrinology 163 659–663
Introduction
Well-differentiated papillary thyroid cancers (PTC)
typically have a favorable prognosis, particularly in
low-risk patients, 80% of whom are cured by primary
surgery followed by radioiodine (
131
I) ablation (1).
Approximately, 15–20% of patients experience recur-
rences; however, two in three of which occur in the first
decade. One in three of these recurrences loses the
ability to trap
131
I, thus making the most important tool
available for treating the tumor ineffectual (2, 3). When
the loss of
131
I uptake tends to coincide with the ability
to actively concentrate glucose (the so-called ‘flip-flop’
phenomenon), the patient’s prognosis becomes particu-
larly unfavorable, associated with an early poor
outcome (4–6). Conventional approaches are of
marginal benefit in such cases, hence the need to
develop novel medical strategies. In this scenario,
mapping the particular genetic alterations in recurrent
PTC enables the use of novel ‘targeted’ molecular
therapies (7, 8).
Since it was first described in thyroid cancer, the
BRAF V600E mutation has proved to be the most
common genetic event in the onset of PTC, responsible
for around 45% of cases. Several studies have also
shown that primary PTC harboring BRAF mutations
are more aggressive and more prone to recur and lose
the capacity for iodine uptake (9, 10).
The molecular profile of paired primary and
recurrent PTC and its relationship to
131
Iand
European Journal of Endocrinology (2010) 163 659–663 ISSN 0804-4643
q2010 European Society of Endocrinology DOI: 10.1530/EJE-10-0290
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2-[
18
F]fluoro-2-deoxy-D-glucose (
18
F-FDG) uptake have
been little characterized in the literature. In a previous
report on a small series of recurrent PTC, we found a
high percentage of BRAF mutations in
131
I-negative
recurrences, and this genetic event has a key role in
silencing the expression of the whole iodine metabolism
enzyme chain and in increasing the expression of
glucose transporter gene (11).
In this mono-institutional study, we analyzed
BRAF status in a relatively large series of recurrent
PTC patients followed up at our Operative Units,
comparing samples of paired primary and recurrent
PTC from the same patient, when available. BRAF
status was correlated with the classical markers of
cancer recurrence and the ability to trap
131
I and/or
18
F-FDG.
Materials and methods
From 2006 to 2009, we collected a series of consecutive
recurrent cancers surgically removed from 50 patients
(16 males and 34 females) with well-differentiated
recurrent PTC, followed up at our operative units; they
all came from north-eastern Italy, a borderline iodine-
sufficient area according to WHO criteria (12).At
diagnosis, all the patients underwent total thyroid-
ectomy, 16 underwent central, 26 underwent central
and lateral, and 1 underwent central and bilateral
compartment lymph nodes dissection.
131
I ablation was
performed in all the patients after surgery.
Tumors were staged according to the 6th TNM
classification (13). Pathological diagnosis showed a
well-differentiated papillary thyroid carcinoma in all but
one case that was a tall cell variant.
After primary treatment, serum thyroglobulin (Tg)
under hormonal suppressive therapy, anti-Tg autoanti-
bodies (anti-Tg abs), and neck ultrasonography (US)
were evaluated every 6 months. At the first follow-up,
ten patients had a suspect of persistence. When the
recurrent disease was proved by US-FNAB and/or neck
positive
131
I whole body scan (WBS) and/or positive
18
F-FDG-positron emission tomography (PET)–
computed tomography (CT), the patients underwent
re-intervention.
At the time of recurrence, WBS was performed after a
therapeutic dose of
131
I (range 3.7–7.4 GBq), following
thyroid hormone withdrawal in all the patients. Thirty
patients also underwent
18
F-FDG-PET–CT. In cases who
were found positive at
18
F-FDG-PET–CT, the surgeon
was careful to isolate the cervical lesion observed in the
scan. The latest stimulated Tg serum level measured
prior to surgery was retained for statistical analysis in
all but eight patients, who had persistent anti-Tg abs.
For 18 patients, paired primary and recurrent PTC
were analyzed simultaneously. In three cases, we studied
different thyroid recurrences from the same patient.
DNA extraction and BRAF status detection
After examining the section stained with hematoxylin
and eosin, cancer tissue specimens containing
O60–70% tumor cells were chosen for molecular
analysis. In cases of multifocal primary PTC, different
microdissected cancer specimens were considered. In
all, we analyzed 71 thyroid cancer tissues, i.e. 46 neck
lymph node recurrences, 6 neck soft tissue recurrences,
1 distant metastasis (skin), and 18 primary PTC.
Genomic DNA was extracted from 5-mm sections of
archived paraffin-embedded tissues using the DNeasy
blood and tissues kit (Qiagen) according to the
manufacturer’s protocol. The BRAF status of exon 15
was assessed by both direct sequencing and mutant
allele-specific PCR amplification for the T to A
substitution at nucleotide 1799 (V600E), using the
procedure described elsewhere (14).
Statistical analysis
The Kaplan–Meier method and standard log-rank test
were used to evaluate the effect of iodine uptake in
recurrences on the probability of disease detection, and
of the BRAF status on patient survival. The t-test was
used to assess the relationship between BRAF status
and Tg serum level, after logarithmic transformation.
The c
2
-test was used to analyze the relationship
between BRAF status and iodine uptake in recurrences.
AP!0.05 was considered statistically significant.
