See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/348784281

The Milan System for Reporting Salivary Gland Cytopathology: Benefits and
Cautions

Article in AJSP Review and Reports · September 2020

DOI: 10.1097/PCR.0000000000000405

CITATIONS READS

7 1,956

3 authors, including:

Annemieke van Zante Marc Philippe Pusztaszeri

UCSF University of California, San Francisco McGill University
107 PUBLICATIONS 2,615 CITATIONS 197 PUBLICATIONS 4,304 CITATIONS

SEE PROFILE SEE PROFILE

All content following this page was uploaded by Marc Philippe Pusztaszeri on 03 February 2021.

The user has requested enhancement of the downloaded file.

 REVIEW
The Milan System for Reporting Salivary Gland
Cytopathology: Benefits and Cautions
Annemieke van Zante, MD, PhD,* Patrick Ha, MD,† and Marc Philippe Pusztaszeri, MD‡
Abstract: Fine-needle aspiration (FNA) is a well-established procedure
for the diagnosis and management of salivary gland lesions despite chal-
lenges imposed by their diversity, complexity, and cytomorphological over-
lap. Until recently, the reporting of salivary gland FNA specimens was
inconsistent among different institutions throughout the world, leading to
diagnostic confusion among pathologists and clinicians. In 2015, an inter-
national group of pathologists initiated the development of an
evidence-based tiered classification system for reporting salivary gland
FNA specimens, the Milan System for Reporting Salivary Gland Cytopa-
thology (MSRSGC). A corresponding MSRSGC Atlas was published in
February 2018. The MSRSGC consists of 6 diagnostic categories that in-
corporate the morphologic heterogeneity and overlap among various
nonneoplastic, benign, and malignant lesions of the salivary glands. In ad-
dition, each diagnostic category is associated with a risk of malignancy and
management recommendations. The main goal of the MSRSGC is to im-
prove communication between cytopathologists and treating clinicians,
while also facilitating cytologic-histologic correlation, quality improve-
ment, and sharing of data from different laboratories for research. Herein,
we review the benefits and the limitations of the MSRSGC, as well as
the challenges of implementing this new reporting system in routine
practice.
Key Words: cytology, FNA, Milan System, reporting, salivary gland
(AJSP: Reviews & Reports 2020;25: 235–242)
A ppropriate management of salivary gland masses is often
guided by cytopathologic diagnosis. Along with clinical his-
tory, physical examination, and imaging studies, fine-needle aspi-
ration (FNA) plays an important role at most institutions in the
presurgical evaluation of salivary gland masses. Based on key
cytomorphologic features, FNA can reliably differentiate between
neoplastic and nonneoplastic salivary gland lesions, accurately di-
agnose commonly occurring benign tumors such as pleomorphic
adenoma and Warthin tumor, and in most cases distinguish
low-grade from high-grade carcinomas.1–8 In their comprehensive
systematic review and meta-analysis of the literature, Schmidt
et al4 reported a sensitivity of 80% and specificity of 97% in dif-
ferentiating benign and malignant salivary gland tumors in the pa-
rotid gland by FNA. False-negative and false-positive diagnoses
are uncommon.1,4,7,8 Thus, the results of salivary gland FNA pro-
vide useful information for planning surgical treatment for pa-
tients with a neoplasm and can obviate the need for surgery in
up to one-third of patients with nonneoplastic diseases.
From the Departments of *Pathology and †Otolaryngology-Head and Neck
Surgery, University of California–San Francisco, San Francisco, CA; and
‡Department of Pathology, Jewish General Hospital, McGill University,
Montreal, Quebec, Canada.
Reprints: Annemieke van Zante, MD, PhD, Pathology, Art Institute of California
San Francisco Jamie A. MacInnis Memorial Library, 1825 4th St, Room
L2190, San Francisco, CA 94143. E‐mail: Annemieke.VanZante@ucsf.edu.
The authors have no funding or conflicts to declare.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 2381-5949
DOI: 10.1097/PCR.0000000000000405
AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Similar to the thyroid, FNA of salivary glands is used as a
method to determine the necessity and extent of surgical treat-
ment. However, unlike with the thyroid, where the majority of
nodules are benign and do not require surgery, most salivary gland
mass lesions represent neoplasia and necessitate removal. The sur-
gical approach, including extent of resection, management of the
facial nerve in the case of parotid tumors, and indication for neck
dissection, depends on the specific diagnosis or at least the nature
(primary vs secondary) and grade (low-grade vs high-grade) of
the neoplasm. Patients with salivary cysts or lymphoma diagnoses
are also likely to be managed differently. A subset of benign sali-
vary gland tumors may be managed nonsurgically by clinical and
imaging follow-up, depending on patient age, preferences, and co-
morbidities. At the same time, metastases of visceral origin may
be treated with surgery, local radiation, or systemic therapy.
In contrast to the thyroid, where the histologic classification
of tumors is relatively straightforward, and most lesions are
follicular-derived, the World Health Organization classification
system of tumors of the salivary gland contains 31 benign and ma-
lignant epithelial tumors.9 Many salivary gland neoplasms show
marked cytohistologic overlap and require the assessment of histo-
logic parameters (ie, invasion) for definitive diagnosis and grad-
ing. Salivary gland FNA is further complicated by the fact that
masses that appear clinically within the parotid or submandibular
gland may originate from the gland itself (intrinsic) or represent an
intraglandular or juxtaglandular lymph node, cyst of the neck, or
soft tissue mass (extrinsic). Thus, the differential diagnosis of a
mass in a major salivary gland area can be extremely broad.
There is a minor subset of salivary gland lesions that are very
difficult to interpret and where a specific diagnosis cannot be
made based on cytologic features alone, even for the most skilled
diagnostician. These include many basaloid neoplasms, cystic le-
sions (mucinous and nonmucinous), lymphoid lesions, and spin-
dle cell lesions, along with a subset of oncocytic lesions and
clear cell tumors.1,3,5,6,8 Each of these categories is associated
with a differential diagnosis that includes benign and malignant
neoplasms; for some, the differential diagnosis includes neoplastic
and nonneoplastic entities. Depending on many other factors such
as adequacy of material, preparation quality, and the availability of
cell block material and ancillary studies, the cytopathologist's de-
gree of confidence in the most likely diagnosis may vary consid-
erably. These limitations can result in inconclusive diagnoses with
inconsistent and overuse use of the terms “atypical,” “suggestive,”
or “suspicious” or in wordy descriptive diagnoses that may be
confusing or incomprehensible, even to other cytopathologists.
In this setting, clinicians may not grasp the key content of vague,
descriptive cytology reports or interpret them in a way that best
matches their clinical impression. For example, “mucinous cyst”
may be interpreted as benign by the clinician, whereas there is a
high probability that it represents a mucinous neoplasm such as
mucoepidermoid carcinoma. Similarly, the presence of “benign
salivary gland elements only” may be reported as “negative for
malignancy” by some cytopathologists and interpreted as
benign/nonneoplastic by the clinician, while it most likely repre-
