1
Title: Whole Body 18F-FDG-PET and 18F-FDG-PET/CT in Patients with Suspected
Paraneoplastic Syndrome: A Systematic Review and Meta-analysis of Diagnostic
Accuracy
Running title: FDG-PET/CT in Paraneoplastic Syndrome
Authors: Sara Sheikhbahaei1, Charles V Marcus1, Roberto S Fragomeni1, Steven P
Rowe1, Mehrbod S Javadi1, Lilja B Solnes1
Affiliations:
1. The Russell H. Morgan Department of Radiology and Radiological Science,
Johns Hopkins University School of Medicine, Baltimore, MD, US
Corresponding author: Lilja B Solnes
The Russell H. Morgan Department of Radiology and Radiological Science, JHOC 3009,
601 N Caroline St, Baltimore, MD 21287,
Ph: 410- 955 6989, Email: [email protected]
First author: Sara Sheikhbahaei, Research Fellow
Department of Radiology and Radiological Sciences, JHOC 4230, 601 N. Caroline St,
Baltimore, MD, 21287, Email: [email protected]
Word count: 4,822
Disclaimer: None, Financial support: None
Journal of Nuclear Medicine, published on December 15, 2016 as doi:10.2967/jnumed.116.183905
2
ABSTRACT
The purpose of this study was to assess the diagnostic performance of whole body 18F-
FDG-PET or 18F-FDG-PET/CT for detection of underlying malignancy in patients with
clinically suspected neurological and non-neurological paraneoplastic syndromes.
Methods: A systematic search was performed in PubMed (Medline), Embase, Scopus
(last updated November 2016) to identify relevant published studies reporting the
performance of 18F-FDG-PET or 18F-FDG-PET/CT in patients with suspected
paraneoplastic syndrome. Histopathologic confirmation or clinical follow-up was
considered as the reference standard. Pooled estimates (95% confidence intervals) of
sensitivity, specificity, diagnostic odds ratio (DOR) were calculated. A summary receiver-
operating-characteristics curve was constructed, and the area under the curve (AUC)
was determined along with the Q* index.
Results: Twenty-one studies including a total of 1,293 individual patients suspected of
having a para-neoplastic syndrome and who underwent 18F-FDG-PET or 18F-FDG-
PET/CT examinations met our inclusion criteria. There was moderate to high
heterogeneity among the included studies. The pooled sensitivity, specificity and DOR of
18F-FDG-PET or 18F-FDG-PET/CT for the detection of underlying malignancy were
0.81 (0.76 to 0.86), 0.88 (0.86 to 0.90) and 34.03 (18.76 to 61.72), respectively. The
AUC and the Q* index were 0.916 (standard error= 0.018) and 0.849, indicating
excellent diagnostic accuracy. The diagnostic accuracy was slightly improved after
excluding studies with high applicability concerns (AUC of 0.931, standard error= 0.020).
In a subgroup analysis, 18F-FDG-PET/CT was found to have significantly higher
specificity (0.89 versus 0.79) compared to 18F-FDG-PET alone, with no evidence of
significant difference in the overall performance (AUC of 0.930 versus 0.891, two-tailed
P-value for difference= 0.31).
3
Conclusion: This meta-analysis of available studies demonstrates that whole body 18F-
FDG-PET or 18F-FDG-PET/CT has high diagnostic accuracy and moderate to high
sensitivity and specificity for detection of underlying malignancy in patients suspected of
having a paraneoplastic syndrome.
Key-words: Paraneoplastic syndrome, 18F-FDG-PET, Sensitivity and Specificity, meta-
analysis
4
INTRODUCTION
Paraneoplastic syndromes are a rare systemic complication of malignancy that is not
directly caused by local tumor extension or metastases 1, 2. The pathogenesis of
paraneoplastic syndromes is not completely understood, yet, it is believed to be
mediated by an altered immune response to the presence of cancer1. Paraneoplastic
syndromes comprises a heterogeneous group of disorders that can affect any organ
system including the central and peripheral nervous systems as well as the
musculoskeletal, dermatologic, hematologic, endocrine or gastrointestinal systems2, 3.
The nervous system involvements are the most commonly reported paraneoplastic
syndrome 2, 4. An immunologic response to an antigenic target that is shared between a
component of the nervous system and tumor cells may be the underlying pathology1, 4.
Paraneoplastic symptoms can be the initial or the most prominent manifestation
of malignancy 2. Timely recognition of these symptoms and detecting the underlying
malignancy can play a critical role in the early treatment of tumor and can guide further
management and improve patients’ survival. Paraneoplastic signs and symptoms may
regress by treating the underlying malignancy. Thus, accurate imaging examinations are
essential in identifying the underlying malignancy whenever a paraneoplastic syndrome
is suspected 5. Anatomical cross-sectional imaging including computed tomography (CT)
and magnetic resonance imaging may fail to detect the underlying malignancy as the
majority of associated malignancies are small, often with only lymphatic metastases 3, 5.
2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (18F-FDG-PET)
and 18F-FDG-PET/CT have emerged as practical imaging modality that allows for the
detection of metabolically active tumors6. Several studies have attempted to address the
role of whole body 18F-FDG-PET and 18F-FDG PET/CT in the workup of patients with
suspected paraneoplastic manifestations 3, 5, 7-17. Although some of these studies have
shown promising results, they were mostly conducted in relatively small and pre-
5
selected patient populations. Variations existed in their methodological designs, patient
populations, and conclusions. Currently, there is no consensus on the value of whole
body 18F-FDG-PET and 18F-FDG-PET/CT in patients with suspected paraneoplastic
syndromes, warranting the need for a meta-analysis.
This study aims to review the literature systematically and to extract the summary
estimates of the diagnostic performances of whole body 18F-FDG-PET or 18F-FDG-
PET/CT for detection of underlying malignancy in patients with clinically suspected
neurological and non-neurological paraneoplastic syndromes. The results of this study
can provide further insight into the usefulness of whole body 18F-FDG-PET and 18F-
FDG PET/CT in patients with suspected paraneoplastic syndromes.
MATERIALS AND METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement was followed18.
Search Strategy
Systematic electronic searches of Medline (PubMed), Embase, Scopus and
abstract proceedings of major scientific meetings (SNMMI, RSNA, EANM) were
performed to identify relevant published studies evaluating the diagnostic performance of
whole body 18F-FDG-PET or 18F-FDG-PET/CT in detecting primary malignancies or
metastasis in patients presenting with a paraneoplastic syndrome. The search strategy
was based on the combination of following keywords; A) “paraneoplastic” OR “para
neoplastic” OR “PNS”; AND B) “PET” OR “Positron emission tomography” OR “18 f
fluorodeoxyglucose” OR “FDG”; AND C) “diagnostic” OR “sensitivity” OR “specificity”
A comprehensive search strategy was used without any restrictions on language
or publication status. The search was last updated in November 2016, without beginning
date limit.