Table 1 Demographic and histological characteristics of patients
according to BRAF status at recurrence level.
Clinical
features
BRAF V600E
(nZ33)
BRAF wild type
(nZ17)
Gender F 23 (70%) F 11 (65%)
M 10 (30%) M 6 (35%)
Age Median 51 years
(17–73)
Median 35 years
(16–74)
Mean 46 years G17 Mean 37 years G15
T1 11 (33%) 6 (35%)
T2 5 (15%) 1 (6%)
T3 13 (40%) 7 (41%)
T4 4 (12%) 3 (18%)
N0 2 (6%) 1 (6%)
N1 25 (76%) 12 (70%)
Nx 6 (18%) 4 (24%)
Stage
I 15 (46%) 12 (70%)
II 0 1 (6%)
III 9 (27%) 0
IV a 7 (21%) 1 (6%)
b0 0
c 0 1 (6%)
NA 2 (6%) 2 (12%)
Multifocality 14 (42%) 6 (35%)
Site of recurrence
Thyroid bed 11 (33%) 2 (12%)
Neck lymph nodes 22 (67%) 15 (88%)
Distant metastasis 5 (15%) 3 (18%)
NA, not available.
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Results
Patients and BRAF mutation status
Patients’ clinical characteristics at diagnosis and BRAF
status at recurrence level were shown in Table 1.
Patients were followed up for a mean 9G6 years
(median 7, min 1, max 28 years).
In our series, 66% of patients (33/50) harbored a
BRAF V600E mutation in their recurrent cancer.
Thirty-nine patients had
131
I-negative recurrences,
and 11 had
131
I-positive recurrences. Calculating the
time elapsing between the end of initial treatment and
the first surgery for recurrence, we found the interval to
be lower in
131
I-positive cases than in
131
I-negative
cases: the median interval before re-intervention was 1
year in the former group, and 5 years in the latter
group. In statistical terms, the likelihood of detecting the
recurrence was higher in
131
I-positive cases than in
131
I-negative cases (PZ0.01), who were followed up for
longer before the site of recurrent disease could be
identified (Fig. 1).
On average, BRAF-mutated patients had lower
stimulated Tg serum levels than those carrying a wild-
type BRAF (19 ng/ml, 95% confidence interval (CI)
7–54 vs 49 ng/ml, 95% CI 9–250), but the difference
was not statistically significant.
Three patients died due to disease progression: one
female 68 years of age with PTC (T2N1M0) recurred
3 years later in thyroid bed and lung, and died 2 years
later from lung disease; one female 73 years of age
with PTC (T2NxM0) recurred 6 years later in thyroid
bed and lung, and died 2 years later from cerebral
metastases; one male 61 years of age with PTC
(T3mN1bM0) recurred 1 year later in lateral neck,
and died 7 months later for local and lung disease. They
were all
131
I-negative,
18
F-FDG-positive, and BRAF
V600E-mutated cases (Fig. 2).
BRAF status and
131
I and
18
F-FDG uptake
In the
131
I-negative group, 79% (31/39) carried a BRAF
V600E mutation in their recurrence, while this was true
of only 18% (2/11) in the
131
I-positive group, in which
most patients harbored a wild-type gene (P!0.001;
Fig. 3). On a whole, BRAF V600E-positive recurrent
patients were
131
I-negative in 94% (31/33) of the cases.
In iodine-avid recurrence group, 63% (7/11) under-
went
18
F-FDG-PET–CT: 86% (6/7) showed positive foci
of
18
F-FDG uptake. In the group of patients undergoing
18
F-FDG-PET–CT, there were 2/7 BRAF V600E cases,
who were all
18
F-FDG PET positive.
In non-iodine avid recurrence group, 59% (23/39)
underwent
18
F-FDG-PET–CT: 83% (19/23) showed positive
foci of
18
F-FDG uptake. In the group of patients under-
going
18
F-FDG-PET–CT, there were 20/23 BRAF V600E
cases, of which 80% were (16/20)
18
F-FDG PET positive.
BRAF status in paired primary and
recurrent PTC
In 18 cases, paired primary and recurrent cancers were
simultaneously analyzed for BRAF status: all but one
showed a concordant genotype, 13 carried a BRAF
V600E mutation in both the primary and the
recurrence, and 4 had wild-type BRAF in both, while
in one case the primary harbored a wild-type BRAF,
and the recurrence harbored a BRAF V600E mutation.
In the three cases where different recurrences
were studied, the genotype was always concordant,
i.e. mutated in two cases and wild type in one.
Discussion
The clinical management of recurrent PTC failing
to trap
131
I is a challenge because
131
Iisofno
benefit in such cases for diagnostic or therapeutic
purposes, making surgery the only curative strategy.
100
131I-Positive
131I-Negative
80
60
Recurrent detection probability (%)
40
20
0
0 50 100 150
Months
200 250 300
Figure 1 Probability of detecting recurrence over time in patients
with or without
131
I uptake in the recurrence.
BRAF
WT
BRAF V600E
80
60
Survival probability (%)
90
100
70
50
0 50 100 150
Months
200 250 300 350
Figure 2 Survival curves for recurrent PTC patients with and without
BRAF V600E mutations. All patients who died during the follow-up
belonged to
131
I negative and BRAF V600E positive cases.