sents a sampling error (a nondiagnostic specimen).
www.pathologycasereviews.com 235
van Zante et al AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020
Historically, there has been inconsistency in the format and
terminology used for reporting the results of salivary gland FNA
between different institutions and pathologists and sometimes
even by the same pathologist.6,10–19 This inconsistency has con-
fused clinicians and resulted in errors in communication and loss
of clinically meaningful data. The absence of standard nomencla-
ture for FNA results precludes standardization of treatment algo-
rithms and creates a barrier to the sharing of data between
institutions.19 Across anatomic sites, the clinical utility of FNA re-
quires consistent diagnostic terminology, precise interpretation,
and data-driven management recommendations.
Initial studies of salivary gland FNA investigated the diag-
nostic accuracy of FNA for the recognition of specific common
neoplasms such as pleomorphic adenoma or the separation of be-
nign from malignant neoplasms.1,4 However, these studies failed to
specifically address how to approach cytologic material that was ei-
ther nondiagnostic or did not provide a specific diagnosis. In a
meta-analysis, Schmidt et al4 found that among studies on salivary
gland FNA, insufficient and indeterminate results were often unad-
dressed, emphasizing the need to standardize reporting and improve
the design of studies in order to reduce the impact of this bias.1,4
THE IDEAL CYTOLOGY REPORT
The written cytology report is the most important means of
communication between the cytopathologist and the clinician, es-
pecially when other communication routes such as direct or multidis-
ciplinary discussion are impossible or impractical.20,21 Regardless of
the report format adopted, the report must be clear and concise and
provide the information necessary to guide the next steps in the
care of the patient.22,23 The cytopathologist's goal should be to
provide succinct, unambiguous, and actionable information to cli-
nicians and patients. From the clinician's point of view, the “mes-
sage” communicated through the cytology report ideally answers
their specific clinical questions and thereby defines the most ap-
propriate management plan for each patient.20 In general, busy
clinicians prefer brief and “to the point” cytology reports and
show no interest in elaborate descriptions of cytomorphology
and cellular architecture.20
The correct format for reporting has been a contentious issue
among cytopathologists over the years and is influenced by strong
personal preferences, often influenced by one's training.20 The
College of American Pathologists' guidelines for the reporting of
nongynecologic cytopathology specimens support either of two
reporting options, of which one may be preferable depending on
specimen type.21 The first option is a general diagnostic category
followed by an interpretation; the second is a concise diagnosis.
Reports are further required to contain “narrative descriptive no-
menclature.” While general diagnostic categories have historically
been applied to screening tests such as cervical Papanicolaou
tests,24 they have been increasingly incorporated as standardized
reporting systems have been adopted more broadly.22,23,25–27 In
this setting, many cytopathologists advocate for headlining a re-
port with a diagnostic category, whereas others favor reporting
FNA specimens as definitively as possible and similar to surgical
specimens. Regardless, the diagnostic interpretation is indisput-
ably the most important element of reporting, and incorporation
of a diagnostic category should not substitute for the interpreta-
tion. Reports that rest with a diagnostic category alone suggest
to clinicians that FNA is a screening test rather than a diagnostic
test, eventually eroding the clinical utility of minimally invasive
biopsies. Except in settings where categorical reporting is pre-
ferred (ie, thyroid FNA), nongynecologic cytology reports should
include a readily identified, concise interpretation or differential
236 www.pathologycasereviews.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
diagnosis, even when a pathologist chooses to include a diagnostic
category.
GENERAL BENEFITS OF STANDARDIZED
CLASSIFICATION SYSTEMS
There has been a global effort to create internationally recognized
diagnostic systems as a means to enhance cytopathologist-clinician
communication, better guide treatment planning, and ultimately im-
prove patient care.19 The Bethesda system pioneered a cytopathologic
reporting system for reporting cervical/vaginal cytologic diagno-
ses in 1988.24 Subsequently, there has been a significant trend to-
ward the uniform reporting of cytology results for various other
specimens, including FNAs (thyroid, pancreas, lung, and
breast)22,23,25–27 and fluid specimens (urine and effusions).28,29
Currently, almost all cytologic specimen types, including salivary
FNAs, have an internationally recognized, standardized reporting
system. Common to all was the need to establish a common
language and framework for pathologists, clinicians, labora-
tory information systems, and research.19 These reporting sys-
tems provide a tiered classification scheme, include diagnostic
categories that are clinically relevant, and provide a framework
for indeterminate cytologic specimens.5,19–29 Depending on
the anatomic site, these systems convey if the test is primarily
designed for screening (Papanicolaou tests)24,27 or for diagnostic
purposes (eg, thyroid and salivary gland FNAs).5,22,23 Despite
the intent of FNA to provide a definitive diagnosis, there are rare
false-positive and false-negative diagnoses, and inevitably, a por-
tion of specimens do not allow for a specific diagnosis. The most
significant benefits of standardized classification systems are
common terminology in reporting of these indeterminate entities
and the ability to gather sufficient data on clinical outcomes for
patients with indeterminate cytologic findings to clarify the risk
of underlying aggressive pathology.
Most of the standardized reporting systems provide informa-
tion on the implied (or explicit) risk of malignancy (ROM) and for
some the risk of neoplasia, for a given diagnostic category.5,19–29
Although there are several caveats, this risk stratification can help
provide a basis for clinical management decisions. Clinician input
is incorporated in the generation of these standardized terminol-
ogy systems through surveys and inclusion in interdisciplinary
discussions and publication efforts.11,15,19 The primary purpose
of the creation of uniform terminology is clarity of communica-
tion. A universally accepted, consistent terminology establishes a
standard of care, enabling a clinician, independent of geography,
to immediately grasp the final diagnostic conclusion of the cyto-
pathologist and better stratify patients according to the severity
of their disease and the implied ROM. Standardized reporting sys-
tems enable the comparison of data among institutions and pro-
vide a reliable tool for quality control. This communication
benefit extends worldwide, regardless of language barriers, as in-
ternational input is sought in the development of these terminol-
ogy systems. When appropriately applied with concurrent
clinician education, such systems may reduce medicolegal issues
arising from communication errors between cytopathologists
and clinicians.
The many benefits of standardized reporting systems for di-
agnostic cytopathology, including the Milan System for Reporting
Salivary Gland Cytopathology (MSRSGC),5 are summarized in