6
Criteria for Study Consideration
Patients with clinically suspected neurological and non-neurological
paraneoplastic syndromes were eligible for inclusion. Diagnostic whole body 18F-FDG-
PET or 18F-FDG-PET/CT studies performed to detect occult malignancy were used as
an index test. Histopathologic confirmation or imaging follow-up after whole body 18F-
FDG-PET or 18F-FDG-PET/CT was considered as the reference standard.
Selection of Studies, Data Extraction, and Management
Two authors (S.S., C.M.) reviewed all records identified through the electronic
search. Studies were initially evaluated on the basis of the title and abstract of the
articles. Review articles, editorials, case-reports, and irrelevant citations were excluded
in the initial assessment. The full-texts of the potentially relevant publications were
retrieved for further consideration. All potentially eligible articles were independently
checked by two authors for predefined inclusion criteria.
To avoid duplication of data, only the most recent articles with no overlapping
study period were included when there was more than one published article from the
same institution17, 19.
Two authors (S.S., C.M.) independently extracted the following data from each
included study; bibliographic details, patient sampling and characteristics, number of
patients or scans, index test, reference standard, prevalence of underlying malignancy,
and the raw data to construct 2 × 2 contingency tables including the number of true-
positive, false-positive, true-negative, and false-negative patients/scans. The diagnostic
performance of whole body 18F-FDG-PET or 18F-FDG-PET/CT for detection of
malignancy was assessed by cross-relating index test results and the reference
standards. All data extracted by two review authors were compared in each step and
any discrepancies were resolved through consensus or by a third author (L.S.).
Assessment of Methodological Quality
7
The methodological qualities of the included studies were assessed using a
modified version of the Quality Assessment Tool for Diagnostic Accuracy (QUADAS-2)
as recommended by Cochrane Collaborations 20.
The tool consists of four domains, each domain appraises the risk of bias and
applicability/ generalizability of the study through a series of questions (Supplemental
Table 1). Two authors (S.S., C.M.) independently assessed the quality of the studies.
Disagreements were mediated by consensus.
Statistical Analysis and Data Synthesis
Studies with adequate data to reconstruct the 2 × 2 diagnostic table were
included in the quantitative analysis. The sensitivity and specificity, along with 95%
confidence intervals (CIs), were calculated for each study. The forest plots of sensitivity
and specificity were used to display the variations in the results of the individual studies.
Homogeneity among the studies was assessed using a chi-square test and p < 0.05
indicated statistically significant heterogeneity 21, 22. The I-squared index (I2) was
measured to quantify the degree of heterogeneity in studies. I2 lies from 0 to 100, and
the respective values around 0, 25, 50, and 75, indicate no, low, moderate, and high
heterogeneity among studies 23. We calculated the pooled estimates of sensitivity,
specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratios (DOR)
using random effect (DerSimonian–Laird) assumptions24. The diagnostic tests with a
DOR more than 25 and 100 are considered moderately and highly accurate,
respectively25. The receiver operating characteristic curve (SROC) space is defined by
sensitivity (y-axis) and 1-specificity (x-axis), and each data point represents one
particular study. The area under the SROC curve (AUC) represented an overall
summary of the diagnostic test performance and presents the tradeoff between
sensitivity and specificity. An AUC value of 1.0 (100%) denotes a perfect discriminatory
ability for a diagnostic test22. To reduce the heterogeneity, subgroup analysis was
8
performed to determine the effect of imaging modality (18F-FDG-PET alone versus.
18F-FDG-PET/CT) on the diagnostic performance. The statistical significance of the
difference between two AUCs was estimated with the Hanley JA method (Two-tailed P-
value) 26.
Publication bias was assessed using funnel plots of standard error (SE) and
Egger’s regression intercept27. To calculate the adjusted DOR, a trim and fill technique
was used to account for the potentially missed studies27. Analyses were performed using
Meta-DiSc (version 1.4; Hospital Universitario Ramon y Cajal, Madrid, Spain),
comprehensive meta-analysis (CMA version 2, Biostat, Englewood, NJ, USA) and
MedCalc statistical software (version 16.8.3, Ostend, Belgium).
RESULTS
Search Results
Figure 1 illustrates the details of the study selection. A total of 887 relevant
records were identified through a comprehensive literature search. After screening titles
and abstracts, we excluded 851 non-relevant articles. To assess the eligibility of the
remaining 36 records, we retrieved the corresponding full-texts or contacted the study
authors inquiring more information. Ultimately, a total of 24 studies were included in the
qualitative assessment and 21 studies met our predefined criteria to be included in the
quantitative analysis 3, 5, 7-17, 28-37.
Study Characteristics and Methodological Quality Assessment
The details of the study design, patient demographics and characteristics,
paraneoplastic presentation, paraneoplastic antibody status, index test, proportion of
patients diagnosed with underlying malignancy and reference standard(s) of each
included study were summarized in supplemental Tables 2 and 3 3, 5, 7-17, 28-31. Among the
24 studies included in the qualitative assessment, four studies were prospective and 20
9
studies were retrospective. All studies enrolled patients with a suspected paraneoplastic
syndrome. The index test was whole body 18F-FDG-PET (seven studies), 18F-FDG-
PET combined with CT (one study), 18F-FDG-PET or 18F-FDG-PET/CT (one study) and
hybrid 18F-FDG-PET/CT (15 studies).
Three studies did not clearly describe the reference standard used in patients
with negative 18F-FDG-PET/CT results and were not included in the quantitative
analysis 29, 30, 36.
Twenty-one studies including 1,293 individual patients suspected to have
paraneoplastic syndrome assessed the diagnostic accuracy of 18F-FDG-PET or 18F-
FDG-PET/CT in the detection of underlying malignancy and were included in the
quantitative analysis. Detailed information on true positive, false negative and false
positive sites is summarized in supplemental Table 4. Figure 2 depicted the risk of bias
and applicability concerns across the included studies according to QUADAS-2.
Findings
The proportion of patients diagnosed with underlying malignancy among the
included studies ranged between 7.5% and 90%, with the pooled estimate of 16.9%
(95% CI= 15.0% to 19.1%).
The sensitivity of whole body 18F-FDG-PET or 18F-FDG-PET/CT in the
detection of underlying malignancy in patients with a suspected paraneoplastic
syndrome ranged between 0.57 and 1.00, with a pooled sensitivity of 0.81 (95%CI= 0.76
to 0.86) (Fig 3A). The specificity of whole body 18F-FDG-PET or 18F-FDG-PET/CT
ranged between 0.25 and 1.00, with a pooled specificity of 0.88 (95% CI= 0.86 to 0.90)
(Fig 3B). The random effects model was used because of moderate to substantial
heterogeneity among the included studies (I2= 57.7% for sensitivity and I2= 81.5% for
specificity). The pooled results for the positive LR, negative LR, and DOR of whole body
10
18F-FDG -PET or 18F-FDG -PET/CT were 5.95 (95% CI= 4.01 to 8.84), 0.25 (95% CI=
0.18 to 0.35) and 34.03 (95% CI= 18.76 to 61.72), respectively.
The SROC curve summarizing the accuracy of whole body 18F-FDG -PET or
18F-FDG-PET/CT examinations across all included studies is depicted in Figure 4. The
AUC was 0.916 (SE= 0.018) and the Q* index was 0.849 indicating excellent diagnostic
accuracy.
We performed a secondary analysis after excluding studies with high applicability
concerns in all domains9, 10, 12, 13, 31. The pooled estimates of sensitivity, specificity and
DOR were 0.88 (95% CI= 0.82 to 0.93), I2 = 24.9%; 0.87 (95%CI= 0.84 to 0.89), I2 =
81.2%; and 44.86 (95%CI= 19.72 to 102.07), respectively. The diagnostic performance
was slightly improved with the AUC of 0.931 (SE= 0.020) and Q* index of 0.866.
Patients with Neurologic Paraneoplastic Syndromes
In a subgroup analysis, we tried to include only patients with exclusively
neurologic paraneoplastic symptoms, where possible. A total of twelve studies on 528
patients were included. The pooled estimates of sensitivity and specificity for 18F-FDG -
PET or 18F-FDG -PET/CT were 0.89 (95%CI= 0.81 to 0.94), I2=38.4% and 0.83
(95%CI= 0.79 to 0.87), I2= 76.9%, respectively. The pooled result for the positive LR,
negative LR, and DOR of 18F-FDG-PET or 18F-FDG-PET/CT were 4.47 (95% CI= 2.7
to 7.40), 0.25 (95% CI= 0.16 to 0.40), and 26.99 (95% CI= 11.17 to 65.23), respectively.
The AUC was 0.915 (SE= 0.028) and the Q* index was 0.848, indicating excellent
diagnostic accuracy.
Whole Body 18F-FDG -PET/CT versus 18F-FDG -PET Alone
In studies in which 18F-FDG-PET alone (7 studies, n= 273) was used, the
pooled sensitivity and specificity were 0.88 (95% CI= 0.78 to 0.95), I2= 0% and 0.79
(95% CI= 0.73 to 0.84), I2= 60.7%, respectively. In studies in which combined 18F-FDG-
PET/CT (13 studies, n= 895) was performed, the pooled sensitivity and specificity were
11
0.77 (95% CI=0.70 to 0.84), I2= 66.9% and 0.89 (95%CI= 0.87 to 0.91), I2= 76.5%,
respectively. 18F-FDG-PET/CT had significantly higher specificity compared to 18F-
FDG-PET alone (no overlap in 95% CIs), but there was no statistically significant
difference in the pooled sensitivity. The pooled result for the positive LR, negative LR
and DOR were 3.5 (95% CI= 2.06 to 5.93), 0.22 (95% CI= 0.12 to 0.41) and 19.26 (95%
CI= 8.45 to 43.92) for FDG-PET alone and 7.17 (95% CI= 4.59 to 11.21), 0.26 (95% CI=
0.17 to 0.42) and 37.34 (95% CI= 17.63 to 79.06) for FDG-PET/CT. There were no
statistically significant differences between 18F-FDG-PET/CT and 18F-FDG-PET in the
AUC with the respective values of 0.930 (SE= 0.023) vs. 0.891 (SE= 0.031); Two-tailed
P-value for difference= 0.31.
Risk of Publication Bias
Figure 5 demonstrates the funnel plot of the included studies. The log-DOR on the x-axis
is plotted against the SE of the log-DOR on the y-axis. Egger’s regression intercepts for
DOR pooling were 1.76 (95% CI= 0.62 to 2.89; two-tailed P-value= 0.004) suggesting
the presence of publication bias. After adjustment for the potential effect of publication
bias, looking for missing studies to the left of mean- trim and fill technique-, the
estimated adjusted DOR was decreased to 18.89 (95% CI= 10.01 to 35.65).
DISCUSSION
This is the first meta-analysis to evaluate the diagnostic performance of whole
body 18F-FDG-PET or 18F-FDG-PET/CT in the detection of underlying malignancy in
patients with paraneoplastic manifestations. This meta-analysis demonstrated a pooled
sensitivity of 0.81, specificity of 0.88 and moderate DOR for 18F-FDG-PET or 18F-FDG-
PET/CT in patients suspected to have a paraneoplastic syndrome. The SROC curve
analysis yielded an excellent trade-off between sensitivity and specificity with an AUC of
0.916.
12
There is considerable heterogeneity in the literature and yet no consensus on the
value of whole body 18F-FDG-PET or 18F-FDG-PET/CT in patients suspected of
harboring a paraneoplastic syndrome. Our results showed substantial difference
between the pre-pooled sensitivity and specificity of individual studies. This can be partly
explained by different patient inclusion criteria, as well as different methods used for the
reference standard. The selection bias appeared as some studies included
heterogeneous group of patients with different manifestations and with or without
inconclusive/negative prior conventional imaging. Others only included highly selective
patients with positive paraneoplastic-antibodies. The pretest-selection of patients
suspected for paraneoplastic syndrome can alter the diagnostic performance of whole
body 18F-FDG-PET or 18F-FDG-PET/CT. We tried to reduce the effect of clinical
diversity and heterogeneity by performing a secondary analysis after exclusion of studies
with high risk of bias. The performance of 18F-FDG-PET or 18F-FDG-PET/CT in the
detection of underlying malignancy was slightly improved (AUC =0.931; sensitivity of
0.88) in this setting. In addition, 18F-FDG-PET or 18F-FDG-PET/CT was found to have
fairly similar diagnostic performance when limiting the analysis to patients with
neurologic paraneoplastic manifestations.
Our results showed a false negative rate of 19% for whole body 18F-FDG-PET or
18F-FDG-PET/CT. Therefore, a negative 18F-FDG-PET/CT cannot rule out the
presence of malignancy. Patients with clinically suspected paraneoplastic syndrome can
have relatively small tumors that may be missed by 18F-FDG-PET/CT or tumors may
not be 18F-FDG avid. Therefore, careful follow-up and repeat screening by 18F-FDG-
PET/CT or other imaging modalities is necessary in these patients. The European
Federation of the Neurological Societies has addressed this by recommending repeat
screening in 3 to 6 months after an initial negative evaluation, followed by screening
every 6 months up to four years, if testing remains unrevealing38.
13
Sets of definitions are taken into consideration to establish diagnostic criteria and
classify patients with paraneoplastic manifestations into “definite” or “possible”
paraneoplastic syndrome categories, mainly based on the presenting clinical symptoms
and presence or absence of paraneoplastic antibodies39. The presence of the well-
characterized paraneoplastic antibodies provide important additional diagnostic
information to predict a specific underlying malignancy1, 39. Recent studies investigated
the performance of whole body 18F-FDG-PET/CT in relation to paraneoplastic antibody
status16. A number of studies showed that whole body 18F-FDG-PET and 18F-FDG-
PET/CT are highly useful in the screening of patients with suspected paraneoplastic
syndrome and positive paraneoplastic antibodies9, 10. However, a recent study by
Vatankulua et al suggested that paraneoplastic antibody presence should not be an
indispensable factor for performing 18F-FDG-PET/CT in patients suspected of harboring
a paraneoplastic syndrome16.
Besides, Vaidyanathan et al. showed that 18F-FDG-PET/CT can help in risk
classification of patients suspected of having a paraneoplastic syndrome. They showed
that the 18F-FDG-PET/CT results could add confidence to clinical likelihood in 28% of
patients and correctly downgrade (16%) or upgrade (12%) the clinical score5. A recent
study by Subramaniam et al. showed that 18F-FDG-PET has substantial impact in the
management of patients with suspected para-neoplastic syndrome and those with
cancer of unknown primary origin, resulted in changing the intended management in
25% and 43% of patients 40. Our meta-analysis showed that the diagnostic performance
of FDG-PET/CT for the detection of underlying malignancy in patients with suspected
paraneoplastic syndrome is comparable with its’ general performance in patients with
cancer of unknown primary origin. A previous meta-analysis of 11 studies including 433
patients with cancer of unknown primary reported a sensitivity and specificity of 84%
(95% CI 78–88%) and 84% (95% CI 78–89%) for FDG-PET/CT in the primary tumor
14
detection41. However, the translation of test performance characteristics into improved
patient management has not been addressed in this meta-analysis and needs to be
further investigated.
The development of the integrated 18F-FDG-PET and CT has helped to
precisely localized lesions on 18F-FDG-PET scans6. Over the last decade, more studies
have investigated the application of combined 18F-FDG-PET/CT in the initial evaluation
and diagnosis of paraneoplastic syndromes and occult malignancy3, 5, 14-17. In our study,
the subgroup analysis by imaging modality revealed that 18F-FDG-PET/CT showed
significantly higher specificity compared with 18F-FDG-PET alone. As 18F-FDG-PET
results are only based on the visual analysis of lesions with no anatomical correlate, any
lesions with higher metabolism than background could have been counted as positive6.
However, we found no evidence of significant difference in the sensitivity and overall
performances (AUC) of whole body 18F-FDG-PET vs. 18F-FDG-PET/CT. A possible
explanation can be the effect of publication year and the fact that older studies were
performed on smaller sample sizes.
Due to the limited number of studies with direct comparison of 18F-FDG-PET or
18F-FDG-PET/CT and conventional imaging, we were not able to report the pooled
diagnostic performance for conventional imaging. Five studies compared the diagnostic
performance of 18F-FDG-PET or 18F-FDG-PET/CT with conventional screening
methods9, 11, 13, 15, 28. In these studies, the sensitivity and specificity of conventional
screening modalities were ranged between 30- 82% and 71- 100%, respectively. Further
studies are needed to investigate the additional value of 18F-FDG-PET/CT and its cost
effectiveness over conventional screening modalities in the work-up of patients with
suspected paraneoplastic syndrome.
Limitations of this analysis include the risk of selection bias and the lack of
histopathologic confirmation of all lesions reported in the included studies. Although
15
clinical follow-up data were recorded in some studies, patients who died shortly after the
18F-FDG-PET or 18F-FDG-PET/CT without proven malignancy were considered as
false positive, which could underestimate the performance of the modality. We cannot
exclude the possibility of positive result publication bias as non-significant or unfavorable
study results tend to be discarded. Besides, most results of the meta-analysis showed
statistic heterogeneity. We analyzed the subgroups according to the index test and those
patients presenting with neurologic symptoms, and this partly eliminated the effect of
heterogeneity although further subgroup analyses were limited by the restricted original
data. Surely, larger observational studies are warranted to further determine the utility of
whole body 18F-FDG-PET and 18F-FDG-PET/CT in relation to paraneoplastic antibody
status and its effect on patient management and outcome.
CONCLUSION
This meta-analysis of available studies demonstrates that whole body 18F-FDG-
PET and 18F-FDG-PET/CT have excellent diagnostic accuracy, and moderate to high
sensitivity and specificity for detection of underlying malignancy in patients suspected of
having a paraneoplastic syndrome.
16
REFERENCES
1. Storstein A, Vedeler CA. Paraneoplastic neurological syndromes and onconeural
antibodies: clinical and immunological aspects. Adv Clin Chem. 2007;44:143-
185.
2. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis
and treatment. Mayo Clin Proc. Sep 2010;85(9):838-854.
3. Kristensen SB, Hess S, Petersen H, Hoilund-Carlsen PF. Clinical value of FDG-
PET/CT in suspected paraneoplastic syndromes: a retrospective analysis of 137
patients. Eur J Nucl Med Mol Imaging. Dec 2015;42(13):2056-2063.
4. de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological
disorders. Oncologist. Mar 2006;11(3):292-305.
5. Vaidyanathan S, Pennington C, Ng CY, Poon FW, Han S. 18F-FDG PET-CT in
the evaluation of paraneoplastic syndromes: experience at a regional oncology
centre. Nucl Med Commun. Aug 2012;33(8):872-880.
6. von Schulthess GK, Steinert HC, Hany TF. Integrated PET/CT: current
applications and future directions. Radiology. Feb 2006;238(2):405-422.
7. Rees JH, Hain SF, Johnson MR, et al. The role of [18F]fluoro-2-deoxyglucose-
PET scanning in the diagnosis of paraneoplastic neurological disorders. Brain.
Nov 2001;124(Pt 11):2223-2231.
8. Berner U, Menzel C, Rinne D, et al. Paraneoplastic syndromes: detection of
malignant tumors using [(18)F]FDG-PET. Q J Nucl Med. Jun 2003;47(2):85-89.
9. Linke R, Schroeder M, Helmberger T, Voltz R. Antibody-positive paraneoplastic
neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology. Jul
27 2004;63(2):282-286.
