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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.
660 S Barollo and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 163
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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.
662 S Barollo and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 163
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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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Received 28 June 2010
Accepted 20 July 2010
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