Table 1. Importantly, the standardized terminology systems are
usually accompanied by a user-friendly atlas with recommenda-
tions for standardized report structure, which may further reduce
the rate of errors in interpretation of the pathology report.5,22,28
In the area of quality assurance, standardized terminology facili-
tates laboratory information system searches and the observation
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020
TABLE 1. Advantages and Considerations Prior to Adoption of the MSRSGC
Main Advantages of the MSRSGC
Standardizes reporting, clarifying communication
among cytopathologists, surgeons, radiologists, and other
health care providers
Creates tiered diagnostic categories with associated ROM
Provides a clinical management algorithm, potentially
expediting patient care
Is relevant and practical for institutions with all levels of
expertise in salivary gland cytology
Facilitates quality improvement review and clinical audits by setting The ROM, as traditionally calculated, is subject to selection bias,
standards (eg, <10% of specimens classified as nondiagnostic or AUS).
Simplifies sharing of data between laboratories for
national and international collaborative studies and
facilitates research into the epidemiology, diagnosis,
molecular biology, and pathology of salivary gland lesions
of established metrics.19 The ease of generating these metrics
allows laboratories to identify specific areas for improvement,
either laboratory-wide or for individual cytotechnologists or
pathologists.19 Standardized terminology further facilitates
cytology-histology correlation, making it easier to define which
cytology cases are discordant and need review. Finally, standard-
ized terminology may facilitate the validation of new technology,
such as molecular testing or digital pathology, by helping re-
searchers clearly define a new technology's performance in the de-
fined diagnostic categories. Akin to the classification of diseases,
these standardized classification systems are dynamic and contin-
ually evolving and improve with time and experience. Significant
advances that may impact the diagnosis, terminology, or manage-
ment in a given field are incorporated in updated versions.19,22
CHALLENGES POSED BY INSTITUTING
STANDARDIZED CLASSIFICATION SYSTEM
The incorporation of standardized diagnostic categories
clearly has numerous benefits; nonetheless, caution should be ap-
plied when considering the immediate and long-term impact of
these systems (Table 1). In the short term, the adoption of stan-
dardized systems should not substitute for providing the most spe-
cific diagnosis possible; pathologists should not lose sight of that
goal. Many entities can be reliably diagnosed by FNA with ex-
ceedingly low false-negative and false-positive rates. Reference
to a ROM for a broader diagnostic category can diminish the
power of the specific diagnosis, with a more precise ROM sup-
ported by the literature. Overuse of categories such as “atypia of
undetermined significance” (AUS) and other indeterminate cate-
gories should be discouraged, as it results in a gradual diminish-
ment of the diagnostic utility of FNA. The availability of
indeterminate categories should not be a “waste basket” and pre-
clude fastidious specimen preparation, appropriate ancillary test-
ing, and expert consultation. The implications of increased
indeterminate diagnoses are significant. In the setting where im-
munohistochemical and molecular testing can be applied, in-
creased indeterminate diagnoses result in unnecessary and
expensive adjunctive testing. In the setting where no adjunctive
studies are available, indeterminate cytologic diagnoses result in
increased rates of core biopsy and increased cost and morbidity
associated with diagnostic excisional procedures.
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
The Milan System: Benefits and Cautions
Points to Consider Prior to Adoption of the MSRSGC
Adoption of new diagnostic terminology requires concurrent
clinician education to maximize its clinical utility.
Incorporation of a diagnostic category into reports should not
substitute for a specific diagnosis or differential diagnosis.
Overuse of categories such as “atypia of undetermined significance”
and other indeterminate categories should be discouraged, as it results
in a gradual diminishment of the diagnostic utility of FNA.
Reference to a ROM for a broader diagnostic category can diminish
the power of the specific diagnosis, with a more precise ROM
supported by the literature.
which increases the implied ROM for low-risk diagnostic categories.
Management recommendations for salivary gland lesions are not
easily generalizable.
One pitfall in assigning all malignancies to a general cate-
gory of malignant is the risk that a clinician jumps to the conclu-
sion that malignant or suspicious for malignancy categorization
implies a primary carcinoma. In fact, the malignant category in-
cludes primary carcinomas, sarcomas, metastatic neoplasms, and
lymphomas. While the recommended clinical management of a
primary carcinoma or sarcoma of salivary gland origin is surgical
resection, metastatic neoplasms may be surgically resected or
treated medically, especially in the era of immunotherapy. In pur-
suit of definitive subclassification and grading of lymphoma,
incisional or excisional biopsy may be required, but a subset of
cases can be accurately classified by flow cytometry and/or cell
block preparation with immunohistochemistry and in situ hy-
bridization. Thus, the diagnosis of lymphoma or suspicious
for lymphoma on an initial FNA may warrant additional sam-
pling by FNA, rather than surgical biopsy. Education of clinicians
highlighting that classification schemas are not restricted to pri-
mary neoplasms is critical, given that the clinical management
of aspirates classified as malignant or suspicious for malignancy
cannot be generalized.
While standardized systems promise data to guide clinical
management, in practice, variables such as specimen preparation
techniques are inconsistent across institutions.11,30 Thus, for the
community pathologist, the published data may not apply to the
specimen at hand. Furthermore, the ROM, as traditionally calcu-
lated, increases the implied ROM for low-risk diagnostic catego-
ries.5,22,31 The estimated ROM is largely based on publications
that rely on the subset of patients with corresponding cytologic
and histologic specimens and exclude patients who underwent clin-
ical follow-up. This selection bias results in the overestimation of
the ROM, because lesions that are resected often have concerning
clinical presentation or imaging features, abnormal repeat FNA re-
sults, or abnormal molecular test results.5,22,31 Thus, the published
ROM for low-risk diagnostic categories does not represent all pa-
tients receiving such an FNA diagnosis, but rather the subset with
clinical findings sufficiently worrisome to warrant excision.
THE MILAN SYSTEM FOR REPORTING SALIVARY
GLAND CYTOPATHOLOGY
Building on the success of prior classification systems for
other organs, including the Bethesda System for Reporting Thyroid
www.pathologycasereviews.com 237
van Zante et al AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020
Cytopathology (TBSRTC),22,23 the MSRSGC was developed as a
joint effort by an international task force of cytopathologists, surgi-
cal pathologists, and head and neck surgeons through the American
Society of Cytopathology and the International Academy of Cytol-
ogy that first met in 2015 in Milan, Italy.5,6,11,13,15,16 Before the
publication of the MSRSGC Atlas in 2018,5 global web-based sur-