BRAF in recurrent PTC 661EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 163
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Chemotherapy and external radiation are often only
palliative measures, and clinical trials with compounds
for blocking the effectors of the MAPK pathway are
currently underway.
BRAF V600E has proved to be the most frequent
genetic event in the onset of PTC in adults, being found
in 36–69% of cases (15). Several retrospective studies
have also shown that primary PTC with BRAF
mutations are more aggressive and more likely to
recur and progress toward dedifferentiation processes,
making BRAF V600E a new predictor of poor outcome,
whatever the status of the other, classical prognostic
factors (10, 16). In a previous study on a small series of
thyroid recurrences, we demonstrated that such
cancers (with no
131
I uptake) carried a high frequency
– around 77% – of BRAF mutations, and that this
genetic event was accompanied by a decreased
expression of TPO, Tg, and Pendred’s syndrome genes,
and an increased expression of the GLUT1 (SLC2A1)
glucose transporter gene. In accordance with earlier
findings in primary PTC, we demonstrated that BRAF
mutations may promote iodine uptake impairment in
recurrences, and we gave a biological basis for the use of
scintigraphy with
18
F-FDG (11). Our preliminary data
were subsequently confirmed by Ricarte-Filho et al.,
(17) whoanalyzedalargeseriesofmetastatic
radioactive iodine-refractory recurrent cancers, 19 of
which belonging to the papillary phenotype. These
authors found that BRAF V600E was the main genetic
event in these cancers, responsible for around 95% of
cases and 100% of the
18
F-FDG-PET-positive ones.
Similar results were also reported by Henderson et al.,
who demonstrated that recur rent PTC were signi-
ficantly associated with BRAF V600E mutations in
77% of cases, though they did not examine the
131
I
uptake status in the recurrences (18).
To our knowledge, the present study concerns the
largest reported series of recurrent PTC with a relatively
lengthy follow-up (around 9 years) evaluated in terms
of their capacity to concentrate
131
I and
18
F-FDG.
As far as the follow-up is concerned, we observed
w4-year delay in cancer coming to site diagnosis and
re-intervention, in patients with
131
I-negative recur-
rences. US scan was routinely assessed to demonstrate
persistent or recurrent disease during follow-up in all
the patients; however if it was not clearly negative, it
was not sufficient by itself to perform the surgery, and
US-FNAB was needed to confirm the suspicion. So, in
patients with serum Tg rising or anti-Tg abs persistence,
with a negative
131
I WBS in the presence of recurrent
tiny or not accessible lymph nodes being unable to
uptake
131
I, a more prolonged follow-up was needed to
confirm the site of recurrence. During this lapse of time,
we cannot rule out the risk of the disease spreading
beyond the neck, such event being particularly
unfavorable in those cases which cannot be treated by
131
I. Actually, the only three deaths – all
131
I-negative
patients – were due to distant metastases. As a
consequence, an effort should be made for early
detection of persistent or recurrent disease, mainly in
131
I-negative patients.
As regards molecular data, we validated our previous
findings demonstrating that BRAF V600E-positive
recurrent patients were
131
I-negative in 94% of cases.
Such observations are consistent with previous studies
by Riesco-Eizaguirre et al., who demonstrated in vitro
that the BRAF V600E transfection had several effects
on NIS regulation: first, the transcriptional activity of
the NIS promoter decreased, then NIS targeting to the
membrane was impaired, and finally protein expression
progressively diminished (19).
The present study also confirms our preliminary
findings that recur rent PTC carrying a mutated BRAF
gene are more likely to be identified using
18
F-FDG
(which was positive in 80% of our cases). As a
consequence, our data suggest the search for BRAF
mutations – possibly even before surgery as proposed by
some authors (20, 21), but still not proven – could help
to stratify PTC patients, identifying persistent or
recurrent cancers, that should be followed up not only
with
131
I WBS, but also with
18
F-FDG-PET.
We also found that BRAF-mutated cancers were also
associated with a trend of low Tg serum levels in
comparison with cases harboring a wild-type BRAF:
such variation was not statistically different and should
be validated by future studies. The present study also
analyzed BRAF status in the largest reported series of
paired primary and recurrent PTC in an attempt to
ascertain whether the molecular pattern of the cancer
in a given patient could change during the follow-up.
We confirmed the findings reported by Ficarte-Filho
et al., i.e. most primary and recurrent cancers had a
concordant BRAF genotype. Only one of our patients
acquired a BRAF mutation as a de novo event in the PTC
80
60
Percent
90
100
70
50
40
30
20
10
0Negative Positive
131I Scan
BRAF
WT
BRAF V600E
Figure 3 Relationship between BRAF status and
131
I uptake in
thyroid recurrences.
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recurrence: so that BRAF testing at the time of primary
PTC diagnosis could identify nearly all mutated cases.
Indeed, a relatively earlier study on paired primary PTC
and metastatic lymph nodes had found that BRAF
mutations could be a de novo event at lymph node level,
due to the favorable influence of the local milieu (22).
In conclusion, our study showed that BRAF
mutations are very frequent in thyroid recurrences
with no
131
I uptake; at the same time, they correlate
with the ability to concentrate
18
F-FDG, and they can
appear, albeit rarely, as a de novo event in the cancer
recurrence.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by a grant from the Ministero dell’Istruzione,
dell’Universita
`e della Ricerca (N8200734RMKE_002 to C Mian).
Acknowledgements
We thank Frances Coburn for text editing. We thank Prof. Mario Vitale
for kindly donating the thyroid carcinoma cell line NPA as a positive
control for our experiments. We thank Mr Cristiano Lanza for his
technical assistance.
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Accepted 20 July 2010
BRAF in recurrent PTC 663EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 163
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... A limited number of studies have investigated the association between FDG-avidity of the tumors with BRAF V600E mutation status and clinicopathological features [13][14][15]. While some studies suggest primary or recurrent tumors bearing BRAF V600E mutation may have higher FDG-avidity [16,17], data on the correlation between other clinicopathological features and FDGavidity are rather sparse. Therefore, we aimed to determine the relationship between clinicopathologic factors, BRAF V600E mutation status and FDG avidity in a rather homogenous group of patients with recurrent or metastatic RAI-negative DTC. ...
... The present study protocol was reviewed and approved by the Institutional Review Board of Viet Nam Ministry of Science and Technology (approval No. 02/ HĐTK-ĐTCT-KC. 10.03/ [16][17][18][19][20]. ...
... Ethics approval and consent to participate This study was approved by the Institutional Review Board of Viet Nam Ministry of Science and Technology (approval No. 02/HĐTK-ĐTCT-KC. 10.03/ [16][17][18][19][20]. ...
Article
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Background In this study, we investigated the relationship between clinicopathologic factors, BRAF V600E mutation status and [ ¹⁸ F] F-fluoro-2-deoxyglucose (FDG) avidity in patients with radioiodine (RAI)-negative recurrent or metastatic differentiated thyroid cancer (DTC). Methods From 2015 to 2018 all patients with suspected recurrent or metastatic radioiodine-negative DTC patients who underwent FDG positron emission tomography/computed tomography (PET/CT) were retrospectively reviewed. Suspected lesions on FDG PET/CT were biopsied and underwent BRAF V600E mutation testing by immunohistochemistry and real-time PCR. Tumor size, recurrent versus metastatic disease, histopathologic features including classical type versus aggressive subtypes (poorly differentiated, tall cell, columnar cell, hobnail variants) and BRAF V600E mutation status were correlated with the SUVmax of highest hypermetabolic lesions on FDG PET/CT by the univariate analysis using logistic regression. Results Sixty-three consecutive patients, 55 (87.3%) female, with median age of 48 (range 17–81) were included. The majority of patients had BRAF V600E mutation and classical subtype, 55/63 (87.3%) and 45/63(71.4%), respectively. Thyroglobulin at the time of suspected recurrence was 262.7 ng/ml (range 16.3–1000) and patients received a median 3 prior RAI treatments. Fifty-four patients (85.7%) had local recurrence. The majority of patients 58/63 (92.1%) had FDG-avid disease on PET/CT. On univariate analysis, tumor size aggressive histopathologic types and distant metastasis are the significant factors for predicting FDG uptake, p = 0.04, p = 0.001 and p = 0.004 respectively. Although FDG uptake of BRAF V600E bearing recurrent/metastatic RAIR DTC lesions was higher than those without the mutation, the difference did not reach statistical significance, SUVmax of 7.11 versus 4.91, respectively, p = 0.2. Conclusion The majority of recurrent or metastatic RAI-negative DTC have BRAF V600E mutation and detectable disease on FDG PET/CT. FDG avidity of the recurrent or metastatic RAI-negative DTC is independently associated with the aggressive histopathologic features.
... Xing et al. reported, for instance, that it was not independently associated with cancer-related death, but it was independently associated with disease persistence/recurrence 34,35 . Some monocentric retrospective studies confirmed the BRAF mutation as an independent negative prognostic factor related to persistent disease 36 , and to aggressive characteristics such as loss of the ability to concentrate radioiodine, or acquisition of a capacity for glucose uptake 37 . On the other hand, prospective studies on patients who underwent fine needle aspiration biopsy for molecular definition and total thyroidectomy failed to confirm an role of BRAF mutations on patient outcomes 38,39 . ...
... There are reports in the literature on associations between TERT mutations and other oncogenic molecular events. This condition was found related to an aggressive DTC behavior, including distant metastases and a lack of radioiodine uptake capability 13,37,45 . We found no such negative impact of simultaneous mutations on the prognosis for patients with DTC, by comparison with those harboring a single TERT promoter mutation. ...
Article
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Only a minority of cases of differentiated thyroid carcinoma (DTC) have a poor clinical outcome. Clinical outcomes and molecular aspects were assessed in: 144 DTC ≤ 40 mm without distant metastases (group 1); 50 DTC > 40 mm without distant metastases (group 2); and 46 DTC with distant metastases (group 3). Group 3 had a worse outcome than the other two groups: during the follow-up, patients more frequently had persistent disease, died, or underwent further treatment. The outcomes did not differ between groups 1 and 2. Group 3 had a higher prevalence of TERT promoter mutations than group 2 (32.6% vs 14%). Group 1 had a higher frequency of BRAF mutations than groups 2 or 3 (61.1% vs 16.0% and 26.1%, respectively), while RAS mutations were more common in group 2 than in groups 1 and 3 (16.0% vs 2.1% and 6.5%, respectively). Groups 1 and 2 shared the same outcome, but were genetically distinct. Only lymph node involvement, distant metastases, older age and (among the molecular markers) TERT promoter mutations were independent predictors of a worse outcome. Metastatic DTC had the worst outcome, while the outcome was identical for large and small non-metastatic DTC, although they showed different molecular patterns. TERT promoter mutations emerged as an independent factor pointing to a poor prognosis.
