Received: 25 September 2018 Accepted: 28 September 2018

DOI: 10.1002/dc.24097

ORIGINAL ARTICLE

Retrospective assessment of the effectiveness of the Milan

system for reporting salivary gland cytology: A systematic
review and meta-analysis of published literature
Sahar J Farahani MD, MPH | Zubair Baloch MD, PhD

Department of Pathology and Laboratory

Medicine, Hospital of the University of
Pennsylvania, University of Pennsylvania,
Philadelphia, Pennsylvania
Correspondence
Sahar J Farahani, Department of Pathology
and Laboratory Medicine, Hospital of the
University of Pennsylvania, University of
Pennsylvania, Perelman School of Medicine,
3400 Spruce St, 6 Founders, Philadelphia, PA
19104
Email: sahar.jalali-farahani@uphs.upenn.edu
Abstract
Introduction: Fine needle aspiration (FNA) has been widely utilized in establishing the nature of
salivary gland lesions and guiding the clinical management. This study aimed to determine the
accuracy of FNA in detecting salivary gland neoplasms and malignancies, employing the “Milan
System for Reporting Salivary Gland Cytopathology” (MSRSGC).
Method: A systematic search was conducted. The data on FNA and histologic diagnosis were
extracted and categorized based on the MSRSGC and risk of malignancy (ROM) was calculated.
The risk of publication bias and level of heterogeneity were evaluated. A mixed-effects model
was used to estimate FNA accuracy. Meta-regression was conducted to assess the potential
effect of different variables on FNA accuracy.
Results: Ninety-two studies with a total of 16 456 FNA with surgical follow-up were included.
ROM was estimated as 17%, 8%, 34%, 4%, 42%, 58%, and 91%, in nondiagnostic, nonneoplastic,
atypia of undetermined significance, benign neoplasm, salivary gland neoplasm of uncertain
malignant potential, suspicious for malignancy, and malignant groups, respectively. High level of
heterogeneity was detected (P-value <.001). Including cases with definite FNA diagnosis of neo-
plasm or malignancy, summary estimates of FNA sensitivity, specificity, diagnostic odds ratio,
and positive and negative likelihood ratio in detecting neoplasms and malignancies were 96.9%,
95.3%, 636.8, 20.5, and 0.03, and 80.5%, 97.9%, 189.5, 37.8, and 0.2, respectively. Meta-
regression showed several variables significantly impacting FNA accuracy; however, subgroup
analysis did not reduce the level of heterogeneity.
Conclusion: FNA can be used as a reliable diagnostic tool in the preoperative evaluation and man-
agement of salivary glands lesions. Concise of abstract is using Milan system for reporting salivary
gland FNA could increase FNA reliability, facilitate communication, and improve patient care.

KEYWORDS

diagnostic accuracy, FNA, meta-analysis, Milan system for reporting salivary gland cytology,
salivary gland malignancy, salivary gland neoplasm

1 | I N T RO D UC T I O N differentiation between a benign and malignant neoplasm is crucial in

Salivary gland tumors account for less than 4-6% of head and neck
masses and comprise a heterogeneous group of lesions with diverse
etiologies and variable biological behavior. The mentioned variations
warrant a specific treatment plan based on the underlying pathology.
The nonneoplastic lesions of salivary glands comprising approximately
20%-50% of all salivary gland lesions are managed conservatively with
medical treatment and clinical follow-up.1,2 The salivary gland neo-
plasms often require surgical resection; nevertheless, the preoperative
determining the urgency, and extent of surgery.3,4 Moreover, in some
cases distinguishing between different subtypes of primary and sec-
ondary malignancies of salivary glands is essential to predict the risk
of occult metastasis, local or distant recurrence and the need for addi-
tional treatment modalities such as local irradiation or systemic che-
motherapy in the biologically aggressive subtypes.5
Fine needle aspiration (FNA) is a minimally invasive, inexpensive,
and widely accessible diagnostic procedure. It has proven to be a use-
ful tool in obviating unnecessary surgical resection of nonneoplastic

Diagnostic Cytopathology. 2018;1–21. wileyonlinelibrary.com/journal/dc © 2018 Wiley Periodicals, Inc. 1