17
10. Younes-Mhenni S, Janier MF, Cinotti L, et al. FDG-PET improves tumour
detection in patients with paraneoplastic neurological syndromes. Brain. Oct
2004;127(Pt 10):2331-2338.
11. Patel RR, Subramaniam RM, Mandrekar JN, Hammack JE, Lowe VJ, Jett JR.
Occult malignancy in patients with suspected paraneoplastic neurologic
syndromes: value of positron emission tomography in diagnosis. Mayo Clin Proc.
Aug 2008;83(8):917-922.
12. Hadjivassiliou M, Alder SJ, Van Beek EJ, et al. PET scan in clinically suspected
paraneoplastic neurological syndromes: a 6-year prospective study in a regional
neuroscience unit. Acta Neurol Scand. Mar 2009;119(3):186-193.
13. Selva-O'Callaghan A, Grau JM, Gamez-Cenzano C, et al. Conventional cancer
screening versus PET/CT in dermatomyositis/polymyositis. Am J Med. Jun
2010;123(6):558-562.
14. Matsuhisa A, Toriihara A, Kubota K, Makino T, Mizusawa H, Shibuya H. Utility of
F-18 FDG PET/CT in screening for paraneoplastic neurological syndromes. Clin
Nucl Med. Jan 2012;37(1):39-43.
15. Schramm N, Rominger A, Schmidt C, et al. Detection of underlying malignancy in
patients with paraneoplastic neurological syndromes: comparison of 18F-FDG
PET/CT and contrast-enhanced CT. Eur J Nucl Med Mol Imaging. Jul
2013;40(7):1014-1024.
16. Vatankulu B, Yilmaz Aksoy S, Asa S, et al. Accuracy of FDG-PET/CT and
paraneoplastic antibodies in diagnosing cancer in paraneoplastic neurological
syndromes. Rev Esp Med Nucl Imagen Mol. Jan-Feb 2016;35(1):17-21.
17. Pena Pardo FJ, Garcia Vicente AM, Amo-Salas M, et al. Utility of 18F-FDG-
PET/CT in patients suspected of paraneoplastic neurological syndrome:
importance of risk classification. Clin Transl Oncol. 2016; [Epub ahead of print].
18
18. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. Int J Surg.
2010;8(5):336-341.
19. Garcia Vicente AM, Vega Caicedo CH, Mondejar Solis R, et al. [(18)F-FDG
PET/CT in the evaluation of patients suspected of paraneoplastic neurological
syndrome]. Rev Esp Med Nucl Imagen Mol. Jul-Aug 2015;34(4):236-243.
20. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the
quality assessment of diagnostic accuracy studies. Ann Intern Med. Oct 18
2011;155(8):529-536.
21. Lijmer JG, Bossuyt PM, Heisterkamp SH. Exploring sources of heterogeneity in
systematic reviews of diagnostic tests. Stat Med. Jun 15 2002;21(11):1525-1537.
22. Lee YH, Choi SJ, Ji JD, Song GG. Diagnostic accuracy of 18F-FDG PET or
PET/CT for large vessel vasculitis : a meta-analysis. Z Rheumatol. Dec 25 2015.
23. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
meta-analyses. BMJ. Sep 6 2003;327(7414):557-560.
24. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to
fixed-effect and random-effects models for meta-analysis. Res Synth Methods.
Apr 2010;1(2):97-111.
25. Deeks JJ. Systematic reviews in health care: Systematic reviews of evaluations
of diagnostic and screening tests. BMJ. Jul 21 2001;323(7305):157-162.
26. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver
operating characteristic (ROC) curve. Radiology. Apr 1982;143(1):29-36.
27. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing
and adjusting for publication bias in meta-analysis. Biometrics. Jun
2000;56(2):455-463.
19
28. Masangkay N. AA, Torigian D., Dalmau J. Comparison of FDG-PET and CT in
detection of neoplasia in patients with paraneoplastic neurologic syndrome
(PNS). J Nucl Med. 2008;49(supplement 1):369P.
29. Bannas P, Weber C, Derlin T, et al. 18F-FDG-PET/CT in the diagnosis of
paraneoplastic neurological syndromes: a retrospective analysis. Eur Radiol. Apr
2009;20(4):923-930.
30. McKeon A, Apiwattanakul M, Lachance DH, et al. Positron emission tomography-
computed tomography in paraneoplastic neurologic disorders: systematic
analysis and review. Arch Neurol. Mar 2010;67(3):322-329.
31. Crandall J GP, Joshi K, Chaudhry M, Wahl R. Diagnostic performance of F18-
FDG PET/CT in patients with suspected paraneoplastic syndrome. J Nucl Med.
2014;55(supplement 1):1892.
32. Han S NC, Poon FW. The role of F-18 FDG PET/CT imaging in the investigation
of suspected paraneoplastic syndrome. Eur J Nucl Med Mol Imaging. 2011 38
(SUPPL. 2 (S256)).
33. Chakraborty PS SP, Soundararajan R, Karunanithi S, Singh H, Kumar R,
Malhotra A, Bal C. Yield of 18F-FDG PET/CT in patients with paraneoplastic
neurological syndrome for detection of primary malignancy. Eur J Nucl Med Mol
Imaging. 2013;40(SUPPL. 2 (S484)).
34. Fuster D VM, Depetris M, Mayoral M, Grau JJ, Muxi A, Lomeña F, Pons F. Value
of PET/CT with 18F-Fluorodeoxyglucose in patients with paraneoplastic
syndrome. Eur J Nucl Med Mol Imaging. 2013;40( SUPPL. 2 (S378)).
35. Iyngkaran G CB, Schultz C. The value of 18-FDG PET in the diagnosis of
tumours associated with paraneoplastic neurological syndromes. Intern Med J.
2009;39(SUPPL. 4 (A114)).
20
36. Gupta N BR, Sasikumar A, Sood A, Bhattacharya A, Mittal BR. Role of F-18 FDG
PET/CT in suspected cases of paraneoplastic neurological syndrome. Eur J Nucl
Med Mol Imaging. 2014;41(SUPPL. 2 (S313)).
37. Grozdic I NM, Odalovic S, Al-Nahhas A. The value of PET and PET/CT imaging
in paraneoplastic syndrome. Nucl Med Commun. 2011;32(5 (453-454)).
38. Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic
syndromes: report of an EFNS task force. Eur J Neurol. Jan 2010;18(1):19-e13.
39. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for
paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. Aug
2004;75(8):1135-1140.
40. Subramaniam RM, Shields AF, Sachedina A, et al. Impact on Patient
Management of [18F]-Fluorodeoxyglucose-Positron Emission Tomography (PET)
Used for Cancer Diagnosis: Analysis of Data From the National Oncologic PET
Registry. Oncologist. Jul 8 2016.
41. Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown
primary tumors: systematic review and meta-analysis. Eur Radiol. Mar
2009;19(3):731-744.
21
FIGURE 1. Flowchart of systematic literature review
22
FIGURE 2. The risk of bias and applicability concerns: review of authors’
judgments about each domain, presented as percentages across included
studies.
23
FIGURE 3. Forest-plots of sensitivity, specificity and diagnostic odds ratio across
the included studies (*conference abstracts)
24
25
FIGURE 4. Summary receiver operating characteristic curve and its’ two sided
95% confidence interval for assessment of the diagnostic accuracy of 18F-FDG-
PET or 18F-FDG-PET/CT in the detection of occult malignancy in patients
suspected for paraneoplastic syndrome.
26
FIGURE 5. Funnel plot of the included studies.
SUPPLEMENTAL TABLE 1. Modified QUADAS-2 questions used to assess the methodological quality of the included studies.
Risk of Bias (Low/ High/ Unclear risk)
Concerns regarding applicability (Low/ High/ Unclear risk)
Patient Selection
Could the selection of patients introduced bias? Was a consecutive or random sample of patients enrolled?
(Yes/ No) Was a case-control design avoided? (Yes/ No) Did the study avoid inappropriate exclusion? (Yes/ No)
Are there concerns that the spectrum of included patients do not match the topic of our study?
Index Test Could the conduct or interpretation of the index test have introduced bias?
Were the index test results interpreted blind to the results of the reference standard? (Yes/ No)
Are there concerns that the index test, its conduct, or interpretation differs from the topic of our study?
Reference Standards
Could the reference standard or its conduct have introduced bias? Are the reference standard likely to correctly classify the target
condition? (Yes/ No) Was the reference standards result interpreted without
knowledge of the results of the index test? (Yes/ No)
Are there concerns that the target condition as defined by the reference standard does not match the review question?
Flow and Timing
Could the patient flow have introduced bias? Was there an appropriate interval between index test and the
reference standard? (Yes/No) Did all patients receive a reference standard? (Yes/ No) Were all patients included in the analysis? (Yes/ No)
SUPPLEMENTAL Table 2. Summary of characteristics of the included studies
Author, Year Country Study design
N. patients (M: F)
Median age (range- Yrs)
Paraneoplastc presentation (N)
Patients with Positive paraneoplastic Ab (type of Ab) †
Previous history of treated cancer
Prior negative or inconclusive imaging ‡
Rees JH, 2001
UK R 43 (24:19)
62 (39- 86) Neurologic (43) 9/43 (20.9%) [8 anti-Hu, 1 anti-Yo]
3 [1 Bladder ca, 1 Melanoma, 1 Breast ca]
43/43 (100%)
Berner U, 2003
Germany R 30 (17:13)
55 (22- 76) Dermatologic (24) Neurologic (6)
NR NR
12/ 12 (100%)
Younes-Mhenni S, 2004
France P 20 (12:8) 62 (49- 78) Neurologic (20) 20/20 (100%) [12 anti-Hu, 1 anti Hu+anti CV2, 1 anti CV2, 4 anti-Yo, 1 anti Ri, 1 anti amphiphysin]
4 [2 Ovarian ca, 1 Breast ca, 1 Vocal cord ca]
20/20 (100%)
Linke R, 2004
Germany P 13 (4:9)
59 (22- 79) Neurologic (13) 13/13 (100%) [8 anti-Hu, 4 anti-Yo, 1 Anti-Tr]
6 [1 Neuroblastoma, 3 Ovarian ca, 1 SCLC, 1 Breast ca]
10/13 (77%)
Patel RR, 2008
US R 104 (46:58)
56 (17- 84) Neurologic (104) 73/104 (70.2%) [14 AchR, 19 ANNA, 1 Amphiphysin, 11 CRMP-5 IgG, 6 Striational, 9 N type Na channel, 9 VGCC, 12 K channel, 9 Glutamic acid decarboxylase]
NR 45 /71 (63.4%)
Hadjivassiliou M, 2008
UK P 80 (NA) NR Neurologic (80) 7/80 (8.7%) [5 Anti-Hu, 2 voltage-gated Ca Ab]
NR 80/80 (100%)
Masangkay N, 2008
US R 22 (8:14) NR (28- 82) Neurologic (22) NR NR 11/22 (50%)
Iyngkaran G, 2009
Australia R 24 (9: 15) 62 (36- 80) Neurologic (24) NR NR NR
Bannas P, 2010 *
Germany R 46 (22:24)
65 (21- 81) Neurologic (46) 4/40 (10%) [2 Anti-Hu, 1 anti-Ri, 1 CV2/CRMP5]
NR 38/46 (82.6%)
McKeon A, 2010 *
US R 56 (28:28)
61 (22- 80) Neurologic (56) 39/56 (69.6%) [6 ANNA-I, 2 PCA, 8 CRMP-5 IgG, 1 Amphihysin A, 9 AChR, 7 VGCC, 6 Striational, 2 VGKC, 1 Ma1, 3 unclassified]
10 [3 Breast ca, 2 Testicular ca, 1 Uterine ca, 1 Myeloma, 1 Lymphoma, 1 Lung ca, 1 Prostate ca]
56/56 (100%)
Selva-O’Callaghan A, 2010
Spain P 55 (18:37)
58 (46- 69) Dermatomyositis/ Polymyositis (55)
NR 0 46/55 (83.6%)
Grozdic I, 2011
Serbia R 124 NR NR NR NR NR
Han S, 2011 Scotland R 47 (18: 29)
58 (46- 70) All types NR NR NR
Matsushia A, 2012
Japan R 27 (16:11)
65 (41- 96) Neurologic (27) 2/7 (28.6%) [1 anti VGCC, 1 anti Hu]
2 [1 Lung ca, 1 HCC]
NR
Vaidyanathan S, 2012
UK R 68 (24:44)
58 (23- 82) Neurologic (55), Musculoskeletal (5),Endocrine (3), Constitutional (5)
34/68 (50%) [6 CA19-9, 6 CEA, 3 CA-125. 3 Anti-Hu, 3 Antiampiphysin, 2 Anti-MAG, 2 Anti-NMDA, 2 IgG, 1 Anti MA-2, 1 Anti Yo, 1 Anti CV2, 1 Anti AChR, 1 Anti PNMA, 1 Anti VGCC, 1 Anti VGKC, 1 beta HCG, 1 Anti-Ri]
8 [1 Breast ca, 1 Rectal ca, 1 Thyroid ca, 1 NHL, 1 Melanoma, 1 AML, 1 Lung ca, 1 Pancreatic ca]
NR