veys of the cytopathology community were carried out in
2015–2016 and provided valuable information regarding partici-
pants' interest in salivary gland cytology, practice methods, and
opinions about diagnosing and reporting salivary gland lesions.11
The objective of the MSRSGC was to standardize reporting of sal-
ivary gland cytology, promote better communication between clini-
cians and institutions, and ultimately improve patient care by
providing a uniform reporting system.5,6,11,13,15,16 Since 2016, the
MSRSGC has been presented and discussed in many international
meetings, conferences, and workshops, leading to multiple research
studies and publications.6,12,30–40 Even before the reference Atlas
was published in 2018, the MSRSGC gained widespread interna-
tional acceptance among cytologists. It is currently used to report
cytology results at many institutions in the United States and world-
wide.38,39 The MSRSGC Atlas includes definitions, morphologic
criteria, diagnostic category explanations, and sample reports for
each of the diagnostic categories.5 The MSRSGC also dedicates
specific chapters to the application of ancillary studies, clinical
management, and current histologic considerations. It has been wel-
comed by cytologists in search of a standardized and user-friendly
reporting system for salivary gland FNA and has been endorsed
by head and neck surgeons.15,38,39 Many retrospective studies on
salivary gland FNA using the MSRSGC have now been published,
including studies from North America, Europe, and several Asian
countries.30–40 Finally, a Japanese version was published in 2019.
The MSRSGC consists of 6 diagnostic categories: (1) nondi-
agnostic, (2) nonneoplastic, (3) AUS, (4) neoplasm (subdivided
into benign and salivary gland neoplasm of uncertain malignant
potential), (5) suspicious for malignancy, and (6) malignant
(Table 2).5 The MSRSGC is designed to be transferable and prac-
tical for institutions with all levels of expertise in salivary gland
cytology.
The reported distribution of specimens among the diagnostic
categories varies depending on individual institutions and patient
populations.39 As expected, the neoplasm-benign and nonneoplastic
categories are consistently among the most frequently used, whereas
the frequency of the malignant diagnostic category ranges from
5% to 22%, depending on the study.30–40 In contrast to the thyroid
gland, where it may be challenging to keep the AUS rate below the
recommended 10% benchmark, the average rate for AUS for sal-
ivary aspirates is 4% based on retrospective studies.30–40 How-
ever, the rate of AUS varies widely across centers,30–40 likely
reflecting the variations in practice at different institutions, includ-
ing the use of rapid on-site interpretation and ancillary studies,
which have been shown to reduce the rate of AUS. Similarly,
the rates of salivary gland neoplasm of uncertain malignant po-
tential (SUMP) and suspicious for malignancy are both low
(<10%).30–40 Similar to TBSRTC, the MSRSGC is an evidence-
based reporting system that also links each diagnostic category
to a ROM and usual management.
A primary goal of the MSRSGC is to improve cytologic
guidance of clinical decision making. As such, the diagnostic cat-
egories reflect the major surgical planning decision points
(Table 2). Most nonneoplastic lesions do not require surgical exci-
sion, whereas benign neoplasms may benefit from conservative
excision or even follow-up in a subset of patients who are asymp-
tomatic or unfit for surgery. Among malignant neoplasms, the cat-
egorization of low-grade versus high-grade malignancies may
dictate whether the facial nerve is sacrificed or whether lymph
238 www.pathologycasereviews.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
node dissection will be pursued. Without going into the details
of each diagnostic category (Table 2), the MSRSGC provides rec-
ommendations for the designation of several different FNA find-
ings or “scenarios” that lack definitive evidence of a neoplasm
and for those that are diagnostic of a neoplasm but where a
specific diagnosis cannot be made. For instance, the MSRSGC
recommends a nondiagnostic designation for FNA cases demon-
strating only cyst contents (excluding those with a mucinous
background), benign salivary gland elements (when a defined mass
is clinically present), or necrosis, with the added recommendation
of including a descriptive note.5 There is a good reason for cases
demonstrating only cyst contents to be considered nondiagnostic
as opposed to negative, as some case series confirm that roughly
a quarter of these cases represent neoplasms, including poorly sam-
pled mucoepidermoid carcinomas.40 Except in rare settings such as
sialadenosis or accessory parotid lobe, the finding of benign sali-
vary gland elements by FNA cytology does not explain the pres-
ence of a clinically or radiologically defined mass and likely
reflects a sampling error. The presence of necrosis only in a salivary
gland FNA specimen would be of concern given its association
with high-grade malignancy; however, it may occur in benign neo-
plastic and nonneoplastic conditions and is not diagnostically useful
in isolation. The MSRSGC recommends the AUS category for
those cases demonstrating only mucinous cyst contents because
of the known risk of mucoepidermoid carcinoma in this group.5,41
Indeed, even when the epithelial elements of a low-grade
mucoepidermoid carcinoma are sampled by FNA, the mucous
cells may mimic histiocytes within a mucinous background and
thus lead to a false-negative diagnosis.
The ROM associated with each diagnostic category is based
on calculations from the available literature (Table 2).5,10 Actual
values for ROM are likely to vary depending on the characteristics
of the patient population at any given institution, the anatomic site,
radiologic features, and other characteristics of the individual
tumor.30–41 As previously mentioned, the cited ROMs from pub-
lished studies may represent an overestimation, particularly for
low-risk diagnostic categories, because it is based on the subset
of patients with corresponding cytologic and histologic speci-
mens. The ROM may be further impacted by publication bias, pa-
tient demographics, and institutional referral patterns. Thus,
population-based studies with long-term clinical follow-up and
rigorous statistical methods are needed to clarify the actual risk
of cancer emerging in patients in each diagnostic category. Future
publications can eliminate patient selection bias by following co-
horts of patients over time and determining the estimated probabil-
ity of a diagnosis of malignancy for each diagnostic category. Data
from regional or national cancer registries can be a useful adjunct to
institutional pathology databases and electronic medical records to
follow patients long-term and establish clinical outcomes.
BARRIERS TO ADOPTING THE MILAN SYSTEM
AND POTENTIAL MISCONCEPTIONS OF THE
MILAN SYSTEM
The MSRSGC does not intend to change any of the
well-known cytomorphologic criteria for salivary gland lesions
or the way to approach salivary gland FNA cytology.38 Rather, it
is a tool to provide a uniform format for reporting the conclusions
with the ultimate result of better communication with the potential
for improved patient care.38,39
Novelty and Unfamiliarity With the MSRSGC
Although there are many benefits of adopting standardized
terminology systems, pathologists may face significant barriers
to the adoption of standardized terminology, especially when
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020 The Milan System: Benefits and Cautions

TABLE 2. The Milan System for Reporting Salivary Gland Cytopathology1

Diagnostic Category and Average Average Risk of

Definitions
Nondiagnostic
Insufficient
cellular material for a
cytologic diagnosis
Nonneoplastic
Benign
entities such
as chronic sialadenitis,
reactive lymph node,
granulomas, and infection
AUS
Reserved for FNA
samples containing
limited atypia;
indefinite for a neoplasm
Neoplasm
(A) Benign
Reserved for
benign neoplasms
diagnosed based
on established
cytologic criteria
(B) SUMP
Reserved for FNA samples
that are diagnostic of a
neoplasm; however,
diagnosis of a specific
entity cannot be made
Suspicious for malignancy
This category is for FNA
samples showing features that
are highly suggestive of, but
not unequivocal for
malignancy
Malignant
This category is for FNA
specimens that are
diagnostic of malignancy
*Intraoperative examination (frozen section) may be helpful to guide the extent of surgery.
Explanatory Notes Prevalence10 Malignancy10 Usual Management
This diagnostic category should only be used <10% 25% Clinical and radiologic
after all the material has been processed and correlation/repeat FNA
examined. Exceptions include matrix
material, mucinous cyst contents, cases
with abundant inflammatory cells, and any
case with significant cytologic atypia
Specimens lacking cytomorphologic evidence 13% 10% Clinical follow-up and
of a neoplastic process. Specimens with radiologic correlation
inflammatory, metaplastic, and reactive
changes. Specimens showing evidence of
reactive lymphoid tissue (flow cytometry is
recommended based on clinical and
morphologic suspicion)
Samples are indefinite for a neoplasm; a <10% ~20% Repeat FNA or surgery
neoplastic process cannot be excluded after
examination of all the material. A majority
of these FNAs represent poorly sampled
neoplasms or reactive atypia
This category includes classic cases of 60% <5% Conservative surgery or
pleomorphic adenoma, Warthin clinical follow-up
tumor, lipoma, etc
This diagnosis should be used for cases where <10% 35% Conservative surgery*
a malignant neoplasm cannot be excluded.
A majority of these cases include cellular
benign neoplasms, neoplasms with
atypical features, and
low-grade carcinomas
The FNA report should state which type of <10% 60% Surgery*
malignant tumor is suspected or provide a
differential diagnosis. A majority of
specimens in this category are high-grade
carcinoma on histopathologic follow-up
(an attempt should be made on
histopathologic examination to subclassify
the neoplasm following complete surgical
excision into specific types and grades of
carcinoma for cytologic-histologic
correlation)
An attempt should be made to subclassify the 22% 90% Surgery* (extent dependent
neoplasm into specific types and grades of on type and grade of
carcinoma: eg, low-grade (low-grade malignancy)
mucoepidermoid carcinoma) vs high-grade
(salivary duct carcinoma). Other malignancies
such as lymphomas, metastases, and
sarcomas are also included in this category
and should be specifically designated