2 FARAHANI AND BALOCH
lesions and in management of neoplasms by differentiating between
salivary gland nonneoplastic lesions, benign and malignant neoplasms
with high accuracy.6–9 However, in some cases, the FNA fails to fulfill
this task due to the architectural and cellular complexity of salivary
gland neoplasms encountered among the same subtypes and even
within an individual tumor. Also, the subtle cytomorphological fea-
tures of low-grade malignant neoplasms, and extensive cellular and
architectural overlap between tumor subtypes with entirely different
biological behaviors can be challenging in arriving at a definite diagno-
10,11
sis based on the limited FNA material. Moreover, the accuracy of
FNA can also be significantly affected by variation in sample collec-
tion, preparation, evaluation and interpretation.
In response to the limitations of salivary gland FNA to increase its
reproducibility and promote its clinical relevance; a group of interna-
tional pathologists proposed a classification system known as the
“Milan system for reporting salivary gland cytology report (MSRSGC)”.
The MSRSGC classifies the results of salivary gland FNA into the fol-
lowing diagnostic categories: “nondiagnostic”, “nonneoplastic”, “atypia
of undetermined significance (AUS)”, “neoplasm-benign”, “neoplasm-
salivary gland neoplasm of uncertain malignant potential (SUMP)”,
“suspicious for malignancy”, and “malignant”. These are based on risk
stratification rather than the specific histological subtypes and are
broad enough to accommodate the morphologic diversity of salivary
gland tumors. It is expected that the MSRSGC classification will facili-
tate the communication between pathologists and treating clinicians
and improve patient care. 12,13
In this study, we conducted a systematic review and meta-
analysis of all available literature on salivary gland FNA to determine
its accuracy in detecting salivary gland neoplasms, to report potential
factors impacting its diagnostic performance, and to evaluate the effi-
ciency and clinical utility of the MSRSGC classification.
2 | MATERIALS AND METHODS
Institutional Review Board (IRB) approval was not obtained for this
study as it only involves a review of published literature. The
Cochrane Guideline for meta-analysis of diagnostic studies and Pre-
ferred Reporting Items for Systematic Review and Meta-Analysis
(PRISMA) were followed in developing the study protocol, in conduct-
ing the review and analysis, and reporting of the results.14,15 Two
authors (ZB and SJF) formulated research questions, primary and sec-
ondary objectives, study protocol with regards to the search strate-
gies, eligibility criteria for primary screening, study selection, and final
inclusion, and application of statistical methods.
The research question was formulated according to PICO
(Patient, Intervention, Comparison, Outcome) format to investigate
the diagnostic performance of FNA in: differentiating between non-
neoplastic, benign and malignant neoplasms in patients presenting
with major and minor salivary gland masses, in comparison to surgical
pathology follow-up, and in the light of the MSRSGC proposed diag-
nostic categories. The primary objective of the study was defined as
determining the accuracy of FNA in diagnosing salivary gland lesions.
The secondary objectives were to evaluate the level of, and identify
the potential factors were causing heterogeneity in diagnostic
performance of FNA across the published literature, and determine
the efficacy of MSRSGC in standardization and reduction of this het-
erogeneity in reporting FNA diagnoses of salivary gland lesions.
2.1 | Literature search
A comprehensive systematic search was conducted across PubMed/
MEDLINE, Embase, and Scopus database, without restrictions on publi-
cation year. The appropriate keywords and subject headings were gener-
ated with a focus on three parameters: salivary gland pathology, FNA,
and diagnostic performance of FNA. For each parameter, an individual
search was carried out for selected keywords and related medical subject
heading (MeSH) terms. This step was followed by a search combining
keywords and MeSH terms using “OR” commands. Afterward, the search
results of the three parameters were connected with “AND” command
to shape the final results. The same strategy was followed searching
Embase database using the keywords and relevant subject heading
(Emtree). Scopus database was searched using the same keywords as
PubMed and Embase. The reference lists of relevant identified studies
were manually searched to ensure the capture of all available literature.
After filtering the duplicate articles using Endnote software (X8.2,
Bld. 13302), title and abstract of the retrieved studies were reviewed
to determine their eligibility to be included in the primary screening
process. The eligibility criteria for s included: studies written in English
language and which evaluated the diagnostic performance of FNA in
detecting salivary gland tumors and differentiating malignant from
benign neoplasms and/or neoplasms from nonneoplastic lesions.
The full text of eligible studies was retrieved and reviewed to
select only those which met the prespecified inclusion criteria. The
inclusion criteria were defined as original study, a total sample size of
100 or more cases of salivary gland or head and neck tumors compris-
ing of at least 50 cases of salivary gland lesions in latter, and corre-
sponding histopathologic follow-up. The studies labeled a review, case
reports, commentary, and editorials or abstracts were excluded.
Moreover, studies were also excluded if number of FNA true and false
positive, and true and false negative in comparison to histology cannot
be reproduced based on the reported data, or the risk of malignancy
(ROM) could not be separately determined for the intermediate and
definite diagnostic categories.
2.2 | Data extraction
A data extraction sheet was developed based on the PRISMA data
extraction template. After pilot-testing of the primary sheet on 10 ran-
domly-selected studies and making adjustments, following information
were extracted from each study: study population (inclusion and exclu-
sion criteria, age, gender, co-morbidities, secondary tumor); setting and
location of subject recruitment; study methods (design and random or
consecutive enrollment); index test (description of FNA procedure in
regards to the needle size, number of passes, conventional or liquid-
based preparation, stains, ancillary techniques, use of image guidance;
rapid on-site cytological examination [ROSE]; and interpretation of the
results); description of the reference test and its interpretation (histo-
pathologic follow-up); the interval between index (FNA) and reference
tests; and the number of FNA cases with histological follow-up. The
FARAHANI AND BALOCH
FNA diagnoses and their corresponding histopathologic follow-up were
used to tabulate 2*2 contingency table.
2.3 | Quality assessment of included studies
Two authors (ZB and SJF) assessed the quality of the selected studies
according to the Quality Assessment of Diagnostic Studies
(QUADAS)-2 questionnaire to evaluate the risk of bias in the domains
concerning the patient selection; index and reference test execution,
evaluation, and interpretation; and study flow and timing.
2.4 | Descriptive statistics, analysis, and data
synthesis
2.4.1 | Milan system for reporting salivary gland cytology
The extracted data on cytology diagnosis of included cases were
sorted and grouped into six diagnostic categories of the MSRSGC.
The corresponding histological diagnoses were categorized as non-
neoplastic, benign neoplasm, and malignant neoplasm. The number
and percentage of neoplastic, benign, and malignant neoplasms in
each MSRSGC categories were determined.
The prevalence of nonneoplastic, benign neoplasm, and malignant
neoplasm in each of the MSRSGC categories was estimated for the indi-
vidual study. The I2 index of heterogeneity and Cochrane Q statistics
test were used to assess the presence of potential variations in classify-
ing cytology and histology diagnosis across the selected studies. When
a moderate to high level of the heterogeneity was observed (indicated
by an I2 index of heterogeneity≥50 with a P-value<.05); a univariate
random-effects model was utilized to estimate the mean prevalence of
nonneoplastic, benign neoplasm, and malignant neoplasm in each of the
MSRSGC categories to take into account the intra and inter-study varia-
16
tions. In estimating the mean prevalence of benign (nonneoplastic/
benign neoplasms) and malignant lesions in each of the MSRSGC cate-
gories, all the studies were included. However, only the studies which
made the distinction between these two categories on histologic
follow-up were used to estimate the prevalence of nonneoplastic and
benign neoplasms (to be representative of general population).
2.4.2 | Diagnostic performance of FNA in detecting
salivary gland neoplasms and malignancy
Descriptive statistics
Data from 2*2 contingency table was used to calculate the FNA sensi-
tivity and specificity, diagnostic odds ratio (DOR), and positive and neg-
ative likelihood ratio (PLR and NLR) in differentiating nonneoplastic
lesions versus neoplasms and benign versus malignant neoplasms of sal-
ivary glands for each study. In order to avoid zero as the denominator
in calculating DOR, PLR, NLR, a fixed continuity correction factor of 0.5
was added to each of TP, FP, FN, TN cells when a zero in FP and FN
cells encountered. The forest plots were generated to illustrate the
FNA sensitivity and specificity in detecting salivary gland neoplasms
and malignancies with their corresponding 95% confidence interval (CI).
Assessment of heterogeneity and data synthesis
The potential presence of intra and inter-study variations were assessed
visually using the forest plots and statistically by the Cochrane Q test
3
and I2 index of heterogeneity. The Spearman's Rho rank correlation test
was used to evaluate the presence of threshold effect by assessing the
correlation between the logit of true positive rate (sensitivity) and false
positive rate (1-specificity). A P-value <.05 in spearman's test was con-
sidered as the presence of the threshold effect.
A bivariate generalized linear mixed-effects model with maximum
likelihood estimation was used to calculate the summary points for the
FNA sensitivity, specificity, DOR, PLR, and NLR in differentiating
between nonneoplastic, benign, and malignant neoplasms.17 A summary
receiver operating characteristics (SROC) curve with 95% confidence
and prediction regions was generated using the parameters estimated
from a hierarchical receiver operating characteristics (HSROC) model
and the area under the curve (AUC) was calculated accordingly.18 In a
SROC curve, 95% confidence region around the summary estimates of
sensitivity and specificity is the area that real value of sensitivity and
specificity would be expected to lie in, based on the observed data. On
the other hand, 95% prediction region indicates the region that the
results of any future study would be expecting to be located. In other
words, the confidence region depicts uncertainty in the overall average
values caused by the intra-study variations, while the prediction region
demonstrates the variation from study heterogeneity. Where heteroge-
neity is high, it is expected that 95% prediction region is much larger
than the 95% confidence region.14
Likelihood ratios, pretest, and posttest probabilities
The clinical utility of FNA in detecting salivary gland neoplasms and
malignancies was evaluated based on the PLRs and NLRs. The PLR
and NLR can be used to update the pretest probability of a target con-
dition, which is equal to its baseline prevalence in the studied popula-
tion, in the form of posttest probability using the followed formulas:
• Posttest Probability (Prob.) on Positive FNA results = (Pretest
Prob.*PLR)/ (1+ {Pretest Prob.*[PLR-1]})
• Posttest Probability (Prob.) on Negative FNA results = (Pretest
Prob.*NLR)/ (1+ {Pretest Prob.*[NLR-1]})
In general, a PLR > 10 and NLR < 0.1 indicate an informative
diagnostic test in ruling in and ruling out the target condition (neo-
plasms or malignancies in this instance), respectively.
Investigating the potential sources of data heterogeneity, meta-
regression, and subgroup analysis
To further investigate the potential source of heterogeneity among
the included studies, multiple univariate linear models were used to
evaluate the impact of different covariates on the summary measures
of sensitivity and specificity. These included: variations in study design
and methodology, patient population and setting, execution, prepara-
tion, and evaluation of the index (FNA) and reference (histologic
follow-up) tests.
An HSROC model was used to assess the potential effect of co-
variables on the shape and asymmetry of SROC. While the general-
ized linear models account for intra and inter-study variations by
modeling the mean logit of sensitivity and specificity against each
other, the HSROC models do it by modeling the accuracy and
4 FARAHANI AND BALOCH
threshold parameters.19 Therefore, in investigating the potential
source of heterogeneity, the effect of covariates which affect the sen-
sitivity or specificity or both without affecting the shape of SROC
could be assessed by a linear model. However, the co-variables that
increase or decrease the sensitivity and specificity with different mag-
nitude alter the shape and symmetry of an SROC. The latter effect
18,19
could be evaluated using an HSROC model.
In addition, in an attempt to generate a more homogeneous group
of studies, the variables with a significant effect (P-value <.05) on the
mean sensitivity, specificity or the SROC shape were used to subdi-
vide the primary studies into the smaller subgroups, and the summary
estimates of sensitivity, specificity, DOR, PLR, and NLR associated
with each subgroup were calculated.
Investigating and handling publication bias
The presence of publication bias was assessed using the Deek's funnel
plot asymmetry test. Visual asymmetry in the funnel plot and P-value
<.1 for the slope coefficient could imply the presence of publication
20
bias. When the Deek's test indicated the presence of publication bias,
the Trim and Filled method was used to generate a hypothetical cohort
of studies by adding the potentially missing studies due to the publica-
tion bias. The DOR and I2 index of heterogeneity were estimated for
this hypothetical cohort. Reduction in the I2 index of heterogeneity
with a significant difference between the DORs evaluated from the
original data and the hypothetical group (P-value <.05) could indicate
that the accuracy of the studied index test is overestimated due to the
publication bias.21,22 However, if the I2 index of heterogeneity does not
change or even increases in the hypothetical data set, the observed
asymmetry in the funnel plot of the original data could be attributable
to the high level of heterogeneity among the included studies.23
Investigating and handling partial verification bias
The majority of included studies were a retrospective review of the
FNA diagnosis and histological follow-up. A majority of cases with a
nonneoplastic diagnosis on FNA did not undergo the surgical resec-
tion. As only studies with the surgical histological follow-up were con-
sidered eligible for this study; it was expected that only a smaller
percentage of cases with the nonneoplastic diagnosis on cytology had
the surgical follow-up as compared to the ones diagnosed as a neo-
plasm. The same scenario could be expected for FNA cases diagnosed
as benign neoplasm, however, in a smaller percentage, since the treat-
ment of choice for most cases will be surgical resection.
This phenomenon is known as the partial verification bias, it is
common in the diagnostic studies and can result in the overestimation
of the disease prevalence and sensitivity, and underestimation of the
specificity.24
An interactive web-based tool known as Global Sensitivity Analy-
sis (uwmsk.org/gsa) was utilized to calculate the corrected sensitivity
and specificity based on the ratio of the FNA cases with the positive
and negative results for a neoplasm/malignancy with or without surgi-
cal follow-up. Besides, this tool conducted several sensitivity analyses
using all the possible results on histologic follow-up for the FNA cases
which did not undergo surgical excision. This helped to determine
whether the chance of not receiving the histologic follow-up was
dependent on the observed (such as the results of FNA or other
reported factors that is, patients age or ultrasound or palpation-guided
FNA) or on unobserved data and most importantly on the histologic
diagnosis (eg, the patients with malignant tumors had less chance of
undergoing excision compared to benign cases due to their poor
health condition).25,26
The analyses were conducted in Stata software (Stata/SE 13.1,
College Station, TX) and Microsoft Excel using MetaXL extension.
3 | RE SU LT S
3.1 | Literature search
After removing the duplicate studies, the literature searches yielded
2209 articles (Figure 1). After reviewing the titles and abstracts, 2034
articles were excluded. The full text of the remaining 175 articles were
reviewed, and 92 studies were identified as eligible for systematic
review and meta-analysis. Three of the 92 articles reported data sepa-
rately on two different cohorts of patients from two different centers.
These were treated as two separate studies, and the systematic
review and meta-analysis included 95 individual patient cohorts.
3.2 | Selected studies characteristics and quality
assessment
The pooled data comprised of 31 852 cases of salivary gland tumors,
which included 908 cases with only clinical follow-up, 3963 cases of
surgically resected lesions without preoperative FNA, 10 525 cases of
FNA without histologic follow-up, and 16 456 cases of FNA with the
histologic follow-up. On average, 44.2%  5.1% (mean  [Standard
Error*1.96]) of FNA cases proceeded to surgical resection. In the stud-
ies which reported the demographics of enrolled patients, the mean
age, and male to female ratio were 51.0  11.1 (ranged between
<1 month to 100 years) and 1.04:1, respectively. Of the 16456 FNA
cases with histologic follow-up, 6733 (41%) were located in parotid,
575 in submandibular (3.5%), and 19 in sublingual or minor salivary
glands (0.1%). The site of salivary gland mass was not specified in
9129 (55%) cases.
Of the 92 included studies, 5 were prospective,27–31 and the rest
were retrospective analyses. In 14 studies the subject enrollment was
carried out consecutively or randomly.27–40
The FNA procedure was performed by cytologists in 11, by radiol-
ogists in 2, by clinicians in 12, and by clinicians/cytologists for the
palpable masses and by radiologists for the impalpable tumors in
16 studies. In seven studies, all FNAs were performed under ultra-
sound guidance,28,30,38,41–44 while eight studies explicitly mentioned
that no radiologic guidance was employed.45–52 The use of ancillary
studies for the selected cases was reported in 8 studies.34,53–59 ROSE
was available in 14 studies.29,32,37,39,47,51,59–66
The quality of included studies was assessed according to the
QUADAS-2 questionnaire. None of the studies were considered as
low-bias-risk in all four domains. Figure 2 summarizes the overall
results of the QUADAS-2 questionnaire for the included studies.
FARAHANI AND BALOCH 5

FIGURE 1 PRISMA flow chart of identified, eligible, included and excluded studies

3.3 | Analysis and data synthesis
3.3.1 | The Milan system for reporting salivary gland
cytopathology classification
The 16 456 FNA cases with the histologic follow-up were sorted into
the diagnostic categories of MSRSGC as follows: “nondiagnostic”,
622; “nonneoplastic”, 1269; “AUS”, 110; “benign neoplasm”, 10 979;
“SUMP”, 397; “suspicious for malignancy”, 122, and “malignant”, 2957
cases.
In estimating the mean prevalence of histologic follow-up diagno-
sis of nonneoplastic, benign neoplasm and malignant neoplasm for dif-
ferent MSRSGC categories, I2 index of heterogeneity and Cochrane Q
test indicated moderate to high level of heterogeneity in all categories
(70%-83%, P-value <.001), except for cases classified as AUS (45%, P-
value: .06). Based on these findings, the pooled mean prevalence was
estimated using mixed-effects generalized linear model.
Table 1 summarizes the number and percentage of the FNA spec-
imens with the histologic follow-up as well as the mean prevalence of
histopathologic diagnoses for the diagnostic categories of MSRSGC
classification, using a mixed-effects model.
Nondiagnostic
The diagnostic terms “nondiagnostic”, “inadequate”, “insufficient”,
“unsatisfactory”, “sampling error” were used in 67 studies. In 49 stud-
ies, these terms were used to describe the samples containing only
blood, necrotic material, acellular cyst content, benign salivary gland
tissue in the presence of a mass; or when there was insufficient cellu-
larity or analyzable material to render a diagnosis based on the FNA
specimen. In 16 studies, the term “nondiagnostic” or “unsatisfactory”
was used without any further explanation. In three studies, the term
“nondiagnostic” was also used to classify specimens with questionable
or indefinite diagnosis or with atypical features. The cases extracted
from these three studies were not classified as a “nondiagnostic” in
the present study, b MSRSGC criteria for the nondiagnostic category.
The histological follow-up of “nondiagnostic” cases was reported in
44 studies. Of these, in 25 studies the authors made a distinction

QUADAS-2 Questionnaire
Enrolled Patients Consecutively or Randomly 15 80

Avoided Case-Control Design 95

Avoided Inappropiate Exclusion 64 3 28

Cytology Was Interpreted Blindly to Histology Result 45 47 3

Hitology Classified SGT Correctly 95

Histology Was Interpreted Blindly to Cytology Result 7 85 3

Appropiate Interval Between Cytology and Histology 3 92

All Patients Received Histology/Clinical Follow-up 27 9 59

All Patients Included in the Analysis 95

0 10 20 30 40 50 60 70 80 90 100

Yes Unclear No

FIGURE 2 Overall summaries of QUADAS-2 checklists in patient selection, index and reference tests, and study flow and timing domains for the
included studies
6 FARAHANI AND BALOCH

TABLE 1 Number of specimens and pooled mean prevalence of histological diagnosis of non-neoplastic, benign neoplasms, and malignant
neoplasms across six categories of the MSRSGC classification
Neoplasm
Cytology Nondiagnostic Nonneoplastic AUS Benign neoplasm SUMP Suspicious for Malignant
Histology Number Number Number Number Number malignancy Number Number
Specimen Number (%) 622 (3.8) 1269 (7.7) 110 (1) 10 979 (66.8) 379 (2.3) 122 (0.1) 2957 (18.0)
Nonneoplastic
Specimen Number (%) 100 (16.1) 1006 (79.3) 23 (20.9) 49 (0.45) 30 (7.56) 4 (3.3) 53 (1.79)
Mean prevalencea (%) 20.0 82.2 36.7 0.7 7.9 5.0 2.1
(95% CI) (15.1-23.9) (79.1-83.3) (25.2-50.2) (0.5-0.9) (4.2-12.2) (1.1-11.1) (1.6-2.7)
Benign neoplastic
Specimen Number (%) 394 (63.4) 150 (11.8) 46 (41.8) 10 342 (94.2) 242 (61.0) 43 (35.3) 269 (9.10)
Mean prevalencea 62.7 9.4 29.5 95.8 50.6 36.6 6.8
(95% CI) (55.1-65.9) (7.8-11.0) (18.7-42.5) (95.2-96.3) (42.5-57.2) (26.2-47.4) (5.9-7.8)
Malignant
Specimen Number (%) 128 (20.6) 113 (8.9) 41 (37.3) 588 (5.4) 125 (31.5) 75 (61.5) 2635 (89.1)
Mean prevalencea 17.3 8.4 33.8 3.5 41.5 58.4 91.1
(95% CI) (12.7-21.0) (6.9-9.9) (22.6-47.1) (3.1-4.0) (33.8-48.2) (47.1-68.7) (90.4-92.5)

Abbreviations: AUS, atypia of undetermined significance; SUMP, salivary gland neoplasm of uncertain malignant potential; CI, confidence interval.
a
Pooled prevalence of nonneoplastic, benign neoplasms, and malignant neoplasms across the six categories of the MSRSGC in the studies which made a
distinction between nonneoplastic lesions and benign neoplasms, adjusted for inter and intra-study variations.

between the nonneoplastic and benign neoplasms on histologic
follow-up.
A total of 622 cases with the FNA diagnosis of “nondiagnostic”
were extracted from the 44 studies mentioned above. The rate of non-
diagnostic FNA ranged from <1% to 44%; 75% had a nondiagnostic rate
of ≤10%. The rate of nondiagnostic salivary gland FNA in the studies
conducted at general hospitals was 21.28%  17.47% as compared to
4.38%  2.32% performed at the tertiary or referral cancer centers.
This difference was statistically significant (P-value: .002). The rate of
nondiagnostic FNA was significantly lower in studies in which the cytol-
ogists performed FNA procedures, when compared to the rest of the
studies (3.63%  6.2% vs 9.78%  2.55%, P-value: .004).
On histologic follow-up, the mean prevalence of benign (nonneo-
plastic/benign neoplasm) and malignant neoplasms in 44 studies, esti-
mated by a random-effects model, was 81% (77%-83%) and 19%
(17%-23%), respectively. The pooled mean prevalence of nonneoplas-
tic, benign and malignant neoplasms, derived from 25 studies, which
distinguished between nonneoplastic and benign neoplasms on histo-
pathologic follow-up was 20% (15%-24%), 63% (55%-66%), and 17%
(13%-21%), respectively.
Nonneoplastic
A total of 1269 specimens could be retrospectively classified as non-
neoplastic in 45 studies. On the histopathologic follow-up, 1006 cases
were diagnosed as nonneoplastic, 150 cases as benign and 113 cases
as the malignant neoplasms. The summary estimates of nonneoplastic,
benign and malignant neoplasms on histologic follow-up were 82%
(79%-83%), 9% (8%-11%), and 8% (7%-10%), respectively.
Atypia of undetermined significance
The 16 studies employed the terms “atypia”, “non-contributory”, “non-
diagnostic”, or “indeterminate” in a total of 110 cases to report the FNA
samples with sufficient cellularity and containing atypical cells. This
term was employed for FNA cases in, which the differentiation
between nonneoplastic and neoplasm could not be made. Using a
random-effects model, the summary prevalence of histologic follow-up
diagnosis of benign (nonneoplastic/benign neoplasms) and malignant
tumors was 63% (54%-71%) and 37% (29%-46%), respectively. In
11 studies in which the histologic follow-up diagnoses of the nonneo-
plastic and benign neoplasms were reported separately, the mean prev-
alence of nonneoplastic, benign neoplasms, and malignant neoplasms
were 37% (25%-50%), 30% (19%-43%), 34% (23%-47%), respectively.
Neoplasm
Benign. A total of 5737 FNA specimens were interpreted as “benign
neoplasm” in 56 studies. This diagnosis was confirmed on the surgical
follow-up in 5464 cases; 46 cases were diagnosed as nonneoplastic
and 227 as malignant neoplasms. The mean prevalence of nonneo-
plastic, benign neoplasm, and malignant neoplasm, estimated by
random-effects model was 1% (0.5%-0.9%), 96% (95%-96%), and 4%
(3%-4%), respectively.
In the remaining studies from the pooled cohort, 5242 cases were
classified as “benign” on FNA without distinguishing between the
nonneoplastic lesion and benign neoplasm. On histologic follow-up,
the mean prevalence of benign and malignant lesions was 5% (5%-6%)
and 95% (94%-96%), respectively.
SUMP. In 29 studies, the diagnostic terms “indeterminate”, “neo-
plasm”, “neoplasm not otherwise specified”, “tumor”,” atypia”, or
“basal cell or basaloid neoplasm” were used for a total of 397 cases to
describe a specimen with sufficient cellularity and definite features of
a neoplasm but lacking of required elements to render a definite diag-
nosis of benign versus malignant neoplasm. The summary estimates of
benign (nonneoplastic/benign neoplasm) and malignant neoplasm
diagnosis on histology was 66% (62%-71%) and 34% (29%-38%)
respectively. In 20 studies, the distinction between the nonneoplastic
lesion and benign neoplasm were made on the histologic follow-up.
The summary estimate of nonneoplastic, benign neoplasm, and
FARAHANI AND BALOCH
malignant neoplasm in these studies was 8% (4%-12%), 51% (43%-
57%), and 42% (34%-48%), respectively.
Suspicious for malignancy
A total of 122 cases extracted from 17 studies were considered as “sus-
picious for malignancy” on FNA. On histologic follow-up, 4 cases were
diagnosed as nonneoplastic, 43 as benign and 75 as malignant
neoplasms. The mean prevalence of benign (nonneoplastic/benign
neoplasms) and malignant neoplasm were 37% (29%-46%) and 63%
(54%-71%). Twelve studies reported the histologic follow-up diagnosis
of the nonneoplastic lesion and benign neoplasms separately, the mean
prevalence of nonneoplastic, benign neoplasm and malignant neoplasm
were 5% (1%-11%), 37% (26%-47%), 58% (47%-69%), respectively.
Malignant
A total of 2957 cases were diagnosed as either a primary or secondary
malignant tumor of the salivary gland on FNA. The malignant diagnosis
was confirmed on histology in 91% (90%-92%) cases. The remaining
2% (2%-3%) and 7% (6%-8%) cases were diagnosed as nonneoplastic
and benign neoplasms on the histopathologic follow-up.
3.3.2 | Analysis and data synthesis
Differentiating non-neoplastic from neoplasm
Of the 92 included studies, 45 had sufficient information to evaluate
the diagnostic accuracy of salivary gland FNA in distinguishing
between a nonneoplastic lesion and a neoplasm. The number of true
and false positive and negative cases, sensitivity, specificity, DOR,
PLR, and NLR in the individual primary studies are summarized in
Table 2.
In estimating the accuracy of salivary gland FNA four scenarios
were considered: (1) recognizing the FNA cases interpreted as “non-
neoplastic” as the negative index test result for neoplasm, and cases
classified as “nondiagnostic”, “AUS”, “benign neoplasm”, “SUMP”, “sus-
picious for malignancy”, and “malignant” as the positive index test
result for neoplasm; (2) excluding “nondiagnostic” cases from the anal-
ysis, considering FNA cases in the diagnostic category of “nonneoplas-
tic” as the negative index test result for neoplasm, and the ones in
“AUS”, “benign neoplasm”, “SUMP”, “suspicious for malignancy”, and
“malignant” categories as the positive index test result for neoplasm;
(3) including the cases with definite diagnosis for neoplasm in the
analysis; considering the FNA cases in diagnostic category of “non-
neoplastic” as the negative index test result for neoplasm, and” benign
neoplasm”, “SUMP”, “suspicious for malignancy”, and “malignant” as
the positive index test result for neoplasm; (4) recognizing FNA cases
classified as “nondiagnostic”, “nonneoplastic”, and “AUS” as the nega-
tive index test result for neoplasm, and cases classified as “benign
neoplasm”, “SUMP”, “suspicious for malignancy”, and “malignant” as
the positive index test result for neoplasm.
The Cochrane Q test showed significant heterogeneity in FNA
sensitivity, specificity, and DOR (P-value <0.001). The I2 index of FNA
sensitivity, specificity, and DOR were 70% (95% CI: 65%-76%), 74%
(95% CI: 68%-82%), and 74% (66%-82%), respectively. The forest
plots (Figure 3A,B) depict the individual study sensitivity and specific-
ity and their corresponding 95% CI and the variations across the
7
included studies. The Spearman rank-order correlation test showed a
significant, although a positive association between the mean sensitiv-
ity and specificity (coefficient: 0.34, P-value: .02).
Table 3 summarizes the estimated FNA summary sensitivity, speci-
ficity, DOR, PLR, and NLR in distinguishing neoplasms and nonneoplas-
tic lesions of the salivary gland in five scenarios mentioned above.
Figure 4 demonstrates the SROC of FNA when only the definite cytol-
ogy diagnosis of neoplasm (scenario 3) was included in the analysis.
In the current series, the prevalence of neoplasm was 82%, which
is expected to be an overestimation of the salivary gland neoplasm
prevalence in the general population due to the partial verification
bias. The previous studies reported a prevalence of 50%-70% for the
neoplastic lesions.1,2 A Fagan nomogram was drawn to demonstrate
the posttest probability of neoplasm with positive and negative FNA
results for neoplasm in four scenarios mentioned earlier for a pretest
probability of 60% (Figure 5).
In the Deek's funnel plot asymmetry test; the regression coefficient
between the DOR and the inverse of the root of the SE of DOR was
−11.7 with a P-value: .001, suggesting the presence of significant publi-
cation bias. Using the Trim and Fill test, a hypothetical database was
generated by adding 27 studies in place of the “missing” studies
assumed to be responsible for the publication bias. Subsequently, the
DOR of this hypothetical database was estimated using an HSROC
model. The analyses showed that the addition of the “missing” studies
resulted in an increased variance between the studies, and the evidence
of heterogeneity in the dataset remained unchanged at a P-value <.01.
Differentiating malignant from benign lesions
All 92 studies were included in calculating the accuracy of FNA in dis-
tinguishing between the benign and malignant salivary gland neo-
plasms. The benign lesions were considered as nonneoplastic or
benign neoplasms. The number of true and false positive and negative
FNA cases with the measures of sensitivity, specificity, DOR, PLR, and
NLR in each of the included study are summarized in Table 4.
The following five scenarios were considered in estimating the FNA
accuracy: (1) identifying the FNA cases classified as “nonneoplastic” and
“benign neoplasm” as the negative index test result for malignancy, and
“nondiagnostic”, “AUS”, “SUMP”, “suspicious for malignancy”, and
“malignant” as the positive index test result for malignancy; (2) excluding
“nondiagnostic” FNA cases from the analysis and recognizing the cases
with the diagnosis of “nonneoplastic” and “benign neoplasm” as the neg-
ative index test result for malignancy, and “AUS”, “SUMP”, “suspicious
for malignancy”, and “malignant” as the positive index test result for
malignancy; (3) excluding “nondiagnostic” and “AUS” cases from the
analysis and considering the cases with diagnosis of “nonneoplastic”
and “benign neoplasm” as the negative index test result for malignancy,
and “SUMP”, “suspicious for malignancy”, and “malignant” as the posi-
tive index test result for malignancy; (4) including FNA cases with the
definite diagnosis for malignancy in the analysis; identifying the cases
with the diagnosis of “nonneoplastic” and “benign neoplasm” as the neg-
ative index test result for malignancy, and “suspicious for malignancy”
and “malignant” as the positive index test result for malignancy;
(5) including FNA cases with the diagnosis of “nonneoplastic”, “benign
neoplasm”, “AUS”, and “SUMP” as the negative index test result for
8 FARAHANI AND BALOCH

TABLE 2 Diagnostic performance of salivary gland FNA in detecting neoplasm in individual primary studies

Author year TP FP FN TN Sensitivity (%) Specificity (%) DOR PLR NLR

27
Rajdeo RN 2017 93 0 3 4 96.9 100.0 240.4 9.6 0.04
Rohilla M 201767 69 0 6 18 92.0 100.0 395.6 34.8 0.09
Mohammed Nur 201668 124 3 9 7 93.2 70.0 32.2 3.1 0.10
Ameli F 201569 72 6 4 19 94.7 76.0 57.0 4.0 0.07
Arul P 201570 112 4 3 21 97.4 84.0 196.0 6.1 0.03
Mairembam P 201671 149 1 0 21 100.0 95.5 4285.7 15.3 0.00
Novoa E 201637 88 2 6 4 93.6 66.7 29.3 2.8 0.10
Omhare A 201472 47 0 0 39 100.0 100.0 7505.0 79.2 0.01
Pastore A 201373 283 4 23 24 92.5 85.7 73.8 6.5 0.09
Kechagias N 201258 72 1 1 4 98.6 80.0 288.0 4.9 0.02
Nanda KDS 201274 39 0 0 17 100.0 100.0 2765.0 35.6 0.01
Nguansangiam S 201255 62 1 2 68 96.9 98.6 2108.0 66.8 0.03
49
Ali NS 2011 113 2 4 5 96.6 71.4 70.6 3.4 0.05
Cho HW 201143 203 1 4 7 98.1 87.5 355.3 7.9 0.02
Ashraf A 201031 86 0 0 14 100.0 100.0 5017.0 29.8 0.01
Christensen RK 201075 294 2 23 63 92.7 96.9 402.7 30.1 0.07
76
Stramandinoli RT 2010 71 0 4 3 94.7 100.0 111.2 7.5 0.07
Daneshbod Y 200977 355 1 3 17 99.2 94.4 2011.7 17.9 0.01
Zhang S 200947 56 4 6 12 90.3 75.0 28.0 3.6 0.13
de Ru JA 200778 83 0 0 5 100.0 100.0 1837.0 11.9 0.01
64
Elagoz S 2007 29 1 11 15 72.5 93.8 39.6 11.6 0.29
Lim CM 200779 72 2 3 4 96.0 66.7 48.0 2.9 0.06
Tan LGL 200680 37 0 7 12 84.1 100.0 125.0 21.7 0.17
Bandyopadhyay A 200581 46 0 1 12 97.9 100.0 775.0 25.2 0.03
82
Riley N 2005 89 2 4 2 95.7 50.0 22.3 1.9 0.09
Seethala RR 200561 158 4 6 18 96.3 81.8 118.5 5.3 0.04
Postema RJ 200467 295 3 21 61 93.4 95.3 285.6 19.9 0.07
Contucci AM 200362 118 0 12 9 90.8 100.0 180.1 18.1 0.10
83
Sengupta S 2002 131 0 4 73 97.0 100.0 4295.7 143.1 0.03
Jayaram G 200150 48 0 2 3 96.0 100.0 135.8 7.6 0.06
Costas A 200054 73 3 2 22 97.3 88.0 267.7 8.1 0.03
Al-Khafaji BM 199832 127 3 9 9 93.4 75.0 42.3 3.7 0.09
68
Boccato P 1998 528 0 1 35 99.8 100.0 25 015.7 71.8 0.00
Filopoulos E 199859 109 0 1 10 99.1 100.0 1533.0 21.7 0.01
Cajulis RS 199784 67 0 4 59 94.4 100.0 1785.0 112.5 0.06
Christallini EG 199751 50 0 2 11 96.2 100.0 464.6 22.9 0.05
85
Atula T 1996 135 8 35 26 79.4 76.5 12.5 3.4 0.27
Atula T 199586 15 11 9 43 62.5 79.6 6.5 3.1 0.47
Orell SR 199587 290 3 2 23 99.3 88.5 1111.7 8.6 0.01
Zurida S 199388 204 0 0 19 100.0 100.0 15 951.0 39.9 0.00
89
Chan MKM 1992 78 1 6 25 92.9 96.2 325.0 24.1 0.07
Nettle WJS 198945 97 0 1 4 99.0 100.0 585.0 9.9 0.02
Layfield LJ 198790 111 1 10 44 91.7 97.8 488.4 41.3 0.08
Persson PS 197391 187 1 1 13 99.5 92.9 2431.0 13.9 0.01
92
Eneroth CM 1967 461 0 8 74 98.3 100.0 8089.8 147.3 0.02

