Download Anaplastic thyroid carcinoma: Failure of conventional therapy but

ORIGINAL ARTICLE
Anaplastic thyroid carcinoma: Failure of conventional therapy but hope of
targeted therapy
Paul Lennon, FRCS, ORL-HNS,1* Sandra Deady, PhD,2 Maire L. Healy, MRCPI,3 Mary Toner, FRCPath,4 John Kinsella, FRCS, ORL-HNS,1
Conrad I. Timon, FRCS, ORL-HNS,1 James P. O’Neill, FRCS, ORL-HNS5
1
Department of Otolaryngology, Head and Neck Surgery, St. James’s Hospital, Dublin, Ireland, 2National Cancer Registry – Ireland, Cork, Ireland, 3Department of Endocrinology,
St. James’s Hospital, Dublin, Ireland, 4Department of Histopathology, St. James’s Hospital, Dublin, Ireland, 5Department of Otolaryngology, Head and Neck Surgery, Royal College
of Surgeons in Ireland, Dublin, Ireland.
Accepted 13 June 2015
Published online 16 February 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24170
ABSTRACT: Background. Anaplastic thyroid cancer has a median
survival between 1.2 and 10 months. The purpose of our study was to
evaluate the outcomes of patients with anaplastic thyroid cancer in
Ireland.
Methods. We carried out a retrospective analysis of the Irish National
Cancer Database for patients with anaplastic thyroid cancer between
2000 and 2010.
Results. Of a total of 64 patients (40 women, 24 men), the median age
was 69 years, and 29.7% of the patients had distant metastases. The
overall median survival was 2.3 months and the 1, 2, and 5-year survival
was 12.5%, 6.25%, and 4.69%, respectively. On univariate analysis
INTRODUCTION
Anaplastic thyroid cancer (ATC) is a rare neoplasm with
a median survival between 1.21 and 10 months.2 ATC
accounts for as little as 0.9%3 to 1.6%4 of total thyroid
cancer cases, but may result in up to half of all thyroid
cancer mortality.5 Because of the rarity of ATC, coupled
with its aggressive clinical course and short prognosis,
there is a paucity of clinical trials on which to base management guidelines, therefore, observational studies
assume a greater importance.6 The American Thyroid
Association (ATA) published 65 recommendations on the
diagnosis and management of ATC and advocated that a
comprehensive multimodality management plan should be
rapidly formulated and implemented in those with favorable prognostic factors.7,8 The British Thyroid Association also recommends prompt management in cases of
localized disease that may be amenable to radical treatment options.6 The purpose of this study was to assess
the outcomes of patients diagnosed with ATC in a
homogenous population and to compare our results with
*Corresponding author: P. Lennon, Department of Otolaryngology, Head and
Neck Surgery, St. James’s Hospital, Dublin 8, Ireland. E-mail: paullennon81@
gmail.com
This work was presented as an abstract at the American Head and Neck Society (AHNS) meeting, Boston, Massachusetts, April 22–23, 2015.
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age, sex, metastases at diagnosis, and multimodality treatment were
statistically significant indicators of prognosis, and metastases at diagnosis remained statistically significant on multivariate analysis.
Conclusion. These results correlate with the American Thyroid Association (ATA) guidelines, in which, when possible, multimodality therapy
offers a survival advantage to a select group of patients. Novel therapies
C 2016 Wiley Periodicals,
may offer the greatest hope for these patients. V
Inc. Head Neck 38: E1122–E1129, 2016
KEY WORDS: anaplastic thyroid cancer, survival, database, targeted
therapies
the literature. We also reviewed the recent literature for
emerging treatments that may provide optimism for the
future.
MATERIALS AND METHODS
The National Cancer Registry of Ireland (NCRI) is a
publicly appointed body under the Health (Provision of
Information) Act 1997 that has collected and classified
information on all newly diagnosed cancer cases occurring in Ireland since 1994. The use of that data for
research is covered by the Statutory Instrument, which
established the NCRI Board in 1991. Completeness of
case registration is estimated to be at least 96% to 97%9
and all data are coded and reported according to internationally established protocols.10 All datasets were anonymized before analysis.
Patients who were diagnosed with ATC between January 1, 2000, and December 31, 2010, were included in
the analysis. Tumors that were diagnosed only at autopsy
or by death certificate were excluded from the survival
analyses. Patient’s age, sex, management, and current status were all noted. Ideally, patients would be classified
into stages according to the American Joint Committee
on Cancer staging manual (seventh edition)11 as either
stage IVa (T4a, any N, or M0), stage IVb (T4b [tumor
invades prevertebral fascia or encases carotid artery or
mediastinal vessels], any N, or M0), or stage IVc (any T,
FAILURE
any N, or M1). However, information to differentiate T4a
from T4b was not available, and therefore patients were
classified into those with or without distant metastases on
presentation.
Data were compiled with Microsoft Excel (Microsoft,
Redmond, WA) and analyzed using Stata 13 software.12
For the univariate survival analysis, the log-rank test was
used to compare the Kaplan–Meier events. For the multivariate survival analysis, a Cox proportional hazards
model was developed for all predictor variables that were
identified as significant in the univariate analysis. It was
assumed that the observed differences were statistically
significant if the probability of chance occurrence was
<0.05.
In order to complete a comprehensive review, we
examined the English language literature for a period of
40 years (1975–2014); we included articles that published
survival data on ATC with at least 20 patients. Randomized controlled trials, cancer database studies, and prospective and retrospective reviews were all included. Data
obtained during this search were compared to this study’s
findings.
RESULTS
A total of 65 patients were diagnosed with ATC over
the time period. Over the 11-year period, this gives us an
incidence of 0.14 in 100,000 of the mean Irish population.13 A single patient was excluded from further analysis as he was diagnosed at postmortem. Nine patients
(14.1%) were diagnosed by fine-needle aspiration (FNA),
whereas the remaining 55 patients (85.9%) had an open
biopsy and or surgery to allow histopathological diagnosis. Twenty-four patients (37.5%) were men and 40 were
women (62.5%). A median age of 72 years (mean, 69.8;
range, 47–93 years) was found among this cohort of
patients. Nineteen patients (29.7%) had distant metastases
diagnosed at presentation. The majority14 of these
occurred in the lungs. Other sites of distant metastases
included the brain, liver, abdominal lymph nodes, adrenal
glands, and skin. Twenty-six patients (40.6%) had
attempted surgical resection, either partial or total thyroidectomy, with 7 patients (10.6%) undergoing both thyroidectomy and neck dissection. Thirty-eight patients
(59.4%) were treated with radiotherapy. Fifteen patients
(23.4%) had treatment with combined surgery and radiotherapy. Eleven patients (17.1%) had attempted resection
with no radiotherapy, whereas 23 patients (35.9%) had
radiotherapy without an attempted resection. Seventeen
patients received chemotherapy, 6 in conjunction with
radiotherapy, 8 in combination with surgery and radiotherapy, and 3 as a single modality treatment. Twelve
patients received supportive care only (Table 1).
The overall mortality was 76.56% at 6 months and
87.5% at 12 months, with a mean survival of 6.68 months
and a median survival of 2.3 months (Figure 1A). No
patient with known distant metastases at diagnosis survived for more than 6 months and just 26.3% of these
patients were alive at 3 months. This compared to 48.9%
of patients with no distant metastases being alive at 3
months. Patients with metastases at diagnosis had a significantly shorter median survival of 1.7 months versus
2.9 months for those staged M0 (log-rank test for sur-
OF CONVENTIONAL TREATMENT IN ANAPLASTIC THYROID CANCER
TABLE 1. Patient characteristics.
Median
survival,
mo
Characteristics
Age, y
Median
Mean
Range
Sex, no. (%)
Female
Male
Smoking status, no. (%)
Current smoker
Ex-smoker
Nonsmoker
Follow-up time, mo
Mean
Median
Minimum, patient alive
Maximum, patient alive
Diagnosis, no. (%)
Autopsy, excluded
FNA
Histopathology
Distant metastases, no. (%)
M1
M0
Treatment, no. (%)
Palliative care
Chemotherapy alone
RT alone
Surgery alone
Surgery and RT
Chemotherapy and RT
Multimodality,
surgery/RT/chemotherapy
p value,
log-rank
72
69.5
47–93
.0476
40 (62.5)
24 (37.5)
2.0
3.2
13 (20.3)
9 (14.1)
21 (32.8)
2.1
5.7
2.6
.8581
6.67
2.3
26.8
71.7
.0981
1
9 (14.1)
55 (85.9)
2.1
2.6
19 (29.7)
45 (71.3)
1.7
3.2
12 (18.6)
3 (4.7)
17 (26.6)
11 (17.2)
7 (10.9)
6 (9.4)
8 (12.5)
0.56
1.1
2.6
2.9
2.0
3.7
6.3
.0064
.0000
Abbreviations: FNA, fine-needle aspiration; RT, radiotherapy.
vival, p 5 .0064). There was no significant difference in
the median survival between those diagnosed by FNA
and those diagnosed by histopathology, with a median
survival of 2.1 and 2.6 months, respectively (p 5 .0981).
Four patients survived longer than 2 years: 3 patients
were alive at the end of follow-up, and 2 of these have
lived for more than 5 years. On univariate analysis, specific age, age over 70 years (Figure 1B), sex (Figure 1C),
surgical resection (Figure 1D), radiotherapy (Figure 2A),
chemotherapy, distant metastases at diagnosis (Figure
2B), and those undergoing palliation (Figure 2C) were
found to be significant prognostic indicators. Smoking
status, those who only received radiotherapy, or only surgical treatment were not (Figure 2D) significant prognostic indicators. On multivariate analysis, distant metastases
at diagnosis, those receiving treatment modalities, and
those receiving palliation remained as independent prognostic factors (Table 2).
Our review of the literature revealed 50 studies1,2,4,15–56
that reported their finding on survival in ATC, for a total
of 7741 patients. A number of articles were excluded, as
they reported survival data only on a subset of their
patients,61–69 or included data on poorly differentiated thyroid carcinoma in their findings.70 The studies included
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FIGURE 1. (A) Overall survival, (B)
survival by age, (C) survival by sex,
and (D) survival by surgery.
38 retrospective case series, 6 prospective studies, and 6
studies on cancer databases. Sixteen countries were represented with the largest number of studies coming from the
United States.12 We found a weighted average age of 68.1
years (n 5 6648), 36.5% of 6646 patients were men, and
33.9% of 6461 patients had distant metastases at presentation. The average median survival of 5840 patients was
3.67 months, and the average 1, 2, and 5-year survival
were found to be 17.9% (n 5 3983), 9.7% (n 5 3323),
and 5.4% (n 5 2674), respectively.
FIGURE 2. (A) Survival by radiotherapy, (B) survival by distant metastases at diagnosis, (C) survival in
those undergoing palliation, and (D)
survival by treatment type.
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FAILURE
OF CONVENTIONAL TREATMENT IN ANAPLASTIC THYROID CANCER
TABLE 2. Univariate and multivariate Cox regression analysis.
Univariate analysis
Age specific
Age >70 y
Female sex
Smoking
Metastases at diagnosis
Surgically treated
RT
Chemotherapy
Only RT, no surgery
Only surgery, no RT
Palliation
Combined surgery/RT
Surgery/chemotherapy/RT
Multivariate analysis
HR
p value
95% CI
HR
p value
95% CI
1.037
1.707
1.717
1.084
2.216
0.510
0.425
0.55
0.982
0.987
5.793
0.351
0.381
.005*
.041*
.048*
.341
.008*
.012*
.001*
.049*
.947
.853
.000*
.004*
.028*
1.011–1.064
1.022–2.851
1.004–2.936
0.585–2.001
1.231–3.990
0.309–0.861
0.251–0.719
0.303–0.999
0.582–1.656
0.489–1.806
2.989–11.230
0.1736–0.710
0.162–0.899
1.020
.156
0.993–1.048
1.399
.238
0.801–2.443
2.470
0.745
0.709
0.573
.004*
.443
.429
.086
1.334–4.575
0.352–1.579
0.303–1.661
0.343–1.08
4.920
0.629
0.697
.000*
.181
.461*
2.410–10.048
0.319–1.241
0.267–1.817
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; RT, radiotherapy.
* Statistically significant.
DISCUSSION
ATC is a disease of the elderly. The average age was
69 years in our cohort. A weighted average of 46 studies
demonstrated a median age 68.1 years (range, 59–77
years; Table 3). A female predominance is wellrecognized in thyroid disease. We found that 63.7% of
our patients were women. A weighted average of 46 studies revealed that 63.5% (range, 39.2% to 86.7%) were
women (Table 3). This sex imbalance may stem from the
epidemiology of well-differentiated thyroid cancer, where
an even greater female predominance (74%) has been
reported,4 as the prevailing theory on the pathogeneses of
ATC is that of dedifferentiation from well-differentiated
thyroid cancer.7,71
Detailed staging was available from a number of
articles with an average of 16.5% of patients being staged
IVa (19 studies) and 42.4% were staged IVb (17 studies).
ATC is an aggressive disease and distant metastases at
diagnosis (or stage IVc) were present, on average, in
40.5% of patients from 42 studies; this is reported in the
literature (Table 3). In our study, 29.7% had distant
metastases. We found distant metastases at presentation to
be an independent poor prognostic indicator and the survival of any patient with distant metastases would bring
the diagnosis of ATC into question.
Thirty-eight of the 50 studies reported an overall
median survival. These ranged from 1.21 to 102 months.
A weighted average median survival of 3.6 months was
calculated for these 6018 patients. Five studies (391
patients) reported only the mean survival and the
weighted average of these was 6.5 months (Table 3). In
our cohort of patients, we found an overall median survival of 2.3 months, which, even by the dismal standards
of ATC, is somewhat disappointing. On the other hand,
we found a mean survival of 6.7 months. Median survival
is the preferred reporting method because of the high
number of deaths within the first 3 months and the few
long-term survivors that may skew the mean values. Oneyear survival was reported as 7.9% to 46.7% by 30
studies, a weighted average of 17.9% for 3983 patients.
Two-year survival is often deemed long-term survival for
ATC. This was reported in 33 articles with an average of
9.7% of 3323 patients surviving >2 years. Five-year survival was reported in 25 articles at an average of 5.4%
(2674 patients). Again the 1, 2, and 5-year survival rates
were somewhat poorer in our cohort at 12.5, 6.25, and
4.6%, respectively.
The presence of any long-term survivors raises the
question of diagnostic accuracy in ATC, with some suggesting that these patients may be misdiagnosed with
poorly differentiated thyroid carcinoma.72,73 A large database study from 1998, which reported 5-year survival
rates of 14%,74 was criticized for not differentiating
between anaplastic thyroid cancer and poorly differentiated thyroid carcinoma.72 Poorly differentiated thyroid
carcinomas are also rare and aggressive in comparison to
well-differentiated thyroid cancer.73 However, their
median survival has been reported at 3.7 years compared
to 3.1 months in ATC by the same institution.43 Other
possible misdiagnoses include lymphomas (thyroid lymphoma) mistakenly diagnosed as small cell anaplastic thyroid carcinomas.28 The first recommendation of the ATA
guidelines is that morphologic diagnosis, with appropriate
immunostaining as relevant, is mandatory to exclude
other less aggressive and treatable entities that can mimic
ATC.8 Some authors have commented that the cytomorphologic features of ATC are highly specific and easy to
recognize,75 and that more recent studies should not
encounter this problem, as immunohistochemical techniques have been routinely utilized for a number of decades.57 Improvements in histopathological methods leading
to more accurate differentiation between ATC, thyroid
lymphoma, and poorly differentiated thyroid carcinoma
may even account for an apparent decrease in the incidence of ATC.76 Histological and immunohistochemical
features of ATC and a number of potential differential
diagnoses are shown in Table 4. In particular, PAX-8 and
TTF-1 can be useful in distinguishing ATC invading the
upper airway from head and neck squamous cell carcinomas (SCCs).77 A number of authors also specifically
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LENNON ET AL.
TABLE 3. Literature review.
Author
Year
City/center
Type
No. of patients
Age, y
Male %
Mets %
Survival
1
1999
2004
1998
1978
1975
1984
1990
1991
1992
1995
1996
1997
1998
1999
1999
2000
2001
2001
2001
2002
2002
2005
2005
2004
2007
2007
2008
2009
2009
2009
2010
2010
2011
2011
2011
2011
2011
2012
2012
2012
2013
2014
2014
2014
2014
2014
2005
1991
1991
2005
Hong Kong
Paris
Honolulu
MD Anderson
Stockholm
Florence
Ljublijana
PMH, Toronto
Glasgow
Albany, NY
Osaka
Albuquerque
Stockholm
Vienna
Helsinki
Padova
PMH, Toronto
Mayo Clinic
Tokyo
Mass General
Lund
Vancouver
Taipei
Toronto
Turin
Seoul
Hong Kong
London
Kobe, Japan
Rotterdam
MD Anderson
Clermont
Helsinki
Tokyo
Lyon
Okayama
Matsumoto
Stockholm
Tokyo
Penn State
Denver
Ann Arbor
Riyadh
Halle
MSKCC
Belgrade
San Francisco
MD Anderson
Paris
Seoul
Retro
PT
NCDB
Retro
Retro
Retro
Retro
PT
Retro
Retro
Retro
SEER
Retro
Retro
Retro
PT
Retro
Retro
Retro
Retro
PT
BCCA
Retro
Retro
Retro
Retro
Retro
Retro
Retro
Retro
Retro
Retro
Retro
Retro
Retro
PT
Retro
Retro
ATCCJ
Retro
Retro
NCDB
Retro
Retro
Retro
Retro
SEER
Retro
PT
Retro
28
30
893
84
79
70
89
32
91
21
37
251
81
120*
33
39
33
134
44
67
55
75
45
47
27
121
50
31
75
75
53
26
44
100
44
74
40
59
547
33
38
2742
120
40
83
150
516
108
20
47
7741
72
59
27.3
40
50
20
1.2 median
10 median
64
40
31.6
24.5
48.8
27.8
15.7
6.2 mean
2.5 median
4 mean
Lo
De Crevoisier2
Hundahl4
Aldinger14
Jereb15
Carcangiu16
Auersperg17
Wong18
Junor19
Tan20
Kobayashi21
Gilliland22
Nilsson23
Passler24
Voutilainen25
Busnardo26
Haigh27
McIver28
Sugitani29
Pierie30
Tennvall31
Goutsouliak32
Jiang33
Wang34
Brignardello35
Kim36
Yau37
Dandekar38
Ito39
Swaak40
Bhatia41
Roche42
Siironen43
Akaishi44
Derbel45
Orita46
Ito47
Segerhammar48
Sugitani49
Tashima50
Brown51
Haymart52
Aldehaim53
Dumke54
Mohebati55
Zivaljevic56
Kebebew57
Venkatesh58
Schlumberger59
Chang60
Total/median
66.5
70
65.1
68
69
71
69
66
69
69
67
66.2
73
76
74
61.9
68.8
69.8
64
72
69
66.9
68
66
72.1
74
68
65
67
74
77
68.7
68
64.5
70
63.3
67
60
64
71.3
61.3
61.5
62
67.8
26.7
47.6
24.3
24.1
35.8
21.2
28.2
39.4
40.3
36.7
32.8
30.9
32
31.1
53.2
33.3
33.9
32
45
13.3
25.3
45.3
27.0
27
20
41
44.6
35
28.8
38
47.6
55.3
38.1
60.8
35
49.3
36
34
45.3
45
40.4
36.5
1y%
2y%
5y%
46.7
23
13
3.6
26.7
18
9.5
1.2
7.9
1.1
0
6.7
14
7.1
1.2
0
1.1
8.1
11
14
8.1
6 median
5 median
4.5 median
24.3
45
45
48.5
56.4
63.6
46.3
52.3
49.3
30.9
16
77.8
17
55.6
23.9
18
51
16
40
47.2
34.6
55
58
45.4
43
37.5
55.9
41
47.4
25
52.9
24.1
32.9
43
25.9
45
46.8
40.5
4 median
4.3 mean
3.1 median
2.5 median
7.2 median
3.8 median
3 median
6 mean
3.5 median
3.45 median
3.1 median
5.4 median†
3.9 median
5.1 median
3.2 median
2.3 median
2.9 median
3 median
4 median
3.1 median
8 median
8.8 mean
4.9 median
3.3 median
3.6 median
4.7 median
3.4 median
1.7 median
5 median
6 median
4.2 median
3 median
7.2 mean
6 median
3.0 median
3.67
10
13
9.9
9.7
10.3
9.7
11.4
34.3
16.3
6.1
7.7
12.1
6
3
2.6
6
14.9
9.1
6.7
5
11.1
4.1
22.2
16
14
12
8
19
19.2
20
40
24
17.5
10.2
18.9
9.1
8
5.3
11.5
6.8
9.4
25
11
2.5
5.1
22.5
22
2.5
6.7
4
7.6
6.8
2.5
1.7
35.2
33
18.7
19.3
11.1
15
22.5
10.6
9.3
10
7.4
0
17.9
9.7
5.4
6.7
Abbreviations: Mets, metastases; Retro, retrospective study; PT, prospective trial; NCDB, National Cancer Database; PMH, Princess Margaret Hospital; SEER, Surveillance, Epidemiology, and End
Results; BCCA, British Columbia Cancer Agency; ATCCJ, Anaplastic Thyroid Carcinoma Research Consortium of Japan; MSKCC, Memorial Sloan–Kettering Cancer Center.
* All patients had surgery.
†
All patients received RT.
comment that they reviewed their histology to ensure
diagnostic accuracy.2,27,28,32,69 The median survival in
this group of studies was 3.6 months, almost identical to
the overall median found in our literature review. The
median 5-year survival reported by 3 of these studies was
6%, just slightly more than the overall median of our litE1126
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erature review. Our data was anonymized at source and
therefore we were not able to review individual patient’s
specimens. However, as our data are contemporary
(2000–2010), and from our outcomes, with poorer than
average median and 5-year survival (2.3 months and
4.6%), and the fact that the NCRI has a reporting system
FAILURE
OF CONVENTIONAL TREATMENT IN ANAPLASTIC THYROID CANCER
TABLE 4. Histological features by differential diagnosis.
Anaplastic
Growth pattern
Tumor cells
Mitoses per
10 high power fields
Tumor necrosis
Immunohistochemical
markers
PDTC
Diffuse, may be biphasic
Spindle cells, epithelioid
(may be squamoid),
giant cells
Usually very high
HN SCC
Solid/insular/trabecular
Small, uniform
Variable
Extensive necrosis; may
be so widespread that
the only viable tumor is
preserved around
blood vessels
Pancytokeratin 1 although
may be focal, p53 1 TG
often negative TTF-1 1/2
PAX-8 1
Epithelioid islands
Polygonal to spindled
in shape, keratinization
variable
Variable
Large cell lymphoma
Usually diffuse
Large uniform cells
Usually high
Single cell necrosis or
small well-defined
necrotic foci in the
center of cell nests
May have
focal necrosis
Variable
TG1, TTF-11,
pancytokeratin 1
PAX-8 1 variable p53
Pancytokeratin 1, p63 1
p53 1 TG, PAX-8, and
TTF-1 negative
Often diffuse
large B cell
lymphoma CD201,
CD451, pancytokeratin
TG, TTF-1, and
PAX-8 negative
Abbreviations: HN, head and neck; PDTC, poorly differentiated thyroid carcinoma; SCC, squamous cell carcinoma.
that separates thyroid cancers into multiple categories,
including ATC, poorly differentiated thyroid carcinoma,
SCC, and others,78 we can surmise that what we have
called ATC is ATC. A coexisting or preexisting welldifferentiated or poorly differentiated carcinoma is often
found on histology15 with the association between welldifferentiated thyroid carcinoma and ATC being reported
in 7% to 89% of cases.8 It has been suggested that survival is likely to be more prolonged in cases in which
anaplastic carcinoma comprises only a small component
of an otherwise well-differentiated papillary or follicular
thyroid carcinoma8; however, other studies have found
that coexisting well-differentiated thyroid cancer was not
associated with any survival difference.27 Unfortunately,
these data were unavailable to us, as was any information
on preexisting well-differentiated thyroid cancer or poorly
differentiated thyroid carcinoma.
The ATA8 and British Thyroid Association6 guidelines
are similar in their approach to the management of ATC.
On presentation, the airway should be assessed and
secured if necessary. A prompt diagnosis should be made
TABLE 5. Common mutations associated with anaplastic thyroid
carcinoma.
Pathway
PI3K-AKT
PI3K-AKT
PI3K-AKT
PI3K-AKT
PI3K-AKT
PI3K-AKT,
ERK1/2-MEK1/2
hTERT
Mutation
Approximate %
BRAFv600E
PIK3CA
PTEN
NRAS
HRAS
ALK
38
12–23
10–20
17
6
11
RASAL1
TP53
C228T
TXNIP
16
12–83
33–50
Abbreviation: hTERT, human telomerase reverse transcriptase.
by FNA cytology, which is highly sensitive for ATC if a
sufficient sample is acquired,79 but there may be insufficient material for immunohistochemical techniques or
core biopsy, and, thus, an open biopsy is often required.
Aggressive treatment with surgical resection followed by
adjuvant treatment, with both radiotherapy and chemotherapy, is recommended. Our research again demonstrates a survival benefit in the small number that can
undergo multimodality treatment. However, the majority
of patients will not be in this category, but many may still
be treated with radical or palliative radiotherapy.
Our review of the literature revealed that, in the majority of studies, almost half of the patients had distant
metastases at presentation (median, 45%; range, 16%39 to
78%33; Table 2). Conventional chemotherapy has not
been shown to improve survival, thus an alternative systemic treatment is required. The genetic changes underpinning most common cancers have been mapped out,80
but the mechanism of tumorigenesis, or dedifferentiation
from well-differentiated thyroid cancer is still poorly
understood and may involve multiple steps along a pathway.81 Mutations of BRAFV600E, PTEN, and PI3KCA
genes are common in ATC.82 These mutations disrupt the
PI3K-AKT pathway and result in altered gene expression,
whereas others, such as TP53, allow tumor growth
because of their inactivation (Table 5).83 The BRAFV600E
mutation is a point mutation that occurs in approximately
38% of ATCs.83,84 It is thought to be involved in the progression of papillary thyroid cancer to ATC by inducing
changes in the tumor microenvironment, thus promoting
tumor invasion and metastasis.83,85 The success of
Vemurafenib (Roche, Basel, Switzerland), a BRAF
enzyme inhibitor, in which the treatment of malignant
melanoma response rates of over 50% in patients with
metastatic disease have been reported,86 has led to a large
number of similar studies been undertaken on a variety of
cancers. Cases of remarkable response of metastatic ATC
to Vemurafenib have been reported.87 Unfortunately, thus
far, phase 2 trials of targeted treatments in ATC have
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LENNON ET AL.
been disappointing.6,88,89 There is, however, a report of a
dramatic, if unsustained, response to everolimus, an inhibitor of the mammalian target of rapamycin, in which a
patient with metastatic ATC had a near complete response
for 18 months.90 This patient had a tumor driven by a dominant oncogene, TSC2. Although these frequently have dramatic responses to targeted kinase inhibitors, the tumors
invariably become resistant to these agents. Future research
will be directed toward developing a comprehensive knowledge of how these tumors become resistant, which may
lead to the development of therapeutic strategies, including
targeted combinations, which are capable of producing
long-term responses in cancers such as ATC.90 Cases such
as the one above may only serve as a “proof of concept” at
this point in time, but mutation-directed therapy is already
the standard of care for BRAF mutant melanoma, epidermal growth factor receptor mutant lung cancer, and KRAS
mutant colorectal cancer, among others.80,91–93 Until such
treatments become available, understanding the behavior of
the disease is essential in identifying the limited group of
patients who may benefit from conventional multimodality
treatment.55
CONCLUSIONS
The majority of patients with ATC will survive at most
only a few months, with metastatic disease commonly
identified at presentation or shortly after initial diagnosis;
therefore, the challenge is to identify the small number of
patients who may gain substantially from aggressive treatment. However, survival has not changed over a period of
40 years and, therefore, we can say that there has been a
failure of conventional therapy. Recent reports suggest
that personalized therapeutic approaches based on the use
of targeted therapy may be the best hope to improve
treatments for patients with ATC.83
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