new, not uniformly accepted by their peers, or unfamiliar to clini-
cians. There may be a concern that a change in terminology may
be unwelcome for clinicians. Clinicians may not be aware of
advances in cytology and the potential benefits of standardized
terminology. The decision to change terminology should un-
doubtedly be undertaken jointly with the clinicians who are
the audience for these reports, and the education of clinicians is
essential for the success of the MSRSGC. Pathologists should
present the standardized terminology to clinicians, including
how it will affect the clinical utility of the test and the potential
benefit of management guidelines. The categories of “AUS” and
“SUMP” need to be carefully explained and compared with any
prior diagnostic terminology. In transitioning to the standardized
terminology, additional explanation and details should be in-
cluded in the comment section of the report. Importantly, the
MSRSGC is intended as a flexible framework that can be modi-
fied to suit the needs of the particular laboratory and the patients
it serves.

© 2020 Wolters Kluwer Health, Inc. All rights reserved. www.pathologycasereviews.com 239

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

van Zante et al AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020
Report Format
Because the complexity of salivary gland cytology is greater
than its thyroid counterpart, there are also significant differences in
the recommendations between the MSRSGC and TBSRTC.5,23,33
In the MSRSGC, the cytology report should include a statement
on adequacy, the diagnostic category, a specific diagnosis as to
the nature of the nonneoplastic process or neoplasm present, and
a brief description of the cytological features. If the aforementioned
is not possible, a concise comment on the reason for the categoriza-
tion of the lesion is required. When a specific diagnosis cannot be
made for any reason, this should be clearly stated and explained.
A brief microscopic description is an optional component of stan-
dardized cytology reports, but morphologic description and differ-
ential diagnostic considerations should always be included where
relevant, and there are occasions in which a descriptive diagnosis
or a microscopic description of the cytologic findings may be par-
ticularly helpful for clinicians, for example, when foreign material
such as cosmetic filler or surgical suture with associated cellular
reaction is aspirated. Concurrent with the use of diagnostic cate-
gories, pathologists are strongly encouraged to make a definitive
diagnosis, rather than a descriptive diagnosis. Pathologists should
further process the specimen, use ancillary studies (when possi-
ble), and seek expert consultation to establish a definitive diagno-
sis whenever possible.
In contrast to the MSRSGC, the TBSRTC does not require a
statement of adequacy or descriptive comments, and subcategori-
zation is recommended only for some of the general diagnostic
categories.22,23 One of the main reasons for these differences is
that the usual management is largely established for the different
Bethesda categories for thyroid FNA and may not require a de-
scription. In contrast, the implied ROMs and management within
a category of the MSRSGC can vary substantially, and the addi-
tional information in a description or explanatory note can signifi-
cantly impact patient management. In other words, no sample
report of the MSRSGC Atlas comes in the form of a
“category-only” cytology report, which would undermine the
complexity of interpretation and reporting of salivary FNA
specimens. The MSRSGC Atlas, akin to TBSRTC, is designed
to be user-friendly and incorporates many examples of reports
with explanatory notes.5 Importantly, standardized systems are
not a universal remedy; they codify the reporting of common
entities, but cannot reflect the full range of findings encoun-
tered in clinical practice. Thus, some unusual cases may not
be reported in a standardized way. In situations where a lesion
is difficult to classify, a descriptive cytology report may some-
times better express the uncertainty of the cytopathologist and
be more accurate than any classification.
Training of Cytotechnologists and Residents
Little attention has been given to the impact of standardized
reporting systems on the training of cytotechnologists and resi-
dents in cytopathology.19,20 An emphasis on categorical reporting
in training programs may have significant practical implications.
The diagnostic process requires integrating the clinical setting
with cytomorphologic and architectural clues and should result
in the most specific interpretation possible. This process should
not be sacrificed as trainees strive to fit microscopic findings into
a standard diagnostic category. Training programs must empha-
size that a diagnosis should be made, and then appropriate diagnos-
tic categories applied. Reporting systems should be presented as an
aid in the communication of a diagnostic interpretation, not a di-
agnostic algorithm.
240 www.pathologycasereviews.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Prospective Evidence
Out of caution, a minority of pathologists may not wish to
change their practice until a preponderance of prospective evi-
dence shows that standardized terminology offers better perfor-
mance than the current practice. This is not yet the case with the
MSRSGC, where the data and the experience are derived from ret-
rospective studies.30–41 Prospective studies with a large number of
cases from various institutions are still needed to validate the ben-
efits of adoption.
MSRSGC and Interobserver Variability
Kurtycz et al,42 belonging to a subgroup of experts who cre-
ated the MSRSGC, described the first image-based Milan Interob-
server Reproducibility Study in 2020. The survey evaluated the
ability of participants (pathologists, cytotechnologists, pathology
residents, cytopathology fellows, and others) to apply the
MSRSGC categories based on the images used in the MSRSGC
Atlas. The overall agreement for all diagnostic categories in the
MSRSGC was 42%. The best agreement was reached on
neoplasm-benign (58.9%), nondiagnostic (49.2%), and malignant
(48.4%). Not surprisingly, indeterminate categories, including
AUS (17.7%) and SUMP (23.6%), showed lower concordance.
The presence of the acellular matrix or mucin, benign acinar cells
in a patient with a salivary gland mass, clear cell features, and
basaloid morphology with a history of facial palsy were images
with the highest discordance between the participants and the
Milan authors. Participants with more experience (up to 24 years
of experience) or based in higher-volume institutions performed
better. Board-certified cytopathologists achieved the best perfor-
mance, followed by cytopathology fellows.
The overall concordance rate of 42% may reflect that salivary
gland cytology is a challenging field requiring knowledge of the
clinical presentation of salivary gland pathology and integration
of this information with microscopic features that are not easily cap-
tured in a single static image. The results may be attributed to that
fact that interpretation of salivary gland aspirates requires evalua-
tion of architectural features that are not easily captured in static im-
ages. Thus, salivary gland cytology may not be comparable to
cervical or thyroid cytology, where higher rates of agreement have
been achieved in similar survey formats. Alternatively, the poor
concordance may simply reflect the novelty of the MSRSGC. The
results of this survey shed light on educational gaps and may, in
fact, argue for the adoption of the MSRSGC and the wide distribu-
tion of the associated atlas as educational tools. The diagnostic cat-
egories with less agreement, including AUS, SFM, SUMP, and
nonneoplastic, require particular attention. The findings in this sur-
vey are a baseline for future studies in interobserver reproducibility
in salivary gland cytology as evaluation of static images of salivary
aspirates may not be comparable to evaluation of glass slides.
SUMMARY
The MSRSGC was developed to provide a universally ac-
cepted reporting structure for salivary gland FNA. The primary
goals of the MSRSGC are to improve cytopathologist-clinician
communication and cytologic guidance of clinical decision mak-
ing. Adoption of the system should enhance diagnostic specificity,
and unlike TBSRTC, categorical reporting should not supplant a
specific diagnosis or interpretation. In practice, adopting this sys-
tem should be undertaken with concurrent clinician education to
maximize its clinical utility. Finally, the MSRSGC can be a resource
for continuing educational efforts to reduce diagnostic errors, given
the high degree of complexity of salivary cytopathology.
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020
REFERENCES
1. Faquin WC, Powers CN. In: Salivary Gland Cytopathology. Essentials in
Cytopathology Series, Vol. 5, New York, Springer; 2008.
2. Jain R, Gupta R, Kudesia M, et al. Fine needle aspiration cytology in
diagnosis of salivary gland lesions: a study with histologic comparison.
Cytojournal 2013;10:5.
3. Colella G, Cannavale R, Flamminio F, et al. Fine-needle aspiration cytology
of salivary gland lesions: a systematic review. J Oral Maxillofac Surg 2010;
68:2146–2153.
4. Schmidt RL, Hunt JP, Hall BJ, et al. A systematic review and meta-analysis
of the diagnostic accuracy of frozen section for parotid gland lesions. Am J
Clin Pathol 2011;136:729–738.
5. Faquin WC, Rossi ED, eds. The Milan System for Reporting Salivary
Gland Cytopathology. Cham, Switzerland: Springer; 2018.
6. Pusztaszeri M, Rossi ED, Baloch ZW, et al. Salivary gland fine needle
aspiration and introduction of the Milan reporting system. Adv Anat Pathol
2019;26:84–92.
7. Hughes JH, Volk EE, Wilbur DC, Cytopathology Resource Committee,
College of American Pathologists. Pitfalls in salivary gland fine-needle
aspiration cytology: lessons from the College of American Pathologists
Interlaboratory Comparison Program in Nongynecologic Cytology. Arch
Pathol Lab Med 2005;129:26–31.
8. Tyagi R, Dey P. Diagnostic problems of salivary gland tumors. Diagn
Cytopathol 2015;43:495–509.
9. El-Naggar AK, Chan J, Takata T, et al. WHO Classification of Tumours.
Pathology and Genetics of Head and Neck Tumours. 4th ed. Lyon, France:
IARC Press; 2017.
10. Wei S, Layfield LJ, LiVolsi VA, et al. Reporting of fine needle aspiration
(FNA) specimens of salivary gland lesions: a comprehensive review. Diagn
Cytopathol 2017;45:820–827.
11. Rossi ED, Faquin WC, Baloch Z, et al. The Milan System for Reporting
Salivary Gland Cytopathology: analysis and suggestions of initial survey.
Cancer 2017;125:757–766.
12. Layfield LJ, Baloch ZW, Hirschowitz SL, et al. Impact on clinical follow-up
of the Milan System for salivary gland cytology: a comparison with a
traditional diagnostic classification. Cytopathology 2018;29:335–342.
13. Rossi ED, Baloch Z, Pusztaszeri M, et al. The Milan System for Reporting
Salivary Gland Cytopathology (MSRSGC): an ASC-IAC–sponsored
system for reporting salivary gland fine-needle aspiration. J Am Soc
Cytopathol 2018;7:111–118.
14. Pusztaszeri M, Baloch Z, Vielh P, et al. Application of the Milan System for
reporting risk stratification in salivary gland cytopathology. Cancer
Cytopathol 2018;126:69–70.
15. Barbarite E, Puram SV, Derakhshan A, et al. A call for universal acceptance