In order to avoid zero as the denominator in calculating DOR, PLR, NLR, a fixed continuity correction factor of 0.5 was added to each of TP, FP, FN, TN
cells when a zero in FP and FN cells encountered.
Abbreviations: TP, true positive; FP, false positive; FN, false negative; TN, true negative; DOR, diagnostic odds ratio; PLR, positive likelihood ratio; NLR,
negative likelihood ratio.

malignancy, and “suspicious for malignancy” and “malignant” as the posi- 79% (95% CI: 75%-83%) with a P-value <.001 by the Cochrane Q test.
tive index test result for malignancy. The forest plots (Figure 6A,B) depict the individual study sensitivity
The I2 index of heterogeneity for the FNA sensitivity, specificity, and specificity and their corresponding 95% CI and the variations
and DOR was 68% (95% CI: 65%-72%), 76% (95% CI: 71%-80%), and across the included studies. The Spearman correlation test did not
FARAHANI AND BALOCH
show any significant association between the mean sensitivity and
specificity.
The results of the FNA summary sensitivity, specificity, DOR,
PLR, and NLR in the five scenarios above were calculated using a
bivariate generalized linear mixed-effects model (Table 5). Figure 7
demonstrates the SROC of FNA when only the definite cytology diag-
nosis for the malignancy (scenario 4) was included in the analysis.
FIGURE 3 (Continued on next page)
9
The malignancy prevalence in the current series was 22%, which
was in concordance with the previous studies.1,2 Considering a pretest
probability of 22%, Figure 8 depicts the posttest probability of malig-
nancy with FNA positive and negative results for malignancy in a
Fagan nomogram for the five mentioned scenarios.
The Deek's funnel plot asymmetry test with a regression coeffi-
cient of −11.2 and a P-value: .06 indicated the presence of significant
10
FIGURE 3 (A,B) FNA sensitivity and specificity forest plots in differentiating salivary glands neoplasms from nonneoplastic lesions. The forest
plot demonstrates a high level of intra and inter-study variations
publication bias. However, in the Trim and Fill test, adding the poten-
tially missed studies and generating a new hypothetical database did
not result in the resolution of heterogeneity among the studies.
Verification bias
The data on the number of FNA cases diagnosed as nonneoplastic,
and neoplasm, and benign and malignant, without histologic follow-up
FARAHANI AND BALOCH
can be extracted from 18 and 24 studies, respectively. The ratios of
the total number of cases with the cytology diagnosis of nonneoplas-
tic, neoplasm, benign, and malignant, with to the ones, without histo-
logic follow-up, was 5.59, 1.44, 2.44, and 1.48, respectively.
By employing the above ratios, a corrected estimate of salivary
gland FNA sensitivity and specificity in detecting salivary gland neo-
plasm and malignancy was calculated using the interactive web-based
FARAHANI AND BALOCH 11

TABLE 3 Summary diagnostic performance of salivary gland FNA in detecting neoplasm in different scenarios

Sensitivity (%) Specificity (%) DOR PLR NLR

(95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
Scenario 1 97.0 90.2 302.3 9.9 0.03
(95.6-98.0) (84.6-93.9) (142.7-640.5) (6.2-15.9) (0.02-0.05)
Scenario 2 96.9 93.7 470.0 15.3 0.03
(95.5-98.0) (89.6-96.2) (217.8-1013.8) (9.2-25.3) (0.02-0.05)
Scenario 3 96.9 95.3 636.8 20.5 0.03
(95.5-97.9) (91.8-97.3) (284.2-1426.5) (11.8-35.6) (0.02-0.05)
Scenario 4 94.4 95.6 368.3 21.7 0.06
(90.6-97.2) (90.9-98.9) (220.1-1561.4) (14.3-34.9) (0.04-0.08)
I2 index of heterogeneity (%) 70.7 74.3 78.2
(65.1-78.4) (69.4-78.8) (74.3-82.5)

Abbreviations: CI, confidence interval; DOR, diagnostic odds ratio; PLR, positive likelihood ratio; NLR, negative likelihood ratio.
Scenario 1, FNA “nonneoplastic” as a negative index test result for neoplasm, and “nondiagnostic”, “AUS”, benign neoplasm”, “SUMP”, “suspicious for malig-
nancy”, and “malignant” as a positive index test result for neoplasm;
Scenario 2, FNA “nonneoplastic” as negative index test result for neoplasm, and “AUS”, “benign neoplasm”, “SUMP”, “suspicious for malignancy”, and
“malignant” as a positive index test result for neoplasm;
Scenario 3, FNA “nonneoplastic” as negative index test result for neoplasm, and “benign neoplasm”, “SUMP”, “suspicious for malignancy”, and “malignant”
as a positive index test result for neoplasm;
Scenario 4, FNA “nondiagnostic”, “nonneoplastic”, and “AUS” as negative index test result for neoplasm, and cases classified as “benign neoplasm”, “SUMP”,
“suspicious for malignancy”, and “malignant” as a positive index test result for neoplasm.

tool, Global Sensitivity Analysis. The corrected sensitivity and specific-
ity of FNA in differentiating a neoplasm from a nonneoplastic lesion
and a malignant from a benign neoplasm were estimated as 84.37%
(95% CI: 81.87%-87.39%) and 98.27% (95% CI: 97.51%-98.94%), and
72.10% (95% CI: 67.65%-79.67%) and 98.62% (95% CI: 98.33%-
98.98%), respectively. Sensitivity analysis showed that the chance of
not receiving the histologic follow-up was not dependent on the his-
tologic diagnosis of neoplastic or malignant diagnosis of the examined
lesions.
Investigating the possible causes of heterogeneity, meta-
regression and sub-group analysis
4 | DI SCU SSION
This comprehensive review and meta-analysis of the literature on sali-
vary gland FNA is an attempt to; assess the accuracy of FNA in the
diagnosis of salivary gland lesions; to investigate the potential factors
impacting its accuracy and to retrospectively evaluate the feasibility
and effectiveness of the MSRSGC (Table 1).
4.1 | Diagnostic accuracy, the posttest probabilities,
and ROM
The systematic review and meta-analysis of available literature showed

Multiple meta-regression analyses showed that the FNA sensitivity that the salivary gland FNA rendered a definite diagnosis of nonneoplas-

and specificity in differentiating a neoplasm from a nonneoplastic tic lesion, benign, and malignant neoplasm in 94% cases. FNA was indi-

lesion and a benign from malignant lesion were significantly higher in cated to be an informative test in both rulings in and ruling out the

the studies in which FNAs were performed in the cancer referral
centers.
The FNA sensitivity and specificity in distinguishing benign from
malignant neoplasm were also significantly higher in the studies,
which employed ancillary techniques in selected cases, the FNA pro-
cedures were performed by cytologist/s, ROSE was available, and in
studies with higher prevalence of malignancy (> 25%). The salivary
gland FNA sensitivity and specificity were also noted to be higher
after the release of the first revision of the WHO classification in
1991 as compared to ones before. The availability of ROSE availability
increased the FNA sensitivity with larger magnitude comparing to the
specificity and affected the shape of the SROC curve.
Although the above variables were demonstrated to significantly
affect the FNA sensitivity, or specificity, or SROC curve or all, subdi-
viding the included studies into the smaller subgroups based on these
variables did not result in a more homogeneous cohort of studies.
Table 6 summarized the summary estimates of FNA diagnostic
performance measures in distinguishing the salivary gland malignancy
in different subgroups.
presence of neoplasm with a PLR of 20.5 and NLR of 0.03. Interestingly,
by considering the cases with an indefinite diagnosis of neoplasm (AUS)
as a positive for neoplasm result, FNA specificity and PLR decreased
without any significant improvement in FNA sensitivity and NLR. A defi-
nite diagnosis for neoplasm on FNA increased the odds of having a neo-
plasm by 20.5 times, and a definite diagnosis of a nonneoplastic lesion
on FNA decreased the odds of having a neoplasm by 0.03 comparing to
its baseline odds. The odds of having a neoplasm on histologic follow-
up with “nondiagnostic” and “AUS” diagnosis on cytology was 2.5 and
1.3 times of having a nonneoplastic lesion, respectively. In addition, by
considering “nondiagnostic” and “AUS” diagnoses in addition to “benign
neoplasm”, “SUMP”, “suspicious for malignancy”, and “malignant” as a
positive result for neoplasm, the odds of having a neoplasm comparing
to the baseline odds decreased to 9.1 and therefore a positive result on
FNA could no longer be considered as informative in ruling in the diag-
nosis of neoplasm.
In distinguishing between benign and malignant salivary gland
tumors, FNA had high specificity, yet moderate sensitivity even when
it was able to deliver a definite diagnosis. With a PLR of 37.7, a
12
FIGURE 4 HSROC curve of FNA in detecting salivary gland neoplasm
when only including the FNA cases with a definite diagnosis for
neoplasm (the MSRSGC categories of “nonneoplastic”, “neoplasm-
benign/SUMP”, “suspicious for malignancy”, “malignant”) in the
analysis. Circles indicate primary studies sensitivity and specificity.
The size of circles corresponds with study sample size. The solid green
line represents FNA summary sensitivity, and specificity line with 95%
prediction region (dotted green line) and the red square indicates the
FNA summary points of sensitivity and specificity with 95%
confidence region (dotted orange line). The 95% confidence region
shows the region the real value of FNA sensitivity and specificity
would expect to lie, based on the observed data. The 95% prediction
region depicts the region the results of a future study would expect to
be located. As it could be expected due to the high level of
heterogeneity between the studies, the 95% prediction region is
much larger than the 95% confidence region
“suspicious for malignancy” or “malignant” diagnosis on FNA could be
considered as informative in ruling in the malignancy diagnosis. How-
ever, the NRL of 0.19 indicated that a diagnosis of a nonneoplastic
lesion or benign neoplasm or generally benign on FNA could not be
considered informative in ruling out the risk of malignancy in the
examined sample. By considering “nondiagnostic”, “AUS”, and “SUMP”
in addition to “suspicious for malignancy”, and “malignant” as a posi-
tive result, NLR of FNA did not improve to the point so it could be
considered informative in ruling out the malignancy diagnosis.
By stratifying the cases from 92 eligible studies according to
MSRSGC classification and comparing the cytology diagnosis with the
corresponding histologic follow-up diagnosis, the ROM in “nondiag-
nostic”, “nonneoplastic”, “AUS”, “neoplasm-benign”, “neoplasm-
SUMP”, “suspicious for malignancy”, and “malignant” was 17%, 8%,
34%, 4%, 42%, 58%, and 91%, respectively.
In this series, the mean prevalence of malignancy was 22%. A
diagnosis of “suspicious for malignancy” or “malignant” increased the
probability of having a malignancy to 91%, while a diagnosis of
FARAHANI AND BALOCH
FIGURE 5 Fagan nomogram for detecting neoplasm: scenario1,
recognizing the FNA cases interpreted as “nonneoplastic” as the
negative index test result for neoplasm, and cases classified as
“nondiagnostic”, “AUS”, “benign neoplasm”, “SUMP”, “suspicious for
malignancy”, and “malignant” as the positive index test result for
neoplasm; scenario 2, excluding “nondiagnostic” cases from the
analysis, considering FNA cases in the diagnostic category of
“nonneoplastic” as the negative index test result for neoplasm, and
the ones in “AUS”, “benign neoplasm”, “SUMP”, “suspicious for
malignancy”, and “malignant” categories as the positive index test
result for neoplasm; scenario 3, including the cases with definite
diagnosis for neoplasm in the analysis; considering the FNA cases in
diagnostic category of “nonneoplastic” as the negative index test
result for neoplasm, and “benign neoplasm”, “SUMP”, “suspicious for
malignancy”, and “malignant” as the positive index test result for
neoplasm; scenario 4, recognizing FNA cases classified as
“nondiagnostic”, “nonneoplastic”, and “AUS” as the negative index test
result for neoplasm, and cases classified as “benign neoplasm”,
“SUMP”, “suspicious for malignancy”, and “malignant” as the positive
index test result for neoplasm. Scenario 1 (blue arrow); scenario 2 (red
arrow); scenario 4 (black arrow); scenario 1-3 (dark green arrow);
scenario 3,4 (Purple arrow). Fagan nomogram depicts the posttest
probability of having a neoplasm after cytology diagnosis positive and
negative for neoplasm, for a pretest probability of 60%. Including
cytology, indefinite diagnosis for neoplasm (MSRSGC categories of
“nondiagnostic” and “AUS”) resulted in decreasing FNA PLR and
therefore the posttest probability of neoplasm, while the not reducing
the likelihood of having a neoplasm after FNA negative result for
neoplasm
FARAHANI AND BALOCH 13

TABLE 4 Diagnostic performance of salivary gland FNA in detecting malignancy in individual primary studies

Sensitivity Specificity
Author year TP FP FN TN (%) (%) DOR PLR NLR
Correia SI 201793 15 4 0 36 100.0 90.0 251.4 8.8 0.04
Eytan DF 201739 123 29 26 273 82.6 90.4 44.5 8.6 0.19
Mikaszewski B 201794 9 11 10 70 47.4 86.4 5.7 3.5 0.61
95
Ramirez-Perez F 2017 21 25 10 116 67.7 82.3 9.7 3.8 0.39
Rajdeo RN 201727 19 0 3 78 86.4 100.0 874.7 134.0 0.15
Rohilla M 201767 25 1 7 58 78.1 98.3 207.1 46.1 0.22
Edizer DT 201644 15 10 9 211 62.5 95.5 35.2 13.8 0.39
96
Feinstein A 2016 75 10 17 189 81.5 95.0 83.4 16.2 0.19
Gudmudsson JK 201697 8 3 3 100 72.7 97.1 88.9 25.0 0.28
Mohammed Nur 201668 25 2 5 111 83.3 98.2 277.5 47.1 0.17
Rossi ED (AGH) 201639 47 3 16 341 74.6 99.1 333.9 85.5 0.26
39
Rossi ED (HUP) 2016 48 3 30 177 61.5 98.3 94.4 36.9 0.39
Ameli F 201569 14 1 3 81 82.4 98.8 378.0 67.5 0.18
Arul P 201570 25 5 6 104 80.7 95.4 86.7 17.6 0.20
Halder S 201552 7 4 3 34 70.0 89.5 19.8 6.7 0.34
98
Hipp J (quick-diff prep) 2015 39 3 4 89 90.7 96.7 289.3 27.8 0.10
Hipp J (ThinPrep) 201598 26 5 6 46 81.3 90.2 39.9 8.3 0.21
Mairembam P 201671 33 3 4 124 89.2 97.6 341.0 37.8 0.11
Naz S 201556 7 3 2 19 77.8 86.4 22.2 5.7 0.26
37
Novoa E 2016 13 3 7 74 65.0 96.1 45.8 16.7 0.36
Song HI 201599 32 4 23 289 58.2 98.6 100.5 42.6 0.42
Diaz KP 2014100 16 0 1 156 94.1 100.0 3443.0 287.8 0.08
Omhare A 201472 15 2 2 67 88.2 97.1 251.3 30.4 0.12
101
Zerpa VZ 2014 4 4 3 79 57.1 95.2 26.3 11.9 0.45
Fassnatch W 201334 4 8 5 62 44.4 88.6 6.2 3.9 0.63
Jeong WJ 201336 9 1 2 90 81.8 98.9 405.0 74.5 0.18
Kim BY 2013102 61 7 34 419 64.2 98.4 107.4 39.1 0.36
74
Pastore A 2013 26 0 3 299 89.6 100.0 4535.3 530.0 0.12
Tryggvason G 2013103 138 2 23 380 85.7 99.5 1140.0 163.7 0.14
Fakhry N 2012104 43 16 11 132 79.6 89.2 32.3 7.4 0.23
Haung YC 201242 10 2 4 44 71.4 95.7 55.0 16.4 0.30
105
Inanch HM 2012 21 4 5 77 80.8 95.1 80.9 16.4 0.20
Javadi M 2012106 11 1 8 45 57.9 97.8 61.88 26.6 0.43
Kechagias N 201258 27 1 1 49 96.4 98.0 1323.0 48.2 0.04
Nanda KDS 201274 12 2 3 39 80.0 95.1 78.0 16.4 0.21
55
Nguansangiam S 2012 13 1 3 116 81.3 99.2 502.7 95.1 0.19
Ali NS 201149 26 2 4 92 86.7 97.9 299.0 40.7 0.14
Cho HW 201143 28 0 9 178 75.7 100.0 1071.0 268.5 0.25
Piccioni LO 201138 13 1 3 123 81.3 99.2 533.0 100.8 0.19
31
Ashraf A 2010 14 1 4 81 77.8 98.8 283.5 63.8 0.22
Christensen RK 201075 44 1 9 322 83.0 99.7 1574.2 268.2 0.17
Gobic MB 201041 13 3 3 147 81.3 98.0 212.3 40.6 0.19
Stramandinoli RT 201076 16 7 7 47 69.6 87.0 15.4 5.4 0.35
29
Carrillo JF 2009 60 1 5 69 92.3 98.6 828.0 64.6 0.08
Daneshbod Y 200977 128 10 13 225 90.8 95.7 221.5 21.3 0.10
Jafari A 2009107 12 3 5 81 70.6 96.4 64.8 19.8 0.31
Zhang S 200947 11 1 5 54 68.8 98.2 118.8 37.8 0.32
63
Inohara H 2008 19 3 2 57 90.5 95.0 180.5 18.1 0.10
Jan IS 2008108 19 9 6 97 76.0 91.5 34.1 9.0 0.26
Mohammad F 2008109 21 6 14 148 60.0 96.1 37.0 15.4 0.42
Zbaren P 2008110 50 5 18 37 73.5 88.1 20.6 6.2 0.30
78
de Ru JA 2007 22 0 0 66 100.0 100.0 5985.0 131.1 0.02

