The document summarizes updates to the salivary gland section of the 5th edition of the World Health Organization Classification of Head and Neck Tumors, including the description and inclusion of several new entities. Specifically, it introduces sclerosing polycystic adenoma, keratocystoma, intercalated duct adenoma, and striated duct adenoma as new benign entities, as well as microsecretory adenocarcinoma and sclerosing microcystic adenocarcinoma as new malignant entities. It also discusses controversies that remain unresolved, such as the classification of mucinous adenocarcinoma and intraductal carcinoma.

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https://doi.org/10.1007/s12105-022-01420-1
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UPDATE FROM THE 5TH EDITION OF THE WORLD HEALTH ORGANIZATION
CLASSIFICATION OF HEAD AND NECK TUMORS
Update from the 5th Edition of the World Health Organization
Classification of Head and Neck Tumors: Salivary Glands
Alena Skálová1,2
· Martin D. Hyrcza3
· Ilmo Leivo4
Received: 14 November 2021 / Accepted: 19 January 2022 / Published online: 21 March 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours
features a description and inclusion of several new entities, including sclerosing polycystic adenoma, keratocystoma, inter-
calated duct adenoma, and striated duct adenoma among the benign neoplasms; and microsecretory adenocarcinoma and
sclerosing microcystic adenocarcinoma as the new malignant entities. The new entry also includes mucinous adenocarcinoma
subdivided into papillary, colloid, signet ring, and mixed subtypes with recurrent AKT1 E17K mutations across patterns sug-
gesting that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that may be related
to salivary intraductal papillary mucinous neoplasm (IPMN). Importantly, the number of entities in the salivary chapter has
been reduced by omitting tumors or lesions if they do not occur exclusively or predominantly in salivary glands, includ-
ing hemangioma, lipoma, nodular fasciitis and hematolymphoid tumors. They are now discussed in detail elsewhere in the
book. Cribriform adenocarcinoma of salivary gland origin (CASG) now represents a distinctive subtype of polymorphous
adenocarcinoma (PAC). PAC is defined as a clinically, histologically and molecularly heterogeneous disease group. Whether
CASG is a different diagnostic category or a variant of PAC is still controversial. Poorly differentiated carcinomas and onco-
cytic carcinomas are discussed in the category “Salivary carcinoma not otherwise specified (NOS) and emerging entities”.
New defining genomic alterations have been characterized in many salivary gland tumors. In particular, they include gene
fusions, which have shown to be tightly tumor-type specific, and thus valuable for use in diagnostically challenging cases.
The recurrent molecular alterations were included in the definition of mucoepidermoid carcinoma, adenoid cystic carci-
noma, secretory carcinoma, polymorphous adenocarcinoma, hyalinizing clear cell carcinoma, mucinous adenocarcinoma,
and microsecretory adenocarcinoma.
Keywords Salivary gland · World Health Organization · Classification · Neoplasm · Gene fusion · WHO
Introduction
The major and minor salivary glands are associated with
a remarkable diversity of neoplasms. Given the number of
already existing entities which show considerable overlap of
histologic and immunohistochemical features between dif-
ferent salivary gland neoplasms, only very well documented
new entities have been accepted in this edition [1]. Reported
tumors and variant morphologies lacking consensus sup-
port and validation by independent investigators have not
been included. This approach resulted in the introduction
of microsecretory adenocarcinoma and sclerosing micro-
cystic adenocarcinoma as the new malignant entities; and
keratocystoma, intercalated duct adenoma, and striated duct
adenoma within benign neoplasms. Further, the neoplastic
* Alena Skálová
skalova@biopticka.cz
1
Sikl’s Department of Pathology, Faculty of Medicine
in Plzen, Charles University, E. Benese 13, 305 99 Plzen,
Czech Republic
2
Department of Pathology and Molecular Genetics, Bioptical
Laboratory Ltd, Plzen, Czech Republic
3
Department of Pathology and Laboratory Medicine,
University of Calgary, Arnie Charboneau Cancer Institute,
Calgary, Canada
4
Institute of Biomedicine, Pathology, University of Turku,
and Turku University Hospital, Turku, Finland

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nature of sclerosing polycystic adenoma moved the lesion
from a non-neoplastic epithelial lesion [2] into the benign
neoplasm category.
Since the last edition, molecular data has become widely
reported, with many salivary gland neoplasms shown to har-
bour tumor type-specific rearrangements (Table 1). Molecu-
lar testing of salivary gland tumors for differential diagnostic
accuracy and appropriate clinical management is becoