bmj open is committed to open peer review. as …...bmj open is committed to open peer review. as...
TRANSCRIPT
BMJ Open is committed to open peer review. As part of this commitment we make the peer review
history of every article we publish publicly available.
Whe a a ti le is pu lished e post the pee e ie e s’ o e ts a d the autho s’ espo ses online. We also post the versions of the paper that were used during peer review. These are the
versions that the peer review comments apply to.
The versions of the paper that follow are the versions that were submitted during the peer review
process. They are not the versions of record or the final published versions. They should not be cited
or distributed as the published version of this manuscript.
BMJ Open is an open access journal and the full, final, typeset and author-corrected version of
record of the manuscript is available on our site with no access controls, subscription charges or pay-
per-view fees (http://bmjopen.bmj.com).
If you ha e a y uestio s o BMJ Ope ’s ope pee e ie p o ess please e ail [email protected]
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
�
�
�
������������� ������������������������������������ ��������������������������������������
���� ��
�
�������� ���������
������ ������ ��������������������
��� ��������� ������!�
�����"��� ���#�����!�����!��� �$�"��������
%��������& ����'����!���� (��� )�%! ���*� �����+����������#�,���' ��#�-,"�.���#�� ��������)��!���� ��"��/�������"����)�(����*� �����+����������#�,���' ��#�-,"�.���#�� ��������)�
%������"��0 �������#��)�" ���*� �����+����������#�,���' ��#�-,"�.���#�� ��������)��!���� ��"��/������ 1 �)�2��# � �*� �����+����������#�,���' ��#�-,"�.���#�� ��������)��!���� ��"��/������0����)�����#*� �����+����������#�,���' ��#�-,"�.���#�� ��������)� �# ���/��&�0�)�"������!*�& 0�������,�������#�%!����,��� ����-,"������)��!���� ��"��/����"!��1����!)� �!���*�& 0�������,�������#�%!����,��� ����-,"������)��!���� ��"��/����3��������)�- 1�����*�&��#������! �/�,��� �����-,"������)��!���� ��"��/����
(���/ ����������)�3�����*�&��#������! �/�,��� �����-,"������)��!���� ��"��/����,�45�#)�6���*�,������#�7����6��1�! ���,��� �����-,"������)��!���� ��"��/����&����� )��!���#*�,������#�7����6��1�! ���,��� �����-,"������)��!���� ��"��/����"��� �� )�.��������*� �������0�����#�78�����-,"�.���#�� ��������)�%��# ��!���� ��"��/����9������)�.�� ��*� �������0�����#�78�����-,"�.���#�� ��������)�%��# ��!���� ��"��/����+��!)����8��#��*�(������!�,��� �����-,"������)��!���� ��"��/����
���!���1)��#� ��*�(������!�,��� �����-,"������)��!���� ��"��/��������)�":��!�*�(��:���!�,��� ����-,"�.���#�� ��������)��!���� ��"��0 ����"���� )�����*�(��:���!�,��� ����-,"�.���#�� ��������)��!���� ��"��0 ����& �)�7� �*� �����+����������#�,���' ��#�-,"�.���#�� ��������)��!���� ��"��/����
3��:��#���# ��� ������������ � ��)�(�� �����7� �� �������/���!��%������#�����/���!�)��# ��� ����# �/��� �)�"��� � 0 �����#����� ' � ��)��# ��� �������/����
��
�
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
�
Page 1 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
Diagnostic accuracy of 18 FDG PET-CT for evaluation of malignancy in anterior mediastinal
lesions – the DECiMaL study
C. Proli (1), P. De Sousa (1), S. Jordan (1), V. Anikin (1), A. Devaraj (1), S.M. Love (2), M.
Shackcloth (2), N. Kostoulas (3), K. Papagiannopoulos (3), Y. Haqzad (4), M. Loubani (4), F.
Sellitri (5), F. Granato (5), A. Bush (6), A. Marchbank (6), S. Iyer (7), M. Scarci (7), E. Lim (1) on
behalf of the UK Thoracic Surgery Research Collaborative
(1) Royal Brompton & Harefield NHS Foundation Trust, London, UK; (2) Liverpool Heart and
Chest Hospital NHS Foundation Trust; (3) Leeds Teaching Hospitals NHS Trust; (4) Hull and
East Yorkshire Hospitals NHS Trust, UK; (5) Royal Devon and Exeter NHS Foundation Trust,
UK (6) Plymouth Hospitals NHS Trust, UK, (7) Papworth Hospital NHS Foundation Trust, UK
Corresponding Author:
Mr Eric Lim
Academic Division of Thoracic Surgery
The Royal Brompton Hospital
Sydney Street
London SW3 6NP
United Kingdom
Tel: +44 (0)207 351 8591
Fax: +44 (0)207 351 8560
Email: [email protected]
Word count: 1554
Page 2 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
2
Abstract
Objectives: The aim of this study is to collate multi-institutional data to determine the value
by defining diagnostic performance of FDG-PET/CT for malignancy in patients undergoing
surgery with an anterior mediastinal mass in order to ascertain the clinical utility of PET/CT
to differentiate malignant from benign aetiologies in patients presenting with an anterior
mediastinal mass
Setting: DECiMaL Study is a multicentre, retrospective, collaborative cohort study in seven
UK surgical sites.
Participants: Between January 2002 and June 2015 a total of 134 patients were submitted
with a mean age (SD) of 55 years (16) of which 69 (51%) were men. We included all patients
undergoing surgery who presented with an anterior mediastinal mass and underwent
PET/CT. PET/CT was considered positive for any reported avidity as stated in the official
report and the reference was the resected specimen reported by histopathology using WHO
criteria.
Primary and secondary outcome measures: Sensitivity, specificity, positive and negative
predicted values of [18F]-FDG PET in determining malignant aetiology for an anterior
mediastinal mass.
Results: The sensitivity and specificity of PET/CT to correctly classify malignant disease were
83% (95% CI 74-89) and 58% (37-78). The positive and negative predictive values were 90%
(83-95) and 42% (26-61%).
Conclusions: The results of our study suggests reasonable sensitivity but no specificity
implying that a negative PET/CT is useful to rule out the diagnosis of malignant disease
whereas a positive result has no value in the discrimination between malignant and benign
disease of the anterior mediastinum.
Page 3 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
3
Strengths and limitations of this study
-� To our knowledge this is the largest study to date (essential to ensure narrow
confidence intervals for estimates) versing this subject
-� We were able to obtain an estimate of test performance relatively quickly through
an established research collaborative
-� The study did not include the entire spectrum of the anterior mediastinal masses, in
particular the small masses that were only kept under surveillance or discharged.
Funding statement
This research received no specific grant from any funding agency in the public, commercial
or not-for-profit sectors.
Competing interests statement
All authors declare no conflicts of interest. Outside this work, Eric Lim reports personal fees
from Abbott Molecular, personal fees from Glaxo Smith Kline, personal fees from Pfizer,
personal fees from Novartis, personal fees from Covidien, personal fees from Roche,
personal fees from Lily Oncology, personal fees from Boehringer Ingelheim, personal fees
from Medela, grants and personal fees from ScreenCell, personal fees from Ethicon, outside
the submitted work; and is the founder of Informative Genomics, a blood based molecular
diagnostic company in London.
Data sharing statement
Anonymised individual patient data that underlie the results reported in this article will be
available to researchers who provide a methodologically sound proposal. Proposals should
be directed to the corresponding author.
Page 4 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
4
Contributorship statement
CP, PDS and EL designed the work, acquired and analysed data and drafted the work; EL
interpreted the data; SJ, VA, AD, SML, MS, NK, KP, YH, ML, FS, FG, AB, AM, SI, MS acquired
and analysed data, revised the work critically; all authors approved the version to be
published and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
Page 5 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
5
Introduction
Abnormalities in the anterior mediastinum are often discovered as an incidental finding.
When detected, often present as a diagnostic challenge as few radiological features are
sufficiently discriminatory to guide clinicians on the best course of management. One of the
principal considerations is the probability of malignancy, as the perceived risk of cancer
guides the recommendation for invasive tissue sampling or excision. Although PET/CT is
widely used in this regard, little is known on the diagnostic and clinical test performance of
18-F fluorodeoxyglucose positron emission tomography [18F]-FDG PET-CT as no large
published series have been reported in the literature.
The aim of our study is to determine the diagnostic accuracy by defining the sensitivity and
specificity of 18
FDG PET-CT scans to identify malignancy in patients who have presented with
an anterior mediastinal mass.
Methods
We conducted a UK wide multi-centre retrospective study under the auspices of the UK
Thoracic Surgery Research Collaborative. Formal application was made to the Research
Ethics Committee (15/SS/0185) and the outcome was that the study did not require NHS
ethics review.
We included patients who have undergone surgery for an anterior mediastinal abnormality
and received 18
FDG PET-CT as part of their pre-operative work up. We excluded patients in
whom a formal histological diagnosis was not obtained or did not have a formal 18
FDG PET-
CT report.