(Continues)
14 FARAHANI AND BALOCH

TABLE 4 (Continued)

Sensitivity Specificity
Author year TP FP FN TN (%) (%) DOR PLR NLR
Elagoz S 200764 7 0 9 40 43.8 100.0 64.0 36.2 0.57
Lim CM 200779 8 0 2 71 80.0 100.0 486.2 37.8 0.11
Van Lierop AC 2007111 8 1 3 55 72.7 98.2 146.7 8.3 0.21
112
Upton DC 2007 20 2 1 29 95.2 93.6 290.0 5.7 0.26
Aversa S 200660 34 0 7 269 82.9 100.0 2479.4 16.7 0.36
Tan LGL 200680 3 0 0 50 100.0 100.0 707.0 42.6 0.42
Balakrishnan K (MH) 2005113 5 3 7 54 41.7 94.7 12.9 287.8 0.08
113
Balakrishnan K (RHH) 2005 15 7 4 37 79.0 84.1 19.8 30.4 0.12
Bandyopadhyay A 200581 13 1 2 43 86.7 97.7 279.5 11.9 0.45
Paris J 200548 25 5 6 97 80.7 95.1 80.8 3.9 0.63
Riley N 200582 31 3 2 61 93.9 95.3 315.2 74.5 0.18
61
Seethala RR 2005 44 2 7 122 86.3 98.4 383.4 39.1 0.36
Cohen EG 2004114 51 10 20 70 71.8 87.5 17.9 530.0 0.12
Postema RJ 200465 73 4 10 293 88.0 98.7 534.7 163.7 0.14
Sergi B 2004115 12 0 9 118 57.1 100.0 311.8 7.4 0.23
116
Stow N 2004 29 1 2 62 93.6 98.4 899.0 16.4 0.30
Contucci AM 200362 14 0 7 118 66.7 100.0 458.2 16.4 0.20
Gooden E 200235 16 8 2 61 88.9 88.4 61.0 26.6 0.43
Sengupta S 200283 28 4 4 172 87.5 97.7 301.0 48.2 0.04
117
Tasi SCS 2002 3 1 2 34 60.0 97.1 51.0 16.4 0.21
Jayaram G 200150 11 1 6 32 64.7 97.0 58.7 95.1 0.19
Costas A 200054 26 5 5 64 83.9 92.8 66.6 40.7 0.14
Santamaria J 2000118 18 6 4 161 81.8 96.4 120.8 22.8 0.19
32
Al-Khafaji BM 1998 58 11 13 64 81.7 85.3 26.0 5.6 0.21
Boccato P 199866 104 0 1 449 99.1 100.0 62 630.3 887.3 0.01
Filopoulos E 199859 37 1 1 81 97.4 98.8 2997.0 79.8 0.03
Cajulis RS 199784 23 1 2 102 92.0 99.0 1173.0 94.8 0.08
51
Christallini EG 1997 4 0 3 56 57.1 100.0 145.3 64.1 0.44
Tew S 1997119 18 0 2 109 90.0 100.0 1620.6 193.8 0.12
Atula T 199685 12 0 21 151 36.4 100.0 176.2 111.8 0.63
Atula T 199586 2 1 10 60 16.7 98.4 12.0 10.2 0.85
87
Orell SR 1995 71 1 8 228 89.9 99.6 2023.5 205.8 0.10
Jayaram G 1994120 37 2 2 99 94.9 98.0 915.8 47.9 0.05
Zurida S 199388 31 0 14 178 68.9 100.0 775.6 245.2 0.32
Chan MKM 199289 31 1 5 72 86.1 98.6 446.4 62.9 0.14
121
Frable MA 1991 51 1 2 131 96.2 99.2 3340.5 127.0 0.04
Nettle WJS 198945 20 1 5 73 80.0 98.7 292.0 59.2 0.20
Layfield LJ 198790 44 6 8 108 84.6 94.7 99.0 16.1 0.16
Lau T 1986122 8 0 7 86 53.3 100.0 196.1 92.4 0.47
123
Qizibash AH 1985 21 0 3 77 87.5 100.0 952.1 134.2 0.14
Lindberg LG 1976124 38 20 20 250 65.5 92.6 23.8 8.8 0.37
Persson PS 197391 30 2 4 166 88.2 98.8 622.5 74.1 0.12
Eneroth CM 196792 44 21 40 396 52.4 95.0 20.7 10.4 0.50

In order to avoid zero as the denominator in calculating DOR, PLR, NLR, a fixed continuity correction factor of 0.5 was added to each of TP, FP, FN, TN
cells when a zero in FP and FN cells encountered.
Abbreviations: TP, true positive; FP, false positive; FN, false negative; TN, true negative; DOR, diagnostic odds ratio; PLR, positive likelihood ratio; NLR,
negative likelihood ratio; AGH, Agostino Gemelli Hospital; HUP, Hospital of the University of Pennsylvania; MH, Monklands Hospital; RHH, Royal Hallam-
shire Hospital.

“nonneoplastic”, “neoplasm-benign”, or benign reduced the probability 4.2 | Investigating heterogeneity

of malignancy to 5%. While the posttest probability of malignancy The results of the meta-analysis of FNA accuracy were highly hetero-
with a diagnosis of “nondiagnostic”, “AUS”, “neoplasm-SUMP”, “suspi- geneous across the different studies, and various variables including
cious for malignancy”, and “malignant” was 86%. population characteristics, the setting of the study, and technical
FARAHANI AND BALOCH 15

TABLE 5 Summary diagnostic performance of salivary gland FNA in detecting malignancy in different scenarios

Sensitivity (%) Specificity (%) DOR PLR NLR

(95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
Scenario 1 82.3 93.8 70.8 13.3 0.19
(79.4-84.9) (92.2-95.1) (50.7-98.9) (10.5-16.9) (0.16-0.22)
Scenario 2 81.6 96.4 116.9 22.3 0.19
(78.6-84.2) (95.2-97.2) (82.9-164.7) 17.2-29.0) (0.16–0.22)
Scenario 3 81.4 96.9 136.3 26.2 0.19
(78.4-84.1) (95.9-97.6) (95.5-194.4) (19.9-34.4) (0.16–0.22)
Scenario 4 80.5 97.9 189.5 37.8 0.20
(77.3-83.3) (97.1-98.4) (130.0-276.2) 28.1-50.6) (0.17-0.23)
Scenario 5 74.0 98.0 138.8 36.9 0.27
(71.2-77.8) (97.2-98.3) (110-7-256.9) (26.9-49.4) (0.24-0.29)
I2 index of heterogeneity (%) 68.2 75.3 78.6
(64.7-72.5) (71.3-79.4) (74.1-81.9)

Abbreviations: CI, confidence interval; DOR, diagnostic odds ratio; PLR, positive likelihood ratio; NLR, negative likelihood ratio.
Scenario 1, FNA “nonneoplastic” and “benign neoplasm” as a negative index test result for malignancy, and “nondiagnostic”, “AUS”, “SUMP”, “suspicious for
malignancy”, and “malignant” as a positive index test result for malignancy;
Scenario 2, FNA “nonneoplastic” and “benign neoplasm” as a negative index test result for malignancy, and “AUS”, “SUMP”, “suspicious for malignancy”,
and “malignant” as a positive index test result for malignancy;
Scenario 3, FNA “nonneoplastic” and “benign neoplasm” as a negative index test result for malignancy, and “SUMP”, “suspicious for malignancy”, and
“malignant” as a positive index test result for malignancy;
Scenario 4, FNA “nonneoplastic” and “benign neoplasm” as a negative index test result for malignancy, and “suspicious for malignancy” and “malignant” as
a positive index test result for malignancy;
Scenario 5, FNA “nonneoplastic”, “benign neoplasm”, “AUS”, and “SUMP” as a negative index test result for malignancy, and “suspicious for malignancy”
and “malignant” as a positive index test result for malignancy.