... Because of its low disease-specific mortality, correct pretreatment diagnosis and classification of malignant risk are important for both clinicians and patients to have individualized treatment planning [38]. In addition to ultrasound and FNA [3,39], molecular testing is also introduced for detailed classification to lower the rate of diagnostic thyroidectomy [40][41][42]. Even though the molecular analysis has its role of risk classification for the patient, insufficient sampling results in false-negative results [13]. ...
Article
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Purpose To establish the optimal and minimally invasive diagnostic approach for targeted next-generation sequencing (NGS) in the indeterminate thyroid tumors. Methods The patients with indeterminate thyroid tumors were prospectively recruited and analyzed in a single tertiary medical center. We performed FNA and core needle biopsy (CNB) at the surgical specimens to confirm the quality of each sampling procedure. Cytological diagnosis by FNA, histological diagnosis by CNB and confirmed diagnosis by final surgery were compared to demonstrate the agreement among these approaches for the indeterminate thyroid tumors. The quality of the samples from FNA and CNB was evaluated, respectively to determine the optimal approach for targeted NGS. Finally, we performed ultrasound-guided CNB and FNA (US-CNB and US-FNA) on one case to confirm the clinical feasibility of being a pre-operative minimally invasive diagnostic approach. Results A total of 6 female patients (average age: 50.83 ± 15.18 years) with indeterminate thyroid tumors (average size: 1.79 ± 0.91 cm) were recruited for further analyses. The pathological diagnoses could be obtained by CNB in the first five cases, and the sample quality of CNB for targeted NGS was better than that of FNA, even after 10X dilution. The gene mutations associated with thyroid malignancy could be detected by NGS. In the case treated with US-CNB, the pathological and targeted NGS results were successfully obtained, which suggested the possibility of thyroid malignancy to facilitate immediate decision of subsequent treatment. Conclusion CNB could serve as a minimally invasive diagnostic approach in the indeterminate thyroid tumors by providing pathological diagnoses and qualified samples for detection of mutated genes, which facilitates appropriate and immediate management.
... 32 Furthermore, Barollo and colleagues established that the BRAF V600E mutation was related to the DovePress iodine uptake status of recurrent PTC. 33 In a study on the clinical outcomes of radioiodine therapy in low-and intermediate-risk PTC patients with the BRAF V600E mutation, Li and associates found no statistical difference between the BRAF-mutated group and the wild-type group. 15 Additionally, some studies have reported no association between the BRAF V600E mutation and radioiodine sensitivity in non-distant metastasis PTC groups. ...
Article
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Objective To study the association between radioiodine refractory papillary thyroid carcinoma, sodium/iodide symporter (NIS) expression, and the BRAFV600E mutation. Methods A study was conducted on 30 radioiodine refractory papillary thyroid carcinoma patients and 30 radioiodine-avid papillary thyroid carcinoma patients. The expressions of sodium/iodide symporter and BRAFV600E mutated protein were determined by immunohistochemistry using formalin-fixed, paraffin-embedded tissue. Results The mutated BRAFV600E protein was identified in 26 radioiodine refractory papillary thyroid carcinoma subjects (86.7%) and 22 radioiodine-avid papillary thyroid carcinoma subjects (73.3%), with no significant difference between the 2 groups (P = 0.3). Sodium/iodide symporter expression was detected in 4 of 30 cases (13.3%) from the radioiodine-avid papillary thyroid carcinoma group but was negative for all radioiodine refractory cases. There was no association between sodium/iodide symporter expression and radioiodine refractory papillary thyroid carcinoma (P = 0.11). Cases with positive NIS expression were likely negative for BRAFV600E mutation (3/4; P = 0.02). Conclusion Papillary thyroid carcinomas with BRAFV600E mutation were more likely to be negative for NIS expression. BRAFV600E mutation and NIS expressions cannot be used to predict radioiodine sensitivity.
... Marked reduction in glucose consumption in LDHA-silenced cells may be accompanied by concurrent decrease in FDG uptake, suggesting a possible association between the FDG uptake and LDHA expression [24,28]. It was also suggested that the presence of the BRAF V600E mutation is associated with the [ 18 F]-FDG uptake and GLUT1 expression rates in PTC [29]. The relationship between LDHA levels and [ 18 F]-FDG uptake was also analyzed but no relevant associations were identified (Supplemental Table S2). ...
Article
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Background: Several cancers show increased levels of lactate dehydrogenase A (LDHA), which are associated with cancer progression. However, it remains unclear whether LDHA levels are associated with papillary thyroid cancer (PTC) aggressiveness or with the presence of the PTC prognostic marker, the BRAFV600E mutation. This study aimed to evaluate the potential of LDHA as a PTC prognostic marker. Methods: LDHA expression was examined in 83 PTC tissue specimens by immunohistochemistry. Human thyroid cell lines were genetically manipulated to overexpress BRAFV600E or were treated with a BRAF-specific short hairpin RNA (shBRAF), whose effects on LDHA expression were evaluated by Western blotting. Data from 465 PTC patients were obtained from The Cancer Genome Atlas (TCGA) database and analyzed to validate the in vitro results. Results: LDHA was aberrantly overexpressed in PTC. Intense immunostaining for LDHA was observed in PTC specimens carrying mutated BRAF, whereas the intensity was less in wild-type BRAF samples. Overexpression of BRAFV600E resulted in LDHA upregulation, whereas treatment with shBRAF downregulated LDHA in human thyroid cell lines. Furthermore, LDHA mRNA expression was significantly elevated and associated with BRAFV600E expression in thyroid cancer tissues from TCGA database. Additionally, LDHA overexpression was found to be correlated with aggressive clinical features of PTC, such as lymph node metastases and advanced tumor stages. Conclusion: LDHA overexpression is associated with the BRAFV600E mutation and an aggressive PTC behavior. Therefore, LDHA may serve as a biomarker and therapeutic target in PTC.
... 86 BRAF mutations have been demonstrated to be commoner in PTC recurrence lacking radioiodide uptake than in those showing positivity for uptake. 87 Therefore the findings that primary PTC with BRAF mutations tend to be more aggressive, have more recurrence rate and lacks radioiodide uptake. 69,88,89 Another importance of BRAF mutation is the contemplated possibility its usage as a tumor marker in areas where its prevalence is high. ...
Article
ABSTRACT Background: The thyroid serves the body with important endocrine functions. A variety of influences impinges on the incidence and pathomorphological picture of the thyroid gland. These influences that include: iodine deficiency; iodine sufficiency; gender and; imaging technology are elucidated further in this work. We used the Google search engine to search for literature on the subject from the internet. Iodine is associated with increased incidence of nodular goiter and follicular carcinoma. The world over the last few decades had transited from an era of iodine deficiency to its sufficiency leading to an increase in incidence of thyroiditis and papillary thyroid carcinoma. Estrogen and Estrogen receptor discovered in the thyroid is implicated in the increased frequency of thyroid disorders in females. Finally, advancement in thyroid imaging technology and its utilization has led to over-diagnosis and overtreatment of thyroid diseases
... As far as we know, this is the first report of such extremely intense FDG uptake in metastatic lymph nodes from incidental PTC mimicking DLBCL involvement. This case exemplifies that accelerated glucose metabolism in thyroid cancer is not always dependent on poor differentiation and/or rapid proliferation, but may be due to genetic alterations, such as BRAF V600E mutation [4,5]. It also highlights that cytological examination of FNAB is necessary for a "PAIN" phenomenon and preventing wrong staging of synchronous malignancy. ...
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Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.
Article
Background: The BRAF V600E mutation (BRAF mut) in papillary thyroid cancer (PTC) has been associated with poor response to therapy with 131I in patients with metastases but the results in postsurgical treatment are controversial. Our main objective is to investigate the impact of the mutation on the biokinetics of the administered 131I therapy after surgery. Materials and methods: A prospective study was designed, from July 2015 to January 2018 which included patients with PTC receiving 131I therapy after surgical treatment. To study the biokinetics of the radioiodine in postoperative thyroid remnants, SPECT-CT images were acquired so as to obtain the following variables: percentage of remnant uptake at 2d and 7d postadministration, effective half-life and time-integrated activity coefficient. All of them were compared depending on the mutational diagnosis and other clinical features and pathological variables. Results: Sixty-one patients, and in total 103 thyroid remnants, were included. 59% of patients were BRAF mutated. The mutation was associated with classic variant (88.5% vs 11.5%; p=0.0001), desmoplastic reaction (85.7% vs 14.3%; p=0.002), smaller tumour size (1.5cm vs 2.1cm; p=0.024), nodal disease (3.3 vs 1; p=0.001) and advanced stages (76.9% vs 23%; p=0.014). The BRAFmut group had a lower percentage of 131I uptake at 2d (0.17% vs 0.47%; p= 0.001) and at 7d (0.02% vs 0.1%; p=0.013); and a lower timeintegrated activity coefficient (0.05h vs 0.17h; p=0.002). In univariate analysis, in addition to the mutation, the histological variant was significant but only for timeintegrated activity coefficient (p=0.04). In multivariate analysis, only mutation determined the 2d uptake (p<0.001) and the time-integrated activity coefficient (p<0.001). Conclusions: The BRAF V600E mutation is associated with lower 131I uptake in thyroid remnants. Furthermore, it is an independent factor that decreases the effect of post-surgical 131I therapy, and therefore, it could be used as a potential tool to optimize the treatment of PTC.
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Mutation BRAFV600E is highly specific for papillary thyroid carcinoma. It’s detected in 40-70% of all papillary thyroid carcinoma cases. Moreover this mutation is noticed in anaplastic carcinoma in 40-50%.This fact gives a chance to select patients and provide targeted therapy with multi-kinase inhibitors in cases of unresectable anaplastic carcinoma. The influence of BRAF V600E mutation for response to radioactive iodine therapy requires more evidence-based research. Existing methods for determining the BRAFV600E mutation have different accuracy, availability and cost. Other methodological aspects are also associated with the sample preparation of biological material, the quality of reagents, and the cross-validation of research results. In this review, on the basis of our own experience and literature data, the indications for determining the mutation of the BRAFV600E gene in clinical practice are refined, and a comprehensive comparative analysis of modern research methods has been conducted. This review is focused on a wide range of specialists of different types: oncologists, endocrinologists, radiologists, pathologists, and biologists.
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Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
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Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, usually possesses BRAF mutation or rearranged in translation (RET)/PTC rearrangements. PTC usually possesses BRAF mutation or RET/PTC rearrangements. The mutation status of patients with recurrent PTC has never been characterized in a large population. Mutation status was determined in a cohort of 54 patients with recurrent PTC and analyzed for clinicopathologic relationships. BRAF and ras mutations were determined by PCR and sequencing of genomic DNA. RET/PTC rearrangements were analyzed by reverse transcription-PCR. BRAF mutation in exon 15 (V600E) was found in 42/54 (77.8%) recurrent PTC patients. The RET/PTC rearrangements were detected in 9 of 54 (16.7%) patients. In addition, 5 of 54 (9.3%) recurrent PTC patients had both a BRAF mutation and a RET/PTC rearrangement. The prevalence of tumors with dual mutations found in the recurrent population far exceeds the frequency historically reported for patients with primary PTC. Patients with dual mutations were significantly older (80% older than 45 years) than patients with a BRAF mutation alone (38% older than 45 years). Recurrent PTC is significantly associated with a predominant BRAF mutation. RET/PTC rearrangements, although commonly associated with primary PTCs in younger patients, are uncommonly found in recurrent PTC patients. In addition, the incidence of dual mutations was higher in patients with recurrent PTC than in those primary PTC, as reported by others.
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The BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAF(V600E) mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAF(V600E) mutation in PTC patients with a long-term follow-up. We studied 102 PTC patients with a median follow-up of 15 yr. The BRAF(V600E) mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAF(V600E) mutation, clinicopathological features, and outcome of PTC patients were evaluated. The BRAF(V600E) mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAF(V600E) mutation (P < 0.002). However, at multivariate analysis only the BRAF(V600E) mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAF(V600E)-mutated group (P = 0.015). In this study the BRAF(V600E) mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAF(V600E) mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.
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We conducted a prospective study to define the sensitivity of 131I scintigraphy and 18FDG PET whole-body scanning in the detection of thyroid cancer and metastases. Forty-one patients with differentiated thyroid carcinoma who underwent thyroidectomy and 131I elimination of the remaining thyroid were studied by 18FDG whole-body PET in 52 examinations and by 131I whole-body scanning. Combined 18FDG and 131I imaging resulted in a sensitivity of about 95%, with alternating uptake of 131I and 18FDG in the metastases: 131I trapping metastases with no 18FDG uptake and 18FDG trapping metastases with no 131I uptake. Five uptake types were differentiated. Alternating uptake was found in about 90% of the patients, which was nearly identical to the sensitivity of the combined 131I/18FDG investigation. In six patients with increasing human thyroglobulin levels, we found that 18FDG whole-body PET localized positive neck metastases of papillary thyroid carcinomas that were histologically confirmed after extirpation. Combination 18FDG and 131I whole-body imaging protocol enables detection of local recurrence or metastases on whole-body scans that are often not shown by other imaging methods. Biochemical grading of thyroid cancer may also be possible with this method: Tumors with remaining functional differentiation for hormone synthesis and iodine uptake have low glucose metabolism in more than 95%; tumors without this functional differentiation of 131I uptake show high, glucose metabolism. Fluorine-18-FDG uptake seems to be an indicator of poor functional differentiation, and possibly higher malignancy, in thyroid cancer.
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Whole-body fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging was performed during the follow-up of 33 patients suffering from differentiated thyroid cancer. Among them there were 26 patients with papillary and seven with follicular tumours. Primary tumour stage (pT) was pT1 in six cases, pT2 in eight cases, pT3 in three cases and pT4 in 14 cases. FDG PET was normal in 18 patients. In three patients a slightly increased metabolism was observed in the thyroid bed, assumed to be related to remnant tissue. In one case local recurrence, in ten cases lymph node metastases (one false-positive, caused by sarcoidosis) and in three cases distant metastases were found with FDG PET. In comparison with whole-body scintigraphy using iodine-131 (WBS) there were a lot of discrepancies in imaging results. Whereas three patients had distant metastases (proven with131I) and a negative FDG PET, in four cases131I-negative lymph node metastases were detectable with PET. Even in the patients with concordant staging, differences between131I and FDG were observed as to the exact lesion localization. Therefore, a coexistence of131I-positive/FDG-negative,131I-negative/FDG-positive and131I-positive/FDG-positive malignant tissue can be assumed in these patients. A higher correlation of FDG PET was observed with hexakis (2-methoxyisobutylisonitrile) technetium-99m (I) (MIBI) scintigraphy (performed in 20 cases) than with WBS. In highly differentiated tumours131I scintigraphy had a high sensitivity, whereas in poorly differentiated carcinomas FDG PET was superior. The clinical use of FDG PET can be recommended in all cases of suspected or proven recurrence and/or metastases of differentiated thyroid cancer and is particularly useful in cases with elevated serum thyroglobulin levels and negative WBS.