Consecutive patients from January 2002 to June 2015 were identified from 7 participating
institutions of the UK Thoracic Surgery Research Collaborative through interrogation of
electronic records. As a pragmatic study, the index test of 18
FDG PET-CT was conducted by
Page 6 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
6
Consultant Radiologists and Nuclear Medicine Physicians according to UK Royal College of
Radiologists recommendations[1]. A positive test result was defined as a formally worded
“positive” uptake for the anterior mediastinal mass. The reference standard was the
histology of the resected anterior mediastinal mass as conducted by Pathologists in
accordance to the UK Royal College of Pathologists guidelines and reported according to
WHO criteria. Malignancy was defined in accordance to what would influence surgical
management including thymic carcinoma, thymoma, lymphoma, and any other malignant
tumours, and the following diseases were classified as non-malignant: thymic hyperplasia,
thymic cyst, and “no malignancy” as per histology report.
As the study was undertaken retrospectively, we know that the results of the histopathology
(reference test) would not be available for the readers of the 18
FDG PET-CT (index test) as
surgical resection only occurs after the pre-operative investigations. We also have no reason
to believe that the reporting pathologists would have access to the pre-operative 18
FDG PET-
CT reports.
Categorical data will be summarised as frequency (%), continuous data will be summarised
as mean (SD) or median (IQR) as appropriate to the data distribution. The primary outcome
is the calculated sensitivity, specificity, positive and negative predictive values with
corresponding 95% confidence intervals. We specified a-priori estimates around 50% would
be considered none, around 75% moderate and around 100% to have excellent clinical test
performance and favour interpretation on sensitivity and specificity (considered robust
estimates) rather than positive or negative predictive values (that can be altered by disease
prevalence).
Page 7 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
7
We estimate a sample size of 70 patients based on estimated sensitivity of 0.90 with a
lowest acceptable confidence interval of 0.75 using sample size calculations detailed by
Flahault et al [2]. Statistical analyses were conducted on Stata 13 (College Station, Texas,
USA).
Results
From January 2002 and June 2015, a total of 672 patients were included of which 521 were
excluded due to not having a PET-CT and 17 excluded due to not having radiology report,
leaving 134 patients for analysis (figure 1). The mean age (SD) was 55 (16) years of which 69
(51%) were men. The baseline and demographic characteristics of the cohort are
summarised in table 1.
Of the 134 patients 110 had a positive and 24 had a negative 18
FDG PET-CT report. A
malignant diagnosis was reported in 101 and a non-malignant diagnosis in 33 patients (table
2).
The sensitivity and specificity of PET-CT to correctly classify malignant disease for anterior
mediastinal masses were 83% (95% CI 74 to 89) and 58% (37 to 78) respectively and the
corresponding positive and negative predictive values were 90% (83 to 95) and 42% (26 to
61%) respectively (table 2).
Discussion
The results of our study, to our knowledge is the largest to date (essential to ensure narrow
confidence intervals for estimates) suggests that 18
FDG PET-CT is moderately useful to rule
out the diagnosis of malignancy when the test result is negative (good sensitivity), however
is not able to rule in the diagnosis of malignancy when the result is positive.
Page 8 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
8
Once an anterior mediastinal mass is diagnosed on imaging, downstream management is
predicated on the risk of malignancy to stratify patients for management, with high risk
patients assigned to invasive biopsy or surgery, intermediate risk patients assigned to
surveillance and low risk patients assigned to discharge. In a recent survey up to 50% of
centres reported the use of PET for this purpose.
In cohort series, it was reported that thymic tumours represent 50% of anterior mediastinal
lesions, followed by lymphomas (25%) and less commonly a mixture of other aetiologies
such as teratoma[3]. A definitive diagnosis can only be achieved after invasive biopsy[4] or
surgical resection. The reported specificity of fine needle aspiration is limited (57-
82%)[5][6][7] and the diagnostic value of computerised tomography (CT) and positron
emission tomography (PET) are not well known as few studies have been conducted and
with sample sizes are very small, typically less than 60[8]. Decisions regarding direct surgical
resection of anterior mediastinal masses can be challenging as the morphological features of
thymic lesions overlap and a definite differentiation between histologic subtypes of thymic
pathology by CT can be difficult[9][10]. Previous studies have shown promising results for
SUVmax values in the differentiation between malignant and benign lesions[11].
With moderately high sensitivity, the results from our study suggest that 18
FDG PET-CT has
moderate utility to ruling out malignancy in patients where the test is negative. There is still
an appreciable proportion (17%) test negative despite the presence of disease. From a
clinical perspective it remains to individual judgement whether this is an acceptable
proportion balances against the consequences of missing a potentially invasive tumour.
It is difficult to define the clinical utility when faced with an “abstract” figure for sensitivity of
83%, to help clinicians understand how this would fit in the clinical setting, it would be
pertinent to look at more developed guidelines on perceived clinical utility of 18
FDG PET-CT
for the solitary pulmonary nodule to assess cancer risk. The results from a 2008 meta-
Page 9 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
9
analysis [12] reported a sensitivity of 95% for PET to diagnose malignancy in pulmonary
nodules, considerably higher than 83% for anterior mediastinal mass. Despite higher levels
of sensitivity, there is still a reluctance for experts to discharge a patient with a negative
18FDG PET-CT, as in the 2013 ACCP guidelines [13] the authors recommended serial CT
monitoring when the 18
FDG PET-CT despite low clinical probability of lung cancer.
Currently, there are no established risk models for malignancy in anterior mediastinal
masses, and therefore numeric quantification of risk is not possible. In the circumstance
where the pre-test probability for malignancy is very low (e.g. if the CT appearance suggests
diffuse enlargement of the thymus only) then it would be reasonable to reassure the patient
(a negative 18
FDG PET-CT would not alter clinical management). If the pre-test probability is
very high (e.g. a large lobulated mass in anterior mediastinum) it would be reasonable to
proceed to invasive biopsy or resection (a negative 18
FDG PET-CT would not reassure). In the
most difficult subgroup where the pre-test probability for malignancy is intermediate, given
than serial CT imaging is recommended for lung cancer (despite sensitivity of 95%) then it
would be reasonable to default to the time tested method of screening for growth by CT for
anterior mediastinal masses as well. If that is the case, then there is clearly no clinical utility
for 18
FDG PET-CT (a negative test does not prevent serial CTs and a positive test is not
reliable to rule in malignancy).
The limitations of our study, aside from that associated with retrospective conduct is that
we did not include the entire spectrum of the anterior mediastinal masses, in particular the
small masses that were only kept under surveillance or discharged. On the other hand, we
have included the larger lesions that are more worrying and in whom 18
FDG PET-CT is usually
requested. We were able to obtain an estimate of test performance relatively quickly
through an established research collaborative as prospective conduct of a validation study is
likely to require significant funding, more centres and time as anterior mediastinal lesions
Page 10 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
10
are not common. Certainly we would welcome and encourage international efforts to
address this important issue, ideally with reference of clinical and cost effectiveness.
Conclusions
18FDG PET-CT is moderately useful to rule out the diagnosis of malignancy when the test
result is negative (good sensitivity), however is not able to rule in the diagnosis of
malignancy when the result is positive (poor specificity). At the existing levels of sensitivity a
negative test is insufficient to reassure and obviate the need for serial CT surveillance of
indeterminate masses in the anterior mediastinum. Therefore, we conclude that 18
FDG PET-
CT does not have a role in routine clinical practice to assess the malignant potential of an
anterior mediastinal mass.
Page 11 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
11
Figure 1 – Flow diagram (STARD)
Page 12 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
12
Table 1 - Demographic characteristics of the cohort and diagnosis classification as per
histology report
(n=134)
Mean age (SD) 55 (16)
Male, n (%) 69 (51)
Histology
Benign, n (%) 33 (25)
Thymic hyperplasia 10 (8)
Thymic cyst 8 (6)
No malignancy 15 (11)
Malignant, n (%) 101 (75)
Thymoma 55 (41)
Other malignant tumours 38 (28)
Thymic carcinoma 8 (6)
Page 13 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
13
Table 2 – Diagnostic test performance for PET-CT evaluation of malignancy in an anterior
mediastinal mass
18
FDG PET-CT positive 18
FDG PET-CT negative
Benign histology 19 14
Malignant histology 91 10
Test performance (with 95% CI)
Sensitivity 82.7 74.3 to 89.3
Specificity 58.3 36.6 to 77.9
Positive predictive value 90.1 82.5 to 95.1
Negative predictive value 42.4 25.5 to 60.8
Page 14 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
14
References
1 The Royal College of Radiologists. The Royal College of Radiologists PET-CT in the UK.
2005.
http://www.bnms.org.uk/~bnms/images/stories/downloads/documents/rcr_petct_fi
nal.pdf
2 Flahault A, Cadilhac M, Thomas G. Sample size calculation should be performed for
design accuracy in diagnostic test studies. J Clin Epidemiol 2005;58:859–62.
doi:10.1016/j.jclinepi.2004.12.009
3 Liu Y. Characterization of thymic lesions with F-18 FDG PET-CT: an emphasis on
epithelial tumors. Nucl Med Commun 2011;32:554–62.
doi:10.1097/MNM.0b013e328345b984
4 Luzzi L, Campione A, Gorla A, et al. Role of fluorine-flurodeoxyglucose positron
emission tomography/computed tomography in preoperative assessment of anterior
mediastinal masses. Eur J Cardio-thoracic Surg 2009;36:475–9.
doi:10.1016/j.ejcts.2009.03.055
5 Assaad MW, Pantanowitz L, Otis CN. Diagnostic accuracy of image-guided
percutaneous fine needle aspiration biopsy of the mediastinum. Diagn Cytopathol
2007;35:705–9. doi:10.1002/dc.20738
6 Desai F, Shah M, Patel S, et al. Fine needle aspiration cytology of anterior mediastinal
masses. Indian J Pathol Microbiol;51:88–
90.http://www.ncbi.nlm.nih.gov/pubmed/18417872 (accessed 14 Nov 2016).
7 Powers CN, Silverman JF, Geisinger KR, et al. Fine-needle aspiration biopsy of the
mediastinum: A multi-institutional analysis. Am J Clin Pathol 1996;105:168–
Page 15 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
15
73.http://www.ncbi.nlm.nih.gov/pubmed/8607440 (accessed 14 Nov 2016).
8 Ahn JM, Lee KS, Goo JM, et al. Predicting the histology of anterior mediastinal
masses: comparison of chest radiography and CT. J Thorac imaging 1996;11:265–
71.http://www.ncbi.nlm.nih.gov/pubmed/8892196 (accessed 14 Nov 2016).
9 Treglia G, Sadeghi R, Giovanella L, et al. Is 18F-FDG PET useful in predicting the WHO
grade of malignancy in thymic epithelial tumors? A meta-analysis. Lung Cancer.
2014;86:5–13. doi:10.1016/j.lungcan.2014.08.008
10 Kaira K, Sunaga N, Ishizuka T, et al. The role of [18
F]fluorodeoxyglucose positron
emission tomography in thymic epithelial tumors. Cancer Imaging 2011;11:195–201.
doi:10.1102/1470-7330.2011.0028
11 Tatci E, Ozmen O, Dadali Y, et al. The role of FDG PET/CT in evaluation of mediastinal
masses and neurogenic tumors of chest wall. Int J Clin Exp Med 2015;8:11146–52.
12 Cronin P, Dwamena BA, Kelly AM, et al. Solitary pulmonary nodules: meta-analytic
comparison of cross-sectional imaging modalities for diagnosis of malignancy.
Radiology 2008;246:772–82. doi:10.1148/radiol.2463062148
13 Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary
nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed:
American college of chest physicians evidence-based clinical practice guidelines.
Chest 2013;143:e93S–120S. doi:10.1378/chest.12-2351
Page 16 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
Section & Topic No Item Reported on page #
TITLE OR ABSTRACT
1 Identification as a study of diagnostic accuracy using at least one measure of accuracy
(such as sensitivity, specificity, predictive values, or AUC)
1
ABSTRACT
2 Structured summary of study design, methods, results, and conclusions
(for specific guidance, see STARD for Abstracts)
2
INTRODUCTION
3 Scientific and clinical background, including the intended use and clinical role of the index test 5
4 Study objectives and hypotheses 5
METHODS
Study design 5 Whether data collection was planned before the index test and reference standard
were performed (prospective study) or after (retrospective study)
5
Participants 6 Eligibility criteria 5
7 On what basis potentially eligible participants were identified
(such as symptoms, results from previous tests, inclusion in registry)
5
8 Where and when potentially eligible participants were identified (setting, location and dates) 5
9 Whether participants formed a consecutive, random or convenience series 5
Test methods 10a Index test, in sufficient detail to allow replication 5
10b Reference standard, in sufficient detail to allow replication 6
11 Rationale for choosing the reference standard (if alternatives exist) 6
12a Definition of and rationale for test positivity cut-offs or result categories
of the index test, distinguishing pre-specified from exploratory
6
12b Definition of and rationale for test positivity cut-offs or result categories
of the reference standard, distinguishing pre-specified from exploratory
6
13a Whether clinical information and reference standard results were available
to the performers/readers of the index test
6
13b Whether clinical information and index test results were available
to the assessors of the reference standard
6
Analysis 14 Methods for estimating or comparing measures of diagnostic accuracy 6
15 How indeterminate index test or reference standard results were handled 6
16 How missing data on the index test and reference standard were handled 6
17 Any analyses of variability in diagnostic accuracy, distinguishing pre-specified from exploratory 6
18 Intended sample size and how it was determined 7
RESULTS
Participants 19 Flow of participants, using a diagram 7, figure 1
20 Baseline demographic and clinical characteristics of participants 7, table 1
21a Distribution of severity of disease in those with the target condition 7, table 2
21b Distribution of alternative diagnoses in those without the target condition 7, table 2
22 Time interval and any clinical interventions between index test and reference standard N/A
Test results 23 Cross tabulation of the index test results (or their distribution)
by the results of the reference standard
7
24 Estimates of diagnostic accuracy and their precision (such as 95% confidence intervals) 7, table 2
25 Any adverse events from performing the index test or the reference standard N/A
DISCUSSION
26 Study limitations, including sources of potential bias, statistical uncertainty, and generalisability 8
27 Implications for practice, including the intended use and clinical role of the index test 6-8
OTHER
INFORMATION
28 Registration number and name of registry N/A
29 Where the full study protocol can be accessed N/A
30 Sources of funding and other support; role of funders 3
Page 17 of 16
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
�
�
�
��������������� ��������������� �������������� ������������������������� ��������������� � ����
!�� �� ������ � ��������!����� ��"���������������������������� �� �����������������#������!�$�%�
������
�
�������� ���������
������ ������ �����������������������
��� ���� !��� �������"�
�����#��� ���$��!��"�����"��� �%�&�'������
(��������) ����*����"���� +��� ,�(" ���-���!���.����������$�/���* ��$�&/#�0���$�� ��� ����,� "���� ��#��1��!����#����,�+����-���!���.����������$�/���* ��$�&/#�0���$�� ��� ����,�(������#��' �������$��,�# ���-���!���.����������$�/���* ��$�&/#�0���$�� ��� ����,�
"���� ��#��1��!��� 2 �,�3��$ � �-���!���.����������$�/���* ��$�&/#�0���$�� ��� ����,� "���� ��#��1��!���'����,�����$-���!���.����������$�/���* ��$�&/#�0���$�� ��� ����,���$ ���1!�)�'�,�#������"-�) '�������/�������$�("����/��� ����&/#� ����,� "���� ��#��1��!�#"��2����",� �"���-�) '�������/�������$�("����/��� ����&/#� ����,� "���� ��#��1��!�4��������,�& 2�����-�)��$�� ���" �1�/��� �����&/#� ����,� "���� ��#��1��!�+���1 ����������,�4�����-�)��$�� ���" �1�/��� �����&/#� ����,� "���� ��#��1��!�
/�56�$,�7���-�/������$�8����7��2�" ���/��� �����&/#� ����,� "���� ��#��1��!�)����� ,��"���$-�/������$�8����7��2�" ���/��� �����&/#� ����,� "���� ��#��1��!�#��� �� ,�0��������-���!�����'�����$�89�����&/#�0���$�� ��� ����,�(��$ ��"���� ��#��1��!�:������,�0�� ��-���!�����'�����$�89�����&/#�0���$�� ��� ����,�(��$ ��"���� ��#��1��!�.��",����9��$��-�+�!����"�/��� �����&/#� ����,� "���� ��#��1��!����"���2,��$� ��-�+�!����"�/��� �����&/#� ����,� "���� ��#��1��!��!��,�#;��"�-�+��;���"�/��� ����&/#�0���$�� ��� ����,� "���� ��#��' ����#���� ,�����-�+��;���"�/��� ����&/#�0���$�� ��� ����,� "���� ��#��' ����
) �,�8� �-���!���.����������$�/���* ��$�&/#�0���$�� ��� ����,� "���� ��#��1��!�
<�=+� ���!�#�������/��$ �1<>�=�
?�����1!�
#����$��!�#�������/��$ �1� #��1��!�
4�!;��$�� �$ ��� ������������ � ��,�+�� �����8� �� ��� ���1���"!�(������$�
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
���1���"!,��$ ��� ����$ �1��� �,�#��� � ' �!���$����� * � �!,��$ ��� �������1��!�
��
�
�
Page 1 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
A diagnostic cohort study on the accuracy of 18-Fluoro-Deoxy-Glucose (18FDG)Positron
Emission Tomography- Computer Tomography (PET-CT) for evaluation of malignancy in
anterior mediastinal lesions – the DECiMaL study
C. Proli (1), P. De Sousa (1), S. Jordan (1), V. Anikin (1), A. Devaraj (1), S.M. Love (2), M.
Shackcloth (2), N. Kostoulas (3), K. Papagiannopoulos (3), Y. Haqzad (4), M. Loubani (4), F.
Sellitri (5), F. Granato (5), A. Bush (6), A. Marchbank (6), S. Iyer (7), M. Scarci (7), E. Lim (1) on
behalf of the UK Thoracic Surgery Research Collaborative
(1) Royal Brompton & Harefield NHS Foundation Trust, London, UK; (2) Liverpool Heart and
Chest Hospital NHS Foundation Trust; (3) Leeds Teaching Hospitals NHS Trust; (4) Hull and
East Yorkshire Hospitals NHS Trust, UK; (5) Royal Devon and Exeter NHS Foundation Trust,
UK (6) Plymouth Hospitals NHS Trust, UK, (7) Papworth Hospital NHS Foundation Trust, UK
Corresponding Author:
Mr Eric Lim
Academic Division of Thoracic Surgery
The Royal Brompton Hospital
Sydney Street
London SW3 6NP
United Kingdom
Tel: +44 (0)207 351 8591
Fax: +44 (0)207 351 8560
Email: [email protected]
Word count: 1554
Page 2 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
2
Abstract
Objectives: The aim of this study is to collate multi-institutional data to determine the value
by defining diagnostic performance of FDG-PET/CT for malignancy in patients undergoing
surgery with an anterior mediastinal mass in order to ascertain the clinical utility of PET/CT
to differentiate malignant from benign aetiologies in patients presenting with an anterior
mediastinal mass
Setting: DECiMaL Study is a multicentre, retrospective, collaborative cohort study in seven
UK surgical sites.
Participants: Between January 2002 and June 2015 a total of 134 patients were submitted
with a mean age (SD) of 55 years (16) of which 69 (51%) were men. We included all patients
undergoing surgery who presented with an anterior mediastinal mass and underwent
PET/CT. PET/CT was considered positive for any reported avidity as stated in the official
report and the reference was the resected specimen reported by histopathology using WHO
criteria.
Primary and secondary outcome measures: Sensitivity, specificity, positive and negative
predicted values of [18F]-FDG PET in determining malignant aetiology for an anterior
mediastinal mass.
Results: The sensitivity and specificity of PET/CT to correctly classify malignant disease were
83% (95% CI 74-89) and 58% (37-78). The positive and negative predictive values were 90%
(83-95) and 42% (26-61%).
Conclusions: The results of our study suggests reasonable sensitivity but no specificity
implying that a negative PET/CT is useful to rule out the diagnosis of malignant disease
whereas a positive result has no value in the discrimination between malignant and benign
disease of the anterior mediastinum.
Page 3 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
3
Strengths and limitations of this study
-� To our knowledge this is the largest study to date (essential to ensure narrow
confidence intervals for estimates) versing this subject
-� We were able to obtain an estimate of test performance relatively quickly through
an established research collaborative
-� The study did not include the entire spectrum of the anterior mediastinal masses, in
particular the small masses that were only kept under surveillance or discharged.
Funding statement
This research received no specific grant from any funding agency in the public, commercial
or not-for-profit sectors.
Competing interests statement
All authors declare no conflicts of interest. Outside this work, Eric Lim reports personal fees
from Abbott Molecular, personal fees from Glaxo Smith Kline, personal fees from Pfizer,
personal fees from Novartis, personal fees from Covidien, personal fees from Roche,
personal fees from Lily Oncology, personal fees from Boehringer Ingelheim, personal fees
from Medela, grants and personal fees from ScreenCell, personal fees from Ethicon, outside
the submitted work; and is the founder of Informative Genomics, a blood based molecular
diagnostic company in London.
Data sharing statement
Anonymised individual patient data that underlie the results reported in this article will be
available to researchers who provide a methodologically sound proposal. Proposals should
be directed to the corresponding author.
Page 4 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
4
Contributorship statement
CP, PDS and EL designed the work, acquired and analysed data and drafted the work; EL
interpreted the data; SJ, VA, AD, SML, MS, NK, KP, YH, ML, FS, FG, AB, AM, SI, MS acquired
and analysed data, revised the work critically; all authors approved the version to be
published and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
Page 5 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
5
Introduction
Abnormalities in the anterior mediastinum are often discovered as an incidental finding.
When detected, often present as a diagnostic challenge as few radiological features are
sufficiently discriminatory to guide clinicians on the best course of management. One of the
principal considerations is the probability of malignancy, as the perceived risk of cancer
guides the recommendation for invasive tissue sampling or excision. Although PET/CT is
widely used in this regard, little is known on the diagnostic and clinical test performance of
18-F fluorodeoxyglucose positron emission tomography [18F]-FDG PET-CT as no large
published series have been reported in the literature.
The aim of our study was to determine the diagnostic accuracy by defining the sensitivity
and specificity of 18
FDG PET-CT scans to identify malignancy in patients who have presented
with an anterior mediastinal mass.
Methods
We conducted a UK wide multi-centre retrospective study under the auspices of the UK
Thoracic Surgery Research Collaborative. Formal application was made to the Research
Ethics Committee (15/SS/0185) and the outcome was that the study did not require NHS
ethics review.
We included patients who have undergone surgery for an anterior mediastinal abnormality
and received 18
FDG PET-CT as part of their pre-operative work up. We excluded patients in
whom a formal histological diagnosis was not obtained or did not have a formal 18
FDG PET-
CT report.
Consecutive patients from January 2002 to June 2015 were identified from 7 participating
institutions of the UK Thoracic Surgery Research Collaborative through interrogation of
electronic records. As a pragmatic study, the index test of 18
FDG PET-CT was conducted by
Page 6 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
6
Consultant Radiologists and Nuclear Medicine Physicians according to UK Royal College of
Radiologists recommendations[1]. A positive test result was defined as a formally worded
“positive” uptake for the anterior mediastinal mass. The reference standard was the
histology of the resected anterior mediastinal mass as conducted by Pathologists in
accordance to the UK Royal College of Pathologists guidelines and reported according to
WHO criteria. Malignancy was defined in accordance to what would influence surgical
management including thymic carcinoma, thymoma, lymphoma, and any other malignant
tumours, and the following diseases were classified as non-malignant: thymic hyperplasia,
thymic cyst, and “no malignancy” as per histology report.
As the study was undertaken retrospectively, we assumed the results of the histopathology
(reference test) would not be available for the readers of the 18
FDG PET-CT (index test) as
surgical resection only occurs after the pre-operative investigations. We also have no reason
to believe that the reporting pathologists would have access to the pre-operative 18
FDG PET-
CT reports (although they may have had access to this inform on the request forms).
Categorical data were summarised as frequency (%), continuous data summarised as mean
(SD) or median (IQR) as appropriate to the data distribution. The primary outcome is the
calculated sensitivity, specificity, positive and negative predictive values with corresponding
95% confidence intervals. We specified a-priori estimates around 50% would be considered
none, around 75% moderate and around 100% to have excellent clinical test performance
and favour interpretation on sensitivity and specificity (considered robust estimates) rather
than positive or negative predictive values (that can be altered by disease prevalence). We
also conducted secondary analysis of receiver operator characteristics curve analyses to
explore the influence of SUVmax (where available) on the diagnosis of malignancy.
We estimated a sample size of 70 patients based on estimated sensitivity of 0.90 with a
lowest acceptable confidence interval of 0.75 using sample size calculations detailed by
Page 7 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
7
Flahault et al [2]. Statistical analyses were conducted on Stata 13 (College Station, Texas,
USA).
Results
From January 2002 and June 2015, a total of 672 patients were included of which 521 were
excluded due to not having a PET-CT and 17 excluded due to not having radiology report,
leaving 134 patients for analysis (figure 1). The mean age (SD) was 55 (16) years (with a
range of 18 to 88 years) of which 69 (51%) were men. The baseline and demographic
characteristics of the cohort are summarised in table 1.
Of the 134 patients 110 had a positive and 24 had a negative 18
FDG PET-CT report. A
malignant diagnosis was reported in 101 and a non-malignant diagnosis in 33 patients (table
2).
The sensitivity and specificity of PET-CT to correctly classify malignant disease for anterior
mediastinal masses were 83% (95% CI 74 to 89) and 58% (37 to 78) respectively and the
corresponding positive and negative predictive values were 90% (83 to 95) and 42% (26 to
61%) respectively (table 2).
Data from SUVmax were available in 96 patients and the calculated ROC area under the
curve was 0.63 (95% CI 0.45 to 0.79) (Figure 2).
Discussion
The results of our study, to our knowledge is the largest to date (essential to ensure narrow
confidence intervals for estimates) suggests that 18
FDG PET-CT is moderately useful to rule
out the diagnosis of malignancy when the test result is negative (good sensitivity), however
is not able to rule in the diagnosis of malignancy when the result is positive.
Page 8 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
8
Once an anterior mediastinal mass is diagnosed on imaging, downstream management is
predicated on the risk of malignancy to stratify patients for management, with high risk
patients assigned to invasive biopsy or surgery, intermediate risk patients assigned to
surveillance and low risk patients assigned to discharge. In a recent survey up to 50% of
centres reported the use of PET for this purpose.
In published cohort series, it was reported that thymic tumours represent 50% of anterior
mediastinal lesions, followed by lymphomas (25%) and less commonly a mixture of other
aetiologies such as teratoma[3]. A definitive diagnosis can only be achieved after invasive
biopsy[4] or surgical resection. The reported specificity of fine needle aspiration is limited
(57-82%)[5][6][7] and the diagnostic value of computerised tomography (CT) and positron
emission tomography (PET) are not well known as few studies have been conducted and
with sample sizes are very small, typically less than 60[8]. Decisions regarding direct surgical
resection of anterior mediastinal masses can be challenging as the morphological features of
thymic lesions overlap and a definite differentiation between histologic subtypes of thymic
pathology by CT can be difficult[9][10]. Previous studies have shown promising results for
SUVmax values in the differentiation between malignant and benign lesions[11]. However,
the results of our analyses suggested that discrimination by SUVmax was relatively poor.
With moderately high sensitivity, the results from our study suggest that 18
FDG PET-CT has
moderate utility to ruling out malignancy in patients where the test is negative. There is still
an appreciable proportion (17%) test negative despite the presence of disease. From a
clinical perspective it remains to individual judgement whether this is an acceptable
proportion balances against the consequences of missing a potentially invasive tumour.
It is difficult to define the clinical utility when faced with an “abstract” figure for sensitivity of
83%, to help clinicians understand how this would fit in the clinical setting, it would be
pertinent to look at more developed guidelines on perceived clinical utility of 18
FDG PET-CT
Page 9 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
9
for the solitary pulmonary nodule to assess cancer risk. The results from a 2008 meta-
analysis [12] reported a sensitivity of 95% for PET to diagnose malignancy in pulmonary
nodules, considerably higher than 83% for anterior mediastinal mass. Despite higher levels
of sensitivity, there is still a reluctance for experts to discharge a patient with a negative
18FDG PET-CT, as in the 2013 ACCP guidelines [13] the authors recommended serial CT
monitoring when the 18
FDG PET-CT is negative despite low clinical probability of lung cancer.
Currently, there are no established risk models for malignancy in anterior mediastinal
masses, and therefore numeric quantification of risk is not possible. In the circumstance
where the pre-test probability for malignancy is very low (e.g. if the CT appearance suggests
diffuse enlargement of the thymus only) then it would be reasonable to reassure the patient
(a negative 18
FDG PET-CT would not alter clinical management). If the pre-test probability is
very high (e.g. a large lobulated mass in anterior mediastinum) it would be reasonable to
proceed to invasive biopsy or resection (a negative 18
FDG PET-CT would not reassure). In the
most difficult subgroup where the pre-test probability for malignancy is intermediate, given
that serial CT imaging is recommended for lung cancer (despite sensitivity of 95%) then it
would be reasonable to default to the time tested method of screening for growth by CT for
anterior mediastinal masses as well. If that is the case, then there is clearly no clinical utility
for 18
FDG PET-CT (a negative test does not prevent serial CTs and a positive test is not
reliable to rule in malignancy).
The limitations of our study, aside from that associated with retrospective conduct is that
we did not include the entire spectrum of the anterior mediastinal masses, in particular the
small masses that were only kept under surveillance or discharged. On the other hand, we
have included the larger lesions that are more worrying and in whom 18
FDG PET-CT is usually
requested. We were able to obtain an estimate of test performance relatively quickly
through an established research collaborative as prospective conduct of a validation study is
Page 10 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
10
likely to require significant funding, more centres and time as anterior mediastinal lesions
are not common. Certainly we would welcome and encourage international efforts to
address this important issue, ideally with reference of clinical and cost effectiveness.
Conclusions
18FDG PET-CT is moderately useful to rule out the diagnosis of malignancy when the test
result is negative (good sensitivity), however is not able to rule in the diagnosis of
malignancy when the result is positive (poor specificity). At the existing levels of sensitivity a
negative test is insufficient to reassure and obviate the need for serial CT surveillance of
indeterminate masses in the anterior mediastinum. Therefore, we conclude that 18
FDG PET-
CT does not have a role in routine clinical practice to assess the malignant potential of an
anterior mediastinal mass.
Page 11 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
11
Table 1 - Demographic characteristics of the cohort and diagnosis classification as per
histology report
(n=134)
Mean age (SD) 55 (16)
Male, n (%) 69 (51)
Histology
Benign, n (%) 33 (25)
Thymic hyperplasia 10 (8)
Thymic cyst 8 (6)
No malignancy 15 (11)
Malignant, n (%) 101 (75)
Thymoma 55 (41)
Other malignant tumours 38 (28)
Thymic carcinoma 8 (6)
Page 12 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
12
Table 2 – Diagnostic test performance for PET-CT evaluation of malignancy in an anterior
mediastinal mass
18
FDG PET-CT positive 18
FDG PET-CT negative
Benign histology 19 14
Malignant histology 91 10
Test performance (with 95% CI)
Sensitivity 82.7 74.3 to 89.3
Specificity 58.3 36.6 to 77.9
Positive predictive value 90.1 82.5 to 95.1
Negative predictive value 42.4 25.5 to 60.8
Page 13 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
13
Figure 1 – Flow diagram (STARD)
Figure 2 – ROC plot of SUVmax versus malignancy
Page 14 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
14
References
1 The Royal College of Radiologists. The Royal College of Radiologists PET-CT in the UK.
2005.
http://www.bnms.org.uk/~bnms/images/stories/downloads/documents/rcr_petct_fi
nal.pdf
2 Flahault A, Cadilhac M, Thomas G. Sample size calculation should be performed for
design accuracy in diagnostic test studies. J Clin Epidemiol 2005;58:859–62.
doi:10.1016/j.jclinepi.2004.12.009
3 Liu Y. Characterization of thymic lesions with F-18 FDG PET-CT: an emphasis on
epithelial tumors. Nucl Med Commun 2011;32:554–62.
doi:10.1097/MNM.0b013e328345b984
4 Luzzi L, Campione A, Gorla A, et al. Role of fluorine-flurodeoxyglucose positron
emission tomography/computed tomography in preoperative assessment of anterior
mediastinal masses. Eur J Cardio-thoracic Surg 2009;36:475–9.
doi:10.1016/j.ejcts.2009.03.055
5 Assaad MW, Pantanowitz L, Otis CN. Diagnostic accuracy of image-guided
percutaneous fine needle aspiration biopsy of the mediastinum. Diagn Cytopathol
2007;35:705–9. doi:10.1002/dc.20738
6 Desai F, Shah M, Patel S, et al. Fine needle aspiration cytology of anterior mediastinal
masses. Indian J Pathol Microbiol;51:88–
90.http://www.ncbi.nlm.nih.gov/pubmed/18417872 (accessed 14 Nov 2016).
7 Powers CN, Silverman JF, Geisinger KR, et al. Fine-needle aspiration biopsy of the
Page 15 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
15
mediastinum: A multi-institutional analysis. Am J Clin Pathol 1996;105:168–
73.http://www.ncbi.nlm.nih.gov/pubmed/8607440 (accessed 14 Nov 2016).
8 Ahn JM, Lee KS, Goo JM, et al. Predicting the histology of anterior mediastinal
masses: comparison of chest radiography and CT. J Thorac imaging 1996;11:265–
71.http://www.ncbi.nlm.nih.gov/pubmed/8892196 (accessed 14 Nov 2016).
9 Treglia G, Sadeghi R, Giovanella L, et al. Is 18F-FDG PET useful in predicting the WHO
grade of malignancy in thymic epithelial tumors? A meta-analysis. Lung Cancer.
2014;86:5–13. doi:10.1016/j.lungcan.2014.08.008
10 Kaira K, Sunaga N, Ishizuka T, et al. The role of [18
F]fluorodeoxyglucose positron
emission tomography in thymic epithelial tumors. Cancer Imaging 2011;11:195–201.
doi:10.1102/1470-7330.2011.0028
11 Tatci E, Ozmen O, Dadali Y, et al. The role of FDG PET/CT in evaluation of mediastinal
masses and neurogenic tumors of chest wall. Int J Clin Exp Med 2015;8:11146–52.
12 Cronin P, Dwamena BA, Kelly AM, et al. Solitary pulmonary nodules: meta-analytic
comparison of cross-sectional imaging modalities for diagnosis of malignancy.
Radiology 2008;246:772–82. doi:10.1148/radiol.2463062148
13 Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary
nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed:
American college of chest physicians evidence-based clinical practice guidelines.
Chest 2013;143:e93S–120S. doi:10.1378/chest.12-2351
Page 16 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
��
�
�
�������������� ����������������
�
�������������������������
�
�
Page 17 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
��
�
�
������������� ����������������������������������
���������� !�����!���"#$%��
�
�
Page 18 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
Section & Topic No Item Reported on page #
TITLE OR ABSTRACT
1 Identification as a study of diagnostic accuracy using at least one measure of accuracy
(such as sensitivity, specificity, predictive values, or AUC)
1
ABSTRACT
2 Structured summary of study design, methods, results, and conclusions
(for specific guidance, see STARD for Abstracts)
2
INTRODUCTION
3 Scientific and clinical background, including the intended use and clinical role of the index test 5
4 Study objectives and hypotheses 5
METHODS
Study design 5 Whether data collection was planned before the index test and reference standard
were performed (prospective study) or after (retrospective study)
5
Participants 6 Eligibility criteria 5
7 On what basis potentially eligible participants were identified
(such as symptoms, results from previous tests, inclusion in registry)
5
8 Where and when potentially eligible participants were identified (setting, location and dates) 5
9 Whether participants formed a consecutive, random or convenience series 5
Test methods 10a Index test, in sufficient detail to allow replication 5
10b Reference standard, in sufficient detail to allow replication 6
11 Rationale for choosing the reference standard (if alternatives exist) 6
12a Definition of and rationale for test positivity cut-offs or result categories
of the index test, distinguishing pre-specified from exploratory
6
12b Definition of and rationale for test positivity cut-offs or result categories
of the reference standard, distinguishing pre-specified from exploratory
6
13a Whether clinical information and reference standard results were available
to the performers/readers of the index test
6
13b Whether clinical information and index test results were available
to the assessors of the reference standard
6
Analysis 14 Methods for estimating or comparing measures of diagnostic accuracy 6
15 How indeterminate index test or reference standard results were handled 6
16 How missing data on the index test and reference standard were handled 6
17 Any analyses of variability in diagnostic accuracy, distinguishing pre-specified from exploratory 6
18 Intended sample size and how it was determined 7
RESULTS
Participants 19 Flow of participants, using a diagram 7, figure 1
20 Baseline demographic and clinical characteristics of participants 7, table 1
21a Distribution of severity of disease in those with the target condition 7, table 2
21b Distribution of alternative diagnoses in those without the target condition 7, table 2
22 Time interval and any clinical interventions between index test and reference standard N/A
Test results 23 Cross tabulation of the index test results (or their distribution)
by the results of the reference standard
7
24 Estimates of diagnostic accuracy and their precision (such as 95% confidence intervals) 7, table 2
25 Any adverse events from performing the index test or the reference standard N/A
DISCUSSION
26 Study limitations, including sources of potential bias, statistical uncertainty, and generalisability 8
27 Implications for practice, including the intended use and clinical role of the index test 6-8
OTHER
INFORMATION
28 Registration number and name of registry N/A
29 Where the full study protocol can be accessed N/A
30 Sources of funding and other support; role of funders 3
Page 19 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
�
�
�
��������������� ��������������� �������������� ������������������������� ��������������� � ����
!�� �� ������ � ��������!����� ��"���������������������������� �� �����������������#������!�$�%�
������
�
�������� ���������
������ ������ �����������������������
��� ���� !��� �������"�
�����#��� ���$��!��"�����"��� ������������
%��������& ����'����"���� (��� )�%" ���*���!���+����������$�,���' ��$�-,#�.���$�� ��� ����)� "���� ��#��/��!����#����)�(����*���!���+����������$�,���' ��$�-,#�.���$�� ��� ����)�%������#��0 �������$��)�# ���*���!���+����������$�,���' ��$�-,#�.���$�� ��� ����)�
"���� ��#��/��!��� 1 �)�2��$ � �*���!���+����������$�,���' ��$�-,#�.���$�� ��� ����)� "���� ��#��/��!���0����)�����$*���!���+����������$�,���' ��$�-,#�.���$�� ��� ����)���$ ���/!�&�0�)�#������"*�& 0�������,�������$�%"����,��� ����-,#� ����)� "���� ��#��/��!�#"��1����")� �"���*�& 0�������,�������$�%"����,��� ����-,#� ����)� "���� ��#��/��!�3��������)�- 1�����*�&��$�� ���" �/�,��� �����-,#� ����)� "���� ��#��/��!�(���/ ����������)�3�����*�&��$�� ���" �/�,��� �����-,#� ����)� "���� ��#��/��!�
,�45�$)�6���*�,������$�7����6��1�" ���,��� �����-,#� ����)� "���� ��#��/��!�&����� )��"���$*�,������$�7����6��1�" ���,��� �����-,#� ����)� "���� ��#��/��!�#��� �� )�.��������*���!�����0�����$�78�����-,#�.���$�� ��� ����)�%��$ ��"���� ��#��/��!�9������)�.�� ��*���!�����0�����$�78�����-,#�.���$�� ��� ����)�%��$ ��"���� ��#��/��!�+��")����8��$��*�(�!����"�,��� �����-,#� ����)� "���� ��#��/��!����"���1)��$� ��*�(�!����"�,��� �����-,#� ����)� "���� ��#��/��!��!��)�#:��"�*�(��:���"�,��� ����-,#�.���$�� ��� ����)� "���� ��#��0 ����#���� )�����*�(��:���"�,��� ����-,#�.���$�� ��� ����)� "���� ��#��0 ����
& �)�7� �*���!���+����������$�,���' ��$�-,#�.���$�� ��� ����)� "���� ��#��/��!�
;�<(� ���!�#�������,��$ �/;=�<�
>�����/!�
#����$��!�#�������,��$ �/� #��/��!�
3�!:��$�� �$ ��� ������������ � ��)�(�� �����7� �� ��� ���/���"!�%������$�
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
���/���"!)��$ ��� ����$ �/��� �)�#��� � 0 �!���$����� ' � �!)��$ ��� �������/��!�
��
�
�
Page 1 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
A diagnostic cohort study on the accuracy of 18-Fluoro-Deoxy-Glucose (18FDG)Positron
Emission Tomography- Computer Tomography (PET-CT) for evaluation of malignancy in
anterior mediastinal lesions – the DECiMaL study
C. Proli (1), P. De Sousa (1), S. Jordan (1), V. Anikin (1), A. Devaraj (1), S.M. Love (2), M.
Shackcloth (2), N. Kostoulas (3), K. Papagiannopoulos (3), Y. Haqzad (4), M. Loubani (4), F.
Sellitri (5), F. Granato (5), A. Bush (6), A. Marchbank (6), S. Iyer (7), M. Scarci (7), E. Lim (1) on
behalf of the UK Thoracic Surgery Research Collaborative
(1) Royal Brompton & Harefield NHS Foundation Trust, London, UK; (2) Liverpool Heart and
Chest Hospital NHS Foundation Trust; (3) Leeds Teaching Hospitals NHS Trust; (4) Hull and
East Yorkshire Hospitals NHS Trust, UK; (5) Royal Devon and Exeter NHS Foundation Trust,
UK (6) Plymouth Hospitals NHS Trust, UK, (7) Papworth Hospital NHS Foundation Trust, UK
Corresponding Author:
Mr Eric Lim
Academic Division of Thoracic Surgery
The Royal Brompton Hospital
Sydney Street
London SW3 6NP
United Kingdom
Tel: +44 (0)207 351 8591
Fax: +44 (0)207 351 8560
Email: [email protected]
Word count: 1554
Page 2 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
2
Abstract
Objectives: The aim of this study is to collate multi-institutional data to determine the value
by defining diagnostic performance of FDG-PET/CT for malignancy in patients undergoing
surgery with an anterior mediastinal mass in order to ascertain the clinical utility of PET/CT
to differentiate malignant from benign aetiologies in patients presenting with an anterior
mediastinal mass
Setting: DECiMaL Study is a multicentre, retrospective, collaborative cohort study in seven
UK surgical sites.
Participants: Between January 2002 and June 2015 a total of 134 patients were submitted
with a mean age (SD) of 55 years (16) of which 69 (51%) were men. We included all patients
undergoing surgery who presented with an anterior mediastinal mass and underwent
PET/CT. PET/CT was considered positive for any reported avidity as stated in the official
report and the reference was the resected specimen reported by histopathology using WHO
criteria.
Primary and secondary outcome measures: Sensitivity, specificity, positive and negative
predicted values of [18F]-FDG PET in determining malignant aetiology for an anterior
mediastinal mass.
Results: The sensitivity and specificity of PET/CT to correctly classify malignant disease were
83% (95% CI 74-89) and 58% (37-78). The positive and negative predictive values were 90%
(83-95) and 42% (26-61%).
Conclusions: The results of our study suggests reasonable sensitivity but no specificity
implying that a negative PET/CT is useful to rule out the diagnosis of malignant disease
whereas a positive result has no value in the discrimination between malignant and benign
disease of the anterior mediastinum.
Page 3 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
3
Strengths and limitations of this study
-� To our knowledge this is the largest study to date (essential to ensure narrow
confidence intervals for estimates) versing this subject
-� We were able to obtain an estimate of test performance relatively quickly through
an established research collaborative
-� The study did not include the entire spectrum of the anterior mediastinal masses, in
particular the small masses that were only kept under surveillance or discharged.
Funding statement
This research received no specific grant from any funding agency in the public, commercial
or not-for-profit sectors.
Competing interests statement
All authors declare no conflicts of interest. Outside this work, Eric Lim reports personal fees
from Abbott Molecular, personal fees from Glaxo Smith Kline, personal fees from Pfizer,
personal fees from Novartis, personal fees from Covidien, personal fees from Roche,
personal fees from Lily Oncology, personal fees from Boehringer Ingelheim, personal fees
from Medela, grants and personal fees from ScreenCell, personal fees from Ethicon, outside
the submitted work; and is the founder of Informative Genomics, a blood based molecular
diagnostic company in London.
Data sharing statement
Anonymised individual patient data that underlie the results reported in this article will be
available to researchers who provide a methodologically sound proposal. Proposals should
be directed to the corresponding author.
Page 4 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
4
Contributorship statement
CP, PDS and EL designed the work, acquired and analysed data and drafted the work; EL
interpreted the data; SJ, VA, AD, SML, MS, NK, KP, YH, ML, FS, FG, AB, AM, SI, MS acquired
and analysed data, revised the work critically; all authors approved the version to be
published and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
Page 5 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
5
Introduction
Abnormalities in the anterior mediastinum are often discovered as an incidental finding.
When detected, often present as a diagnostic challenge as few radiological features are
sufficiently discriminatory to guide clinicians on the best course of management. One of the
principal considerations is the probability of malignancy, as the perceived risk of cancer
guides the recommendation for invasive tissue sampling or excision. Although PET/CT is
widely used in this regard, little is known on the diagnostic and clinical test performance of
18-F fluorodeoxyglucose positron emission tomography [18F]-FDG PET-CT as no large
published series have been reported in the literature.
The aim of our study was to determine the diagnostic accuracy by defining the sensitivity
and specificity of 18
FDG PET-CT scans to identify malignancy in patients who have presented
with an anterior mediastinal mass.
Methods
We conducted a UK wide multi-centre retrospective study under the auspices of the UK
Thoracic Surgery Research Collaborative. Formal application was made to the Research
Ethics Committee (15/SS/0185) and the outcome was that the study did not require NHS
ethics review.
We included patients who have undergone surgery for an anterior mediastinal abnormality
and received 18
FDG PET-CT as part of their pre-operative work up. We excluded patients in
whom a formal histological diagnosis was not obtained or did not have a formal 18
FDG PET-
CT report.
Consecutive patients from January 2002 to June 2015 were identified from 7 participating
institutions of the UK Thoracic Surgery Research Collaborative through interrogation of
electronic records. As a pragmatic study, the index test of 18
FDG PET-CT was conducted by
Page 6 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
6
Consultant Radiologists and Nuclear Medicine Physicians according to UK Royal College of
Radiologists recommendations[1]. A positive test result was defined as a formally worded
“positive” uptake for the anterior mediastinal mass. The reference standard was the
histology of the resected anterior mediastinal mass as conducted by Pathologists in
accordance to the UK Royal College of Pathologists guidelines and reported according to
WHO criteria. Malignancy was defined in accordance to what would influence surgical
management including thymic carcinoma, thymoma, lymphoma, and any other malignant
tumours, and the following diseases were classified as non-malignant: thymic hyperplasia,
thymic cyst, and “no malignancy” as per histology report.
As the study was undertaken retrospectively, we assumed the results of the histopathology
(reference test) would not be available for the readers of the 18
FDG PET-CT (index test) as
surgical resection only occurs after the pre-operative investigations. We also have no reason
to believe that the reporting pathologists would have access to the pre-operative 18
FDG PET-
CT reports (although they may have had access to this inform on the request forms).
Categorical data were summarised as frequency (%), continuous data summarised as mean
(SD) or median (IQR) as appropriate to the data distribution. The primary outcome is the
calculated sensitivity, specificity, positive and negative predictive values with corresponding
95% confidence intervals. We specified a-priori estimates around 50% would be considered
none, around 75% moderate and around 100% to have excellent clinical test performance
and favour interpretation on sensitivity and specificity (considered robust estimates) rather
than positive or negative predictive values (that can be altered by disease prevalence). We
also conducted secondary analysis of receiver operator characteristics curve analyses to
explore the influence of SUVmax (where available) on the diagnosis of malignancy.
We estimated a sample size of 70 patients based on estimated sensitivity of 0.90 with a
lowest acceptable confidence interval of 0.75 using sample size calculations detailed by
Page 7 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
7
Flahault et al [2]. Statistical analyses were conducted on Stata 13 (College Station, Texas,
USA).
Results
From January 2002 and June 2015, a total of 672 patients were included of which 521 were
excluded due to not having a PET-CT and 17 excluded due to not having radiology report,
leaving 134 patients for analysis (figure 1). The mean age (SD) was 55 (16) years (with a
range of 18 to 88 years) of which 69 (51%) were men. The baseline and demographic
characteristics of the cohort are summarised in table 1.
Of the 134 patients 110 had a positive and 24 had a negative 18
FDG PET-CT report. A
malignant diagnosis was reported in 101 and a non-malignant diagnosis in 33 patients (table
2).
The sensitivity and specificity of PET-CT to correctly classify malignant disease for anterior
mediastinal masses were 83% (95% CI 74 to 89) and 58% (37 to 78) respectively and the
corresponding positive and negative predictive values were 90% (83 to 95) and 42% (26 to
61%) respectively (table 2).
Data from SUVmax were available in 96 patients and the calculated ROC area under the
curve was 0.63 (95% CI 0.45 to 0.79) (Figure 2).
Discussion
The results of our study, to our knowledge is the largest to date (essential to ensure narrow
confidence intervals for estimates) suggests that 18
FDG PET-CT is moderately useful to rule
out the diagnosis of malignancy when the test result is negative (good sensitivity), however
is not able to rule in the diagnosis of malignancy when the result is positive.
Page 8 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
8
Once an anterior mediastinal mass is diagnosed on imaging, downstream management is
predicated on the risk of malignancy to stratify patients for management, with high risk
patients assigned to invasive biopsy or surgery, intermediate risk patients assigned to
surveillance and low risk patients assigned to discharge. In a recent survey up to 50% of
centres reported the use of PET for this purpose.
In published cohort series, it was reported that thymic tumours represent 50% of anterior
mediastinal lesions, followed by lymphomas (25%) and less commonly a mixture of other
aetiologies such as teratoma[3]. A definitive diagnosis can only be achieved after invasive
biopsy[4] or surgical resection. The reported specificity of fine needle aspiration is limited
(57-82%)[5][6][7] and the diagnostic value of computerised tomography (CT) and positron
emission tomography (PET) are not well known as few studies have been conducted and
with sample sizes are very small, typically less than 60[8]. Decisions regarding direct surgical
resection of anterior mediastinal masses can be challenging as the morphological features of
thymic lesions overlap and a definite differentiation between histologic subtypes of thymic
pathology by CT can be difficult[9][10]. Previous studies have shown promising results for
SUVmax values in the differentiation between malignant and benign lesions[11]. However,
the results of our analyses suggested that discrimination by SUVmax was relatively poor.
With moderately high sensitivity, the results from our study suggest that 18
FDG PET-CT has
moderate utility to ruling out malignancy in patients where the test is negative. There is still
an appreciable proportion (17%) test negative despite the presence of disease. From a
clinical perspective it remains to individual judgement whether this is an acceptable
proportion balances against the consequences of missing a potentially invasive tumour.
It is difficult to define the clinical utility when faced with an “abstract” figure for sensitivity of
83%, to help clinicians understand how this would fit in the clinical setting, it would be
pertinent to look at more developed guidelines on perceived clinical utility of 18
FDG PET-CT
Page 9 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
9
for the solitary pulmonary nodule to assess cancer risk. The results from a 2008 meta-
analysis [12] reported a sensitivity of 95% for PET to diagnose malignancy in pulmonary
nodules, considerably higher than 83% for anterior mediastinal mass. Despite higher levels
of sensitivity, there is still a reluctance for experts to discharge a patient with a negative
18FDG PET-CT, as in the 2013 ACCP guidelines [13] the authors recommended serial CT
monitoring when the 18
FDG PET-CT is negative despite low clinical probability of lung cancer.
Currently, there are no established risk models for malignancy in anterior mediastinal
masses, and therefore numeric quantification of risk is not possible. In the circumstance
where the pre-test probability for malignancy is very low (e.g. if the CT appearance suggests
diffuse enlargement of the thymus only) then it would be reasonable to reassure the patient
(a negative 18
FDG PET-CT would not alter clinical management). If the pre-test probability is
very high (e.g. a large lobulated mass in anterior mediastinum) it would be reasonable to
proceed to invasive biopsy or resection (a negative 18
FDG PET-CT would not reassure). In the
most difficult subgroup where the pre-test probability for malignancy is intermediate, given
that serial CT imaging is recommended for lung cancer (despite sensitivity of 95%) then it
would be reasonable to default to the time tested method of screening for growth by CT for
anterior mediastinal masses as well. If that is the case, then there is clearly no clinical utility
for 18
FDG PET-CT (a negative test does not prevent serial CTs and a positive test is not
reliable to rule in malignancy).