aspects involved in cytology material collection and preparation were
shown to have a measurable effect on FNA accuracy.
Presence of ROSE was associated with increased sensitivity and
specificity of salivary gland FNA in differentiating neoplasm from a
nonneoplastic lesion and a malignant from benign. Moreover, the rate
of nondiagnostic FNA was significantly lower in the studies in which
ROSE was available compared to the rest of the studies (4% vs 10%,
P-value: .004) it. Previous studies have demonstrated that ROSE can
reduce the rate of nondiagnostic samples by 50% by evaluating the
sample adequacy, especially in cases where a less experienced pathol-
ogist or clinician are performing the FNA.125,126
Of the 92 included studies, eight only included FNA cases per-
formed by palpation and seven solely enrolled US-guided FNA cases.
The sensitivity, specificity, and accuracy of FNA in differentiating
malignant and benign tumors were significantly lower in both sub-
groups compared to the rest of the studies. This finding was in con-
trast with the studies which argued that performing FNA under
ultrasound-guidance increases the FNA yield by ensuring the place-
ment of biopsy needle within the viable and cellular components of a
salivary gland lesion leading to a reduction in the rate of nondiagnostic
sample and improve the overall accuracy of FNA.127,128 The lower
accuracy of ultrasound-guided FNA comparing to palpation-guided
FNA could be attributable to the difference in referral patterns, study
population, malignancy prevalence, the histological complexity of
studied lesions, and ROSE. Further investigation of the concurrent
impact of mentioned factors on the accuracy of FNA was not possible
due to the limited numbers of studies in this subgroup.
Utilizing ancillary studies in the selective FNA cases showed to
increase the sensitivity and specificity of FNA in detecting neoplasms
of the salivary gland. It has been demonstrated that various ancillary
techniques including immunohistochemistry, fluorescence in-situ
hybridization (FISH), reverse transcription-polymerase chain reaction
(RT-PCR), and next-generation sequencing can prove to be useful in
the cytological evaluation of salivary gland neoplasms. The primary
applications of these techniques are in differentiating between the
benign neoplasms such as basal cell adenoma and pleomorphic ade-
noma and pleomorphic adenoma and the malignant tumors such as
adenoid cystic carcinoma and mucoepidermoid carcinoma; or in distin-
guishing between the lymphoid hyperplasia and low-grade lymphoma
in lymphocyte-rich specimens.129
The sensitivity and specificity of salivary gland FNA in differenti-
ating malignant and benign lesions were significantly higher in the
studies in which FNA was performed and evaluated in a cancer refer-
ral center. On the other hand, the prevalence of malignancy was
higher in these studies compared to the rest of the studies, and this
appeared to be associated with higher sensitivity. This phenomenon
could be attributable to partial verification bias. Only a fraction of
FNA cases with a diagnosis of a nonneoplastic lesion (benign) received
the reference test (surgical resection and histologic diagnosis); this
results in an underestimation of the false negative rate and overesti-
mation of sensitivity and malignancy prevalence. The higher FNA
accuracy in this subgroup could also be attributable to the fact that a
large number of cases of salivary gland neoplasms are encountered in
cancer referral centers. This most likely is also associated with a higher
level of operator experience in performing and interpretation of sali-
vary gland FNA leading to overall improvement of FNA accuracy.
4.3 | Limitations
This study has many limitations. First, the majority of the included
studies were retrospective studies, and in general, these are prone to
various biases especially regarding consecutive enrollment of subjects,
variability in execution and evaluation, and blindness to the results of
the index test when evaluating the reference test and vice versa. The
second limitation was the presence of partial verification bias in
16
FIGURE 6 (A, B) FNA sensitivity and specificity forest plots in distinguishing between malignant and benign lesion of salivary glands. The forest
plot demonstrates a high level of intra and inter-study variations
almost all selected studies, which can result in overestimation of dis-
ease prevalence and sensitivity, and underestimation of specificity.
By using an interactive web-based tool, first, we demonstrated
that the chance of not having the histologic follow-up was not depen-
dent on the neoplastic or malignant nature of the examined cases.
Second, the result of corrected sensitivity and specificity calculated
using the ratio of FNA cases with a positive and negative result for
FARAHANI AND BALOCH
neoplasm/malignancy with histologic follow-up showed that FNA sen-
sitivity was overestimated by 8%-10%. However, this method is
designed initially for the tests with a binary outcome and classifying
FNA cases as indeterminate (eg, “nondiagnostic”, “AUS”, or “neo-
plasm-SUMP”) reduces the chance of having false negative FNA cases
with a negative result for neoplasm/malignancy on histologic follow-
up. Therefore, it could be concluded that although the partial
FARAHANI AND BALOCH
FIGURE 7 HSROC curve of FNA in detecting salivary gland
malignancy when only including the FNA cases with a definite
diagnosis for malignancy (the MSRSGC categories of “nonneoplastic”,
“neoplasm-benign”, “suspicious for malignancy”, “malignant”) in the
analysis. Circles indicate primary studies sensitivity and specificity.
The size of circles corresponds with study sample size. The solid green
line represents FNA summary sensitivity, and specificity line with 95%
prediction region (dotted green line) and the red square indicates the
FNA summary points of sensitivity and specificity with 95%
confidence region (dotted orange line). The 95% confidence region
shows the region the real value of FNA sensitivity and specificity
would expect to lie, based on the observed data. The 95% prediction
region depicts the region the results of a future study would expect to
be located. As it could be expected due to the high level of
heterogeneity between the studies, the 95% prediction region is
much larger than the 95% confidence region
verification bias could overestimate the sensitivity, the true value of
sensitivity would lie somewhere between the value corrected and
uncorrected sensitivity.
The third limitation was the high level of heterogeneity across the
included studies. Although various variables were demonstrated to
have a significant effect on FNA sensitivity and specificity in meta-
regression analysis; subdividing the studies into smaller subgroups
based on these variables did not result in generating a more homoge-
neous cohort. According to Cochrane guideline for meta-analysis, the
available statistical tests which are used to evaluate the level of het-
erogeneity are designed for meta-analysis of treatment effect and
they generally overestimate the level of heterogeneity in meta-
analysis of diagnostic studies since they cannot take into account the
correlation between sensitivity and specificity.
In conclusion, this meta-analysis confirms that FNA has proven to
be a useful tool in the diagnosis of salivary gland lesions with appre-
ciable sensitivity, specificity, and diagnostic accuracy. The retrospec-
tive application of diagnostic categories of MSRSGC to the existing
17
FIGURE 8 Fagan nomogram for detecting malignancy: scenario
1, identifying the FNA cases classified as “nonneoplastic” and “benign
neoplasm” as the negative index test result for malignancy, and
“nondiagnostic”, “AUS”, “SUMP”, “suspicious for malignancy”, and
“malignant” as the positive index test result for malignancy; scenario
2, excluding “nondiagnostic” FNA cases from the analysis and recognizing
the cases with the diagnosis of “nonneoplastic” and “benign neoplasm” as
the negative index test result for malignancy, and “AUS”, “SUMP”,
“suspicious for malignancy”, and “malignant” as the positive index test result
for malignancy; scenario 3, excluding “nondiagnostic” and “AUS” cases from
the analysis and considering the cases with diagnosis of “nonneoplastic”
and “benign neoplasm” as the negative index test result for malignancy, and
“SUMP”, “suspicious for malignancy”, and “malignant” as the positive index
test result for malignancy; scenario 4, including FNA cases with the definite
diagnosis for malignancy in the analysis; identifying the cases with the
diagnosis of “nonneoplastic” and “benign neoplasm” as the negative index
test result for malignancy, and “suspicious for malignancy” and “malignant”
as the positive index test result for malignancy; scenario 5, including FNA
cases with the diagnosis of “nonneoplastic”, “benign neoplasm”, “AUS”, and
“SUMP” as the negative index test result for malignancy, and “suspicious for
malignancy” and “malignant” as the positive index test result for malignancy.
Scenario 1 (blue arrow); scenario 2 (red arrow); scenario 3 (light green
arrow); scenario 5 (black arrow); scenario 1-4 (dark green arrow); scenario
4,5 (purple arrow). Fagan nomogram depicts the posttest probability of
having a malignancy after cytology diagnosis positive and negative for
malignancy, for a pretest probability of salivary gland malignancy of 22%.
Including cytology, indefinite diagnosis for malignancy (MSRSGC categories
of “nondiagnostic”, “AUS”, “neoplasm-SUMP”) resulted in decreasing FNA
PLR and therefore the posttest probability of malignancy without any
significant increase in NLR or reduction in posttest probability of
malignancy after a negative FNA result for malignancy
18 FARAHANI AND BALOCH

TABLE 6 Diagnostic performance of salivary gland FNA in detecting malignancy in different subgroups

Sensitivity (%) Specificity (%) DOR PLR NLR

Variable (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
Malignancy prevalence
≤0.25 77.1 98.5 223.7 52.0 0.23
(72.5-81.1) (97.8-99.0) (128.6-389.1) (33.5-80.8) (0.2-0.3)
>0.25 84.7 96.3 144.7 23.0 0.16
(80.8-87.9) (94.8-97.4) (87.8-238.4) (16.1-32.9) (0.13-0.20)
Setting
Tertiary cancer centers 86.4 97.8 282.7 39.2 0.14
(75.5-93.0) (96.3-98.9) (98.2-813.9) (21.4-69.9) (0.07-0.26)
Private clinics and general hospitals 79.8 97.9 180.8 37.5 0.21
(76.4-82.6) (97.1-98.5) (121.0-270.2) (27.2-51.8) (0.17-0.24)
Ancillary studies
Yes 86.4 97.4 238.2 33.4 0.14
(74.4-93.2) (93.0-99.1) (46.0-1232.9) (11.3-98.4) (0.07-0.28)
No or not reported 80.1 98.0 194.4 39.5 0.20
(76.8-83.1) (97.2-98.5) (131.1-288.2) (28.8-54.1) (0.17-0.24)
ROSE
Yes 83.2 99.0 496.1 84.4 0.17
(72.5-90.2) (97.4-99.6) (144.3-1705.8) (31.5-226.5) (0.10-0.29)
No or not reported 80.1 97.7 167.9 34.2 0.20
(76.7-83.1) (96.8-98.3) (113.3-248.8) (25.1-46.6) (0.17-0.23)

Abbreviations: CI, confidence interval; DOR, diagnostic odds ratio; PLR, positive likelihood ratio; NLR, negative likelihood ratio.

literature proves that this classification scheme will be helpful in stan-
dardization and unification of salivary gland FNA results to increase
the FNA reliability and reproducibility. The standardization in report-
ing the results of the salivary glands cytology will result in improving
communication between pathologists and treating clinicians and facili-
tate the intra and inter-institution data collection and quality improve-
ment measures.
DIS CLOSUR E OF INTERESTS
Authors have nothing to disclose.
ORCID
Sahar J Farahani http://orcid.org/0000-0003-0845-4659
Zubair Baloch http://orcid.org/0000-0001-9342-3069
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How to cite this article: Farahani SJ, Baloch Z. Retrospective
assessment of the effectiveness of the Milan system for
reporting salivary gland cytology: A systematic review and
meta-analysis of published literature. Diagn Cytopathol. 2018;
1–21. https://doi.org/10.1002/dc.24097