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Papillary thyroid cancer (PTC) is a common endocrine malignancy that frequently harbors the oncogenic T1799A BRAF mutation. As a novel prognostic molecular marker, this mutation has received considerable attention in recent years for its potential utility in the risk stratification and management of PTC. In PTC, BRAF mutation is closely associated with extrathyroidal extension, lymph node metastasis, advanced tumor stages, disease recurrence, and even patient mortality. Many of the responsible molecular derangements promoted by, or associated with, BRAF mutation have been identified, including over-expression of tumor-promoting genes, suppression of tumor-suppressor genes, and silencing of thyroid iodide-handling genes, resulting in impairment or loss of radioiodine avidity and hence the failure of radioiodine treatment of PTC. BRAF mutation can be readily tested on thyroid fine needle aspiration biopsy specimens, with high preoperative predictive probabilities for clinicopathological outcomes of PTC. As such, the knowledge of BRAF mutation status can facilitate more accurate risk stratification and better decision making at various steps in the management of PTC, from preoperative planning of initial surgical scale to postoperative decisions about appropriate radioiodine treatment and thyroid-stimulating hormone suppression, and to selections of appropriate surveillance modalities for PTC recurrence. The greatest utility of BRAF mutation status is in those cases where traditional clinicopathological criteria alone would otherwise be unreliable in the risk stratification and management of PTC. Use of this unique molecular marker, in conjunction with conventional clinicopathological risk factors, to assist the prognostication of PTC is likely to improve the efficiency of contemporary management of thyroid cancer.prs.rt("abs_end");KeywordsBRAF mutation; Papillary thyroid cancer; Risk stratification; Prognosis; Molecular markerFigures and tables from this article:
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To date, a mutation of the BRAF oncogene is the most common genetic alteration found in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal extension, lymph node metastasis, and tumor recurrence. It is not known whether pre-operative identification of BRAF mutations in cytologic specimens should alter surgical management. From 2006 to 2008, the clinical, cytologic, and pathologic parameters of 106 consecutive surgically treated patients with BRAF-positive PTC were compared with a concurrent cohort of 100 patients with BRAF-negative PTC. In all, 99 BRAF-positive PTC patients underwent initial treatment, and 7 BRAF-positive patients had surgical resection of recurrent/persistent PTC. BRAF mutations were identified on preoperative cytologic samples (31 patients) or after thyroidectomy (75 patients). All 31 patients with BRAF-positive fine-needle aspiration (FNA) had PTC at thyroidectomy (specificity 100%). At short-term follow-up, 11/106 BRAF-positive patients have required reoperation for recurrent/persistent disease compared with 3 BRAF-negative patients (P = .04). Preoperative knowledge of BRAF mutation positivity could have productively altered initial PTC surgical management in 24% of patients. In PTC, BRAF mutations are associated with cervical recurrence and with reoperation. Pre-operative cytologic identification of BRAF mutation has high specificity and may guide the initial extent of thyroidectomy and node dissection.
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Whole-body fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging was performed during the follow-up of 33 patients suffering from differentiated thyroid cancer. Among them there were 26 patients with papillary and seven with follicular tumours. Primary tumour stage (pT) was pT1 in six cases, pT2 in eight cases, pT3 in three cases and pT4 in 14 cases. FDG PET was normal in 18 patients. In three patients a slightly increased metabolism was observed in the thyroid bed, assumed to be related to remnant tissue. In one case local recurrence, in ten cases lymph node metastases (one false-positive, caused by sarcoidosis) and in three cases distant metastases were found with FDG PET. In comparison with whole-body scintigraphy using iodine-131 (WBS) there were a lot of discrepancies in imaging results. Whereas three patients had distant metastases (proven with 131I) and a negative FDG PET, in four cases 131I-negative lymph node metastases were detectable with PET. Even in the patients with concordant "staging", differences between 131I and FDG were observed as to the exact lesion localization. Therefore, a coexistence of 131I-positive/FDG-negative, 131I-negative/FDG-positive and 131I-positive/FDG-positive malignant tissue can be assumed in these patients. A higher correlation of FDG PET was observed with hexakis (2-methoxyisobutylisonitrile) technetium-99m (I) (MIBI) scintigraphy (performed in 20 cases) than with WBS. In highly differentiated tumours 131I scintigraphy had a high sensitivity, whereas in poorly differentiated carcinomas FDG PET was superior. The clinical use of FDG PET can be recommended in all cases of suspected or proven recurrence and/or metastases of differentiated thyroid cancer and is particularly useful in cases with elevated serum thyroglobulin levels and negative WBS.
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Papillary and follicular carcinomas of the thyroid are differentiated carcinomas developed from the follicular epithelium, that keep some of its morphological and functional characteristics. Their increased incidence is related to an improved screening. Thyroid carcinoma usually presents as a thyroid nodule. Only 5% of nodules are malignant and fine needle biopsy is the most accurate tool for their diagnosis. Initial treatment is standardized and includes a total thyroidectomy with central lymph node dissection in case of papillary carcinoma, that is followed by the administration of a large activity of radioiodine in case of incomplete surgery, distant metastases or high risk factors. Papillary carcinomas of less than I cm in diameter, when unifocal and intra-thyroid are treated with surgery only, and radioiodine is not indicated. Thyroxine treatment is given to all patients. The majority of patients are cured, as demonstrated by the work-up performed at I year (undetectable serum thyroglobulin following stimulation with recombinant human TSH and normal neck ultrasonography). Subsequent follow-up is yearly with serum Tg and TSH determinations that is maintained within the normal range. In the other patients, other tests may be indicated, star-Ling with the administration of a large activity of radioiodine. In these patients, serum TSH should be decreased to a low level. (c) 2007 Public par Elsevier Masson SAS.