Chakraborty PS, 2013
India R 65 (44: 21)
65 (52- 78) Neurologic (65) 12/ 65 (18.5%) [Anti-Hu] NR NR
Fuster D, 2013
Spain R 24 (13: 11)
(38- 87) Neurologic (18), Hematologic (3), others (3)
NR NR NR
Schramm N, 2013
Germany R 66 (28:38)
60 (21- 87) Neurologic (60) 19/58 (32.7%) NR 54/66 (81.8%)
Crandall J, 2014
US R 226 (102:124)
60 (5- 86) All types NR NR NR
Gupta N, 2014 *
India R 80 (58: 22)
NR (10- 86) Neurologic (80) NR NR NR
Kristensen SB, 2015
Denmark R 137 (70:67)
61 (19- 63) Neurologic (67) Dermatologic (18) Rheumatologic(25) Nephrologic (6) Hematologic (2) others (19)
NR NR NR
Penapardo FJ, 2016
Spain R 73(47:26) 61 (NR) Neurologic (73) 14/55 (25.4%) 8 [1 Lymphoma, 2 Breast ca, 1 Prostate ca, 2 Colorectal ca, 1 Teratoma, 1 Renal ca]
NR
Vatankulu B, 2016
Turkey R 42 (26:16)
58 (14- 82) Neurologic (42) 21/34 (61.8%) [19 Anti-Hu, 18 Anti-yo, 9 Anti-Ri]
NR NR
Gupta K, 2016
India R 44 (25: 19)
NR NR NR NR NR
*Excluded from the quantitative analysis No reference standard for PET negative patients were reported
†: Proportion of patients with at least one positive paraneoplastic antibody among those with available results for paraneoplastic antibodies
‡: Proportion of patients with prior negative or inconclusive radiologic investigation among those with available prior imaging examinations
Ca, cancer; R, retrospective; P, prospective; Ab, antibody; NR, not reported; NHL, non-Hodgkin lymphoma; HCC, hepatocellular carcinoma; M:F,
male to female ratio; VGCC, Voltage gated Ca Channel; VGKC, Voltage gated K channel; CRMP-5 IgG, collapsin response-mediator protein 5
IgG; Yrs, years.
SUPPLEMENTAL Table 3. Summary of the index test, reference standard and proportion of patients diagnosed with underlying malignancy across the included studies.
Author, Year Index tests Index test interpretation
proportion of patients diagnosed with underlying malignancy
Reference standard (N) True positive PET / Total PET positive
Rees JH, 2001 18F-FDG-PET 2 NM physicians 10/43 (23.2%)6 Histo confirm (7) & FU of 18 mo (range 2 to 40 mo)
9/16
Berner U, 2003 18F-FDG-PET 2 NM physicians 7/30 (23.3%) Histo confirm (14) & FU of 43 mo (range 12 to 72 mo)
6/8
Younes-Mhenni S, 2004 18F-FDG-PET NR 18/20 (90%) Histo confirm (14) & FU of 12 mo (range 1 to 24 mo)
15/18
Linke R, 2004 18F-FDG-PET+ CT & CT
Various readers 10/13 (76.9%) Histo confirm (9) & FU of 48 to 60 mo
9/10
Patel RR, 2008 18F-FDG-PET & CT Various readers & 1 NM physician
10/104 (9.6%) Histo confirm (31) & FU of 18 mo (range 0.7 to 84 mo)
8/24
Hadjivassiliou M, 2008 18F-FDG-PET 1 radiologist 9/80 (11.2%) Histo confirm (8) & FU (NR) 9/18 Masangkay N, 2008 18F-FDG-PET & CT NR 9/22 (40.9%) Histo confirm (NR) 9/9 Iyngkaran G, 2009 18F-FDG-PET NR 3/ 24 (12.5%) Histo confirm (NR) & FU of 27 mo 3/8 Bannas P, 2010 * 18F-FDG-PET/CT 2 NM physicians &
2 radiologists 5 /46 (10.9%) Histo confirm (7) & FU (NR) 5/10
McKeon A, 2010 * 18F-FDG-PET/CT NR 10 / 56 (17.9%) Histo confirm (10) & FU (NR) 10/22 Selva-O’Callaghan A, 2010
18F-FDG-PET/CT & conventional screening#
1 NM physician & 1 radiologist
9/55 (16.4%) Histo confirm/ surgery (7) & FU of 14 mo (range 8 to 30 mo)
6/7
Grozdic I, 2011 18F-FDG-PET or PET/CT
NR 14/130 (10%) Histo confirm (9) & FU of 37 mo (range 11 to 63.5 mo)
13/13
Han S, 2011 18F-FDG-PET/CT NR 8/47 (17%) Histo confirm (16) & FU of at least 12 mo
7/13
Matsushia A, 2012 18F-FDG-PET/CT NR 6/27 (22.2%) Histo confirm/ surgery (6) & FU of 23.6 mo (range 1 to 86 mo)
5/6
Vaidyanathan S, 2012 18F-FDG-PET/CT Various readers 8/68 (11.8%) Histo confirm/ surgery (19) & FU of 8.9 mo (range 0.2 to 40 mo)
8/18
Chakraborty PS, 2013 18F-FDG-PET/CT 2 NM physicians 11/65 (16.9%) Histo confirm (NR) & FU of at least 11/14
6 mo (NR) Fuster D, 2013 18F-FDG-PET/CT NR 9/24 (37.5%) Histo confirm (9) & FU of at least 6
mo (15) 8/9
Schramm N, 2013 18F-FDG-PET/CT and CECT
1 radiologist & 1 radiology resident
9 /66 (13.6%) Histo confirm (10) & FU of 20 mo (range 3 to 57 mo)
9/10
Crandall J, 2014 18F-FDG-PET/CT Various readers 1246/226 (20.3%) Histo confirm (23) & FU of 60 mo (at least 12 mo)
26/34
Gupta N, 2014 * 18F-FDG-PET/CT 2 NM physicians 6/80 (7.5%) Histo confirm (12) 6/12 Kristensen SB, 2015 18F-FDG-PET/CT 1 NM physician 12/137 (8.8%) Histo confirm/ surgery (10) & FU of
26 mo (range 0.5 to 51.5 mo) 9/31
Penapardo FJ, 2016 18F-FDG-PET/CT 2 NM physicians 8/73 (10.9%) Histo confirm (17) & FU of 33 mo (range 12 to 96 mo)
6/7
Vatankulu B, 2016 18F-FDG-PET/CT 2 NM physicians 7/42 (16.7%) Histo confirm (7) & FU of 35 mo (range 8 to 68 mo)
6/6
Gupta K, 2016 18F-FDG-PET/CT NR 8/ 44 (18.2%) Histo confirm (25) & FU (range 13.5 to 17 mo)
8/12
*Excluded from the quantitative analysis; no reference standard for PET negative patients were reported
#Conventional screening, a combination of physical exam, laboratory tests, CT, mammography or ultrasonography
FN, False-Negative; TP, True-positive; Histo confirm, histopathology confirmation; NR, not reported; FU, follow-up; N, number; NM,
nuclear medicine physician.