The limitations of our study, aside from that associated with retrospective conduct is that
we did not include the entire spectrum of the anterior mediastinal masses, in particular the
small masses that were only kept under surveillance or discharged. On the other hand, we
have included the larger lesions that are more worrying and in whom 18
FDG PET-CT is usually
requested. We were able to obtain an estimate of test performance relatively quickly
through an established research collaborative as prospective conduct of a validation study is
Page 10 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
10
likely to require significant funding, more centres and time as anterior mediastinal lesions
are not common. Certainly we would welcome and encourage international efforts to
address this important issue, ideally with reference of clinical and cost effectiveness.
Conclusions
18FDG PET-CT is moderately useful to rule out the diagnosis of malignancy when the test
result is negative (good sensitivity), however is not able to rule in the diagnosis of
malignancy when the result is positive (poor specificity). At the existing levels of sensitivity a
negative test is insufficient to reassure and obviate the need for serial CT surveillance of
indeterminate masses in the anterior mediastinum. Therefore, we conclude that 18
FDG PET-
CT does not have a role in routine clinical practice to assess the malignant potential of an
anterior mediastinal mass.
Page 11 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
11
Table 1 - Demographic characteristics of the cohort and diagnosis classification as per
histology report
(n=134)
Mean age (SD) 55 (16)
Male, n (%) 69 (51)
Histology
Benign, n (%) 33 (25)
Thymic hyperplasia 10 (8)
Thymic cyst 8 (6)
No malignancy 15 (11)
Malignant, n (%) 101 (75)
Thymoma 55 (41)
Other malignant tumours 38 (28)
Thymic carcinoma 8 (6)
Page 12 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
12
Table 2 – Diagnostic test performance for PET-CT evaluation of malignancy in an anterior
mediastinal mass
18
FDG PET-CT positive 18
FDG PET-CT negative
Benign histology 19 14
Malignant histology 91 10
Test performance (with 95% CI)
Sensitivity 82.7 74.3 to 89.3
Specificity 58.3 36.6 to 77.9
Positive predictive value 90.1 82.5 to 95.1
Negative predictive value 42.4 25.5 to 60.8
Page 13 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
13
Figure 1 – Flow diagram (STARD)
Figure 2 – ROC plot of SUVmax versus malignancy
Page 14 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
14
References
1 The Royal College of Radiologists. The Royal College of Radiologists PET-CT in the UK.
2005.
http://www.bnms.org.uk/~bnms/images/stories/downloads/documents/rcr_petct_fi
nal.pdf
2 Flahault A, Cadilhac M, Thomas G. Sample size calculation should be performed for
design accuracy in diagnostic test studies. J Clin Epidemiol 2005;58:859–62.
doi:10.1016/j.jclinepi.2004.12.009
3 Liu Y. Characterization of thymic lesions with F-18 FDG PET-CT: an emphasis on
epithelial tumors. Nucl Med Commun 2011;32:554–62.
doi:10.1097/MNM.0b013e328345b984
4 Luzzi L, Campione A, Gorla A, et al. Role of fluorine-flurodeoxyglucose positron
emission tomography/computed tomography in preoperative assessment of anterior
mediastinal masses. Eur J Cardio-thoracic Surg 2009;36:475–9.
doi:10.1016/j.ejcts.2009.03.055
5 Assaad MW, Pantanowitz L, Otis CN. Diagnostic accuracy of image-guided
percutaneous fine needle aspiration biopsy of the mediastinum. Diagn Cytopathol
2007;35:705–9. doi:10.1002/dc.20738
6 Desai F, Shah M, Patel S, et al. Fine needle aspiration cytology of anterior mediastinal
masses. Indian J Pathol Microbiol;51:88–
90.http://www.ncbi.nlm.nih.gov/pubmed/18417872 (accessed 14 Nov 2016).
7 Powers CN, Silverman JF, Geisinger KR, et al. Fine-needle aspiration biopsy of the
Page 15 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
15
mediastinum: A multi-institutional analysis. Am J Clin Pathol 1996;105:168–
73.http://www.ncbi.nlm.nih.gov/pubmed/8607440 (accessed 14 Nov 2016).
8 Ahn JM, Lee KS, Goo JM, et al. Predicting the histology of anterior mediastinal
masses: comparison of chest radiography and CT. J Thorac imaging 1996;11:265–
71.http://www.ncbi.nlm.nih.gov/pubmed/8892196 (accessed 14 Nov 2016).
9 Treglia G, Sadeghi R, Giovanella L, et al. Is 18F-FDG PET useful in predicting the WHO
grade of malignancy in thymic epithelial tumors? A meta-analysis. Lung Cancer.
2014;86:5–13. doi:10.1016/j.lungcan.2014.08.008
10 Kaira K, Sunaga N, Ishizuka T, et al. The role of [18
F]fluorodeoxyglucose positron
emission tomography in thymic epithelial tumors. Cancer Imaging 2011;11:195–201.
doi:10.1102/1470-7330.2011.0028
11 Tatci E, Ozmen O, Dadali Y, et al. The role of FDG PET/CT in evaluation of mediastinal
masses and neurogenic tumors of chest wall. Int J Clin Exp Med 2015;8:11146–52.
12 Cronin P, Dwamena BA, Kelly AM, et al. Solitary pulmonary nodules: meta-analytic
comparison of cross-sectional imaging modalities for diagnosis of malignancy.
Radiology 2008;246:772–82. doi:10.1148/radiol.2463062148
13 Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary
nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed:
American college of chest physicians evidence-based clinical practice guidelines.
Chest 2013;143:e93S–120S. doi:10.1378/chest.12-2351
Page 16 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
��
�
�
�������������� ����������������
�
�������������������������
�
�
Page 17 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
��
�
�
������������� ����������������������������������
���������� !�����!���"#$%��
�
�
Page 18 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from
For peer review only
Section & Topic No Item Reported on page #
TITLE OR ABSTRACT
1 Identification as a study of diagnostic accuracy using at least one measure of accuracy
(such as sensitivity, specificity, predictive values, or AUC)
1
ABSTRACT
2 Structured summary of study design, methods, results, and conclusions
(for specific guidance, see STARD for Abstracts)
2
INTRODUCTION
3 Scientific and clinical background, including the intended use and clinical role of the index test 5
4 Study objectives and hypotheses 5
METHODS
Study design 5 Whether data collection was planned before the index test and reference standard
were performed (prospective study) or after (retrospective study)
5
Participants 6 Eligibility criteria 5
7 On what basis potentially eligible participants were identified
(such as symptoms, results from previous tests, inclusion in registry)
5
8 Where and when potentially eligible participants were identified (setting, location and dates) 5
9 Whether participants formed a consecutive, random or convenience series 5
Test methods 10a Index test, in sufficient detail to allow replication 5
10b Reference standard, in sufficient detail to allow replication 6
11 Rationale for choosing the reference standard (if alternatives exist) 6
12a Definition of and rationale for test positivity cut-offs or result categories
of the index test, distinguishing pre-specified from exploratory
6
12b Definition of and rationale for test positivity cut-offs or result categories
of the reference standard, distinguishing pre-specified from exploratory
6
13a Whether clinical information and reference standard results were available
to the performers/readers of the index test
6
13b Whether clinical information and index test results were available
to the assessors of the reference standard
6
Analysis 14 Methods for estimating or comparing measures of diagnostic accuracy 6
15 How indeterminate index test or reference standard results were handled 6
16 How missing data on the index test and reference standard were handled 6
17 Any analyses of variability in diagnostic accuracy, distinguishing pre-specified from exploratory 6
18 Intended sample size and how it was determined 7
RESULTS
Participants 19 Flow of participants, using a diagram 7, figure 1
20 Baseline demographic and clinical characteristics of participants 7, table 1
21a Distribution of severity of disease in those with the target condition 7, table 2
21b Distribution of alternative diagnoses in those without the target condition 7, table 2
22 Time interval and any clinical interventions between index test and reference standard N/A
Test results 23 Cross tabulation of the index test results (or their distribution)
by the results of the reference standard
7
24 Estimates of diagnostic accuracy and their precision (such as 95% confidence intervals) 7, table 2
25 Any adverse events from performing the index test or the reference standard N/A
DISCUSSION
26 Study limitations, including sources of potential bias, statistical uncertainty, and generalisability 8
27 Implications for practice, including the intended use and clinical role of the index test 6-8
OTHER
INFORMATION
28 Registration number and name of registry N/A
29 Where the full study protocol can be accessed N/A
30 Sources of funding and other support; role of funders 3
Page 19 of 18
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on Septem
ber 27, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2017-019471 on 6 February 2018. D
ownloaded from