of the Milan System for Reporting Salivary Gland Cytopathology.
Laryngoscope 2020;130:80–85.
16. Rossi ED, Faquin WC. The Milan System for Reporting Salivary Gland
Cytopathology (MSRSGC): an international effort toward improved patient
care—when the roots might be inspired by Leonardo da Vinci. Cancer
Cytopathol 2018;126:756–766.
17. Rossi ED, Wong LQ, Bizzarro T, et al. The impact of FNAC in the
management of salivary gland lesions: institutional experiences leading to a
risk-based classification scheme. Cancer Cytopathol 2016;124:388–396.
18. Griffith CC, Pai RK, Schneider F, et al. Salivary gland tumor fine-needle
aspiration cytology: a proposal for a risk stratification classification. Am J
Clin Pathol 2015;143:839–853.
19. Sundling KE, Kurtycz DFI. Standardized terminology systems in
cytopathology. Diagn Cytopathol 2019;47:53–63.
20. Grapsa D, Politi E. Standardized Categorical Reporting of Cytopathology
Results: the strengths and weaknesses of a constantly evolving and
expanding system. Diagn Cytopathol 2013;41:917–921.
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
The Milan System: Benefits and Cautions
21. Crothers BA, Tench WD, Schwartz MR, et al. Guidelines for the reporting
of nongynecologic cytopathology specimens. Arch Pathol Lab Med 2009;
133:1743–1756.
22. Ali SZ, Cibas ED, eds. The Bethesda System for Reporting Thyroid
Cytopathology: Definitions, Criteria and Explanatory Notes. New York:
Springer; 2017.
23. Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and
morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis
of the National Cancer Institute thyroid fine-needle aspiration state of the
science conference. Diagn Cytopathol 2008;36:425–437.
24. Nayar R, Wilbur DC. The Pap test and Bethesda 2014. Cancer Cytopathol
2015;123:271–281.
25. Pitman MB, Centeno BA, Ali SZ, et al. Standardized terminology and
nomenclature for pancreatobiliary cytology: the Papanicolaou Society of
Cytopathology guidelines. Diagn Cytopathol 2014;42:338–350.
26. Layfield LJ, Baloch Z, Elsheikh T, et al. Standardized terminology and
nomenclature for respiratory cytology: the Papanicolaou Society of
Cytopathology guidelines. Diagn Cytopathol 2016;44:399–409.
27. Layfield LJ, Wang G, Yang ZJ, et al. Interobserver agreement for the
International Academy of Cytology Yokohama System for reporting breast
fine-needle aspiration biopsy cytopathology. Acta Cytol 2020;1–7.
28. Rosenthal DL, Wojcik EM, Kurtycz D. The Paris System for Reporting
Urinary Cytology. Cham, Switzerland: Springer; 2016.
29. Crothers BA, Chandra A. Proceedings of the American Society of
Cytopathology Companion Session at the 2019 United States and Canadian
Academy of Pathology meeting part 1: towards an international system for
reporting serous fluid cytopathology. J Am Soc Cytopathol 2019;8:
362–368.
30. Behaeghe M, Vander Poorten V, Hermans R, et al. The Milan System for
Reporting Salivary Gland Cytopathology: single center experience with
cell blocks [published online June 7, 2020]. Diagn Cytopathol 2020. doi:
10.1002/dc.24515.
31. Iskandar ME, Bonomo G, Avadhani V, et al. Evidence for overestimation of
the prevalence of malignancy in indeterminate thyroid nodules classified as
Bethesda Category III. Surgery 2015;157:510–517.
32. Maleki Z, Miller JA, Arab SE, et al. “Suspicious” salivary gland FNA: risk
of malignancy and interinstitutional variability. Cancer Cytopathol 2018;
126:94–100.
33. Viswanathan K, Sung S, Scognamiglio T, et al. The role of the Milan
System for Reporting Salivary Gland Cytopathology: a 5-year institutional
experience. Cancer Cytopathol 2018;126:541–551.
34. Wang H, Malik A, Maleki Z, et al. “Atypical” salivary gland fine needle
aspiration: risk of malignancy and interinstitutional variability. Diagn
Cytopathol 2017;45:1088–1094.
35. Rohilla M, Singh P, Rajwanshi A, et al. Three-year cytohistological
correlation of salivary gland FNA cytology at a tertiary center with the
application of the Milan System for risk stratification. Cancer Cytopathol
2017;125:767–775.
36. Thiryayi SA, Low YX, Shelton D, et al. A retrospective 3-year study of
salivary gland FNAC with categorisation using the Milan reporting system.
Cytopathology 2018;29:343–348.
37. Liu H, Ljungren C, Lin F, et al. Analysis of histologic follow-up and risk of
malignancy for salivary gland neoplasm of uncertain malignant potential
proposed by the Milan System for Reporting Salivary Gland
Cytopathology. Cancer Cytopathol 2018;126:490–497.
38. Rossi ED, Faquin WC. The Milan System for Reporting Salivary Gland
Cytopathology: the clinical impact so far. Considerations from theory to
practice. Cytopathology 2020;31:181–184.
39. Jalaly JB, Farahani SJ, Baloch ZW. The Milan System for Reporting
Salivary Gland Cytopathology: a comprehensive review of the literature.
Diagn Cytopathol 2020;1–10.
www.pathologycasereviews.com 241
van Zante et al AJSP: Reviews & Reports • Volume 25, Number 5, September/October 2020

40. Maleki Z, Baloch Z, Lu R, et al. Application of the Milan System for
Reporting Submandibular Gland Cytopathology: an international,
multi-institutional study. Cancer Cytopathol 2019;127:306–315.
41. Lubin D, Buonocore D, Wei XJ, et al. The Milan System at Memorial Sloan
Kettering: utility of the categorization system for in-house salivary gland
fine-needle aspiration cytology at a comprehensive cancer center. Diagn
Cytopathol 2020;48:183–190.
42. Kurtycz DFI, Rossi ED, Baloch Z, et al. Milan Interobserver
Reproducibility Study (MIRST): Milan System 2018. J Am Soc Cytopathol
2020;9:116–125.

242 www.pathologycasereviews.com © 2020 Wolters Kluwer Health, Inc. All rights reserved.

View publication stats Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.