SUPPLEMENTAL Table 4. Detailed information on true positive, false negative and
false positive results among the included studies.
Author, Year Detailed information on true positive, false negative and false positive sites (N) Rees JH, 2001 TP (9): SCLC (3), Lung (2), Adenoca unknown primary (1), Cecal ca (2), Colon ca (1)
FN (1): Breast ca (1) FP (7): Prostate (1), pleural fibrosis (1), hilum (1), Died w/o PM [Hilum (4)]
Berner U, 2003 TP (6): Bronch ca(3), Colon ca (1), Ovarian ca (1), Lymphoma (1) FN (1): Bronchial ca (1) FP (2): Adrenal adenoma (1), NR (1)
Younes-Mhenni S, 2004
TP (15): SCLC (9), Lung adenoca (2), Breast ca (2), Ovarian Ca (1), Thymoma (1) FN (1): Abdominal metastasis from ovarian ca (1), SCLC (1) FP (3): Parotid (1), mediastinum (2)
Linke R, 2004 TP (10): SCLC (5), HL (1), LN adenoca (1), Ovarian ca (2), Neuroblastoma (1) TN (0): None FP (1): Axillary node (1)
Patel RR, 2008 TP (8): thymoma (1), mixed adenoca/SCLC (1), mixed large cell/SCLC(1), SCLC (4), adenoca of unknown origin (1) FN (2): Serous ca of fallopian tube (1), metastatic spindle cell uterine ca (1) FP (16): NR
Hadjivassiliou M, 2008 TP (9): SCLC (4), NHL (1), Colon ca (1). Thymoma (1), Endometrial ca (1), high clinical suspicion (2) FN (3): SCLC in LN (1), high clinical suspicion (2) FP (9): Liver (1), Mediastinum (1), Hilum (1), Lung (1), Died w/o PM [Thoracic vertebra (1) and Mediastinum (4)]
Masangkay N, 2008 NR Iyngkaran G, 2009 NR Bannas P, 2010 TP (6): Neuroendocrine ca (1), SCLC (1), Adenoca (1), Gastric ca (1), Thymoma (1)
FN: Not mentioned FP (4): Vagina (1), Urinary bladder (1), Uterus (1), Maxilla (1)
McKeon A, 2010 TP (10): PC Thyroid (2), NSCLC (1), SCC of tonsil (1), Lung adenoca (1), Prostate ca (1), SCLC (2), Breast ca (1), Colon ca (1) FN: Not mentioned FP (12): Colon (1), Thyroid (2), LN (4), Lung (2), Esophagus (1), Cecum (1), Multiple foci (1)
Selva-O’Callaghan A, 2010
TP (6): Pancreatic ca (1), Lung ca (1), Colon ca (1), Breast ca (3) FN (3): Breast ca (2), Vaginal ca (1) FP (1): colon (1)
Grozdic I, 2011 TP (13): NR FN (1): cerebral tumor (1)
Han S, 2011 TP (7): PTC (1) SCLC (2), pulmonary carcinoid (1), recurrent colorectal ca (1), multiple metastases (1), active TB (1) FN (2): Lymphoma (1), brain tumor (1) FP (6): Vocal cord (1), thyroid (1), stomach (1), colon (1), ovary (1), bone marrow (1)
Matsushia A, 2012 TP (5): SCLC (1), Colon ca (1), Pancreas ca (1), Lung adenoca (1), PCT (1) FN (1): HCC (1) FP (1): lung granuloma (1)
Vaidyanathan S, 2012 TP (8): Pulmonary carcinoid (1), PCT (2), SCLC (2), Sigmoid ca (1), LN enlargement by CT treated as Ca (1), Died soon after (1) FN (0): None FP (11): NR
Chakraborty PS, 2013 TP & FP (14): Thyroid ca (4), Lung ca (2), lymphoma (2), Colon ca (2), breast ca (1), Prostate ca (1), brain metastases (1), bone metastases (1)
FN (0): None
Fuster D, 2013 TP & FN (9): Lung ca (4), CNS tumor (3), ovarian ca (1), duodenal ca (1) FP (1): NR FN (1): NR
Schramm N, 2013 TP (9): SCLC (1), Cervical ca (2), Bladder ca/bronchial ca (1), Breast ca (2), Ovarian ca (1), Lung adenoca/ tonsil ca (1), Tonsil ca (1) FN (0): None FP (5): Thymus (1), NR (4)
Crandall J, 2014 TP (26): SCLC (6), Adenoca of UO (2), Ca of UO (1), Pancreas ca (3), Ovarian ca (2), NSCLC (2), Lymphoma (2), Thyroid ca (1), Renal ca (1), Esophageal ca (1), Colorectal ca (1), Breast ca (1), high clinical suspicion (3) FN (20): NR FP (8): NR
Gupta N, 2014 TP (8): Lung ca (3), urinary bladder transitional cell ca (1), Colon ca (2), Sarcoidosis (1), Tuberculosis (1) FP (4): NR
Kristensen SB, 2015 TP (9): NSCLC (4), Breast ca (1), Lymphoma (2), Pheochromocytomoa (1), Unknown primary (1) FN (3): Gastric ca(1), Glottis ca (1), Parotid Small cell neuroendocrine ca(1) FP (22): Lymph node (5), pelvis (1), breast (3), intestine (3), rectum (4), lung (4), uterus (1), bone marrow (1)
Penapardo FJ, 2016 TP (7): Lung ca (3), Breast ca (1), Lymphoma (1), Rectal ca (1), NR (1) FN (4): Prostate ca (1), Bladder ca (1), NR (2) FP (18): NR
Vatankulu B, 2016 TP (6): NHL (1), Thymic ca (1), SCLC (3), Gallbladder ca (1) FN (1): Gastric ca (1) FP (0): None
Gupta K, 2016 TP (8): mostly SCLC, lymphoma
NR, not reported; HL, Hodgkins’ lymphoma; NHL, Non-Hodgkin lymphoma; ca, cancer; UO,
unknown origin; SCLC, small cell lung cancer; adenoca, adenocarcinoma; N, number; PCT,
papillary thyroid carcinoma; w/o PM, without proven malignancy; ca, Cancer; (N), number of
patients; LN, lymph node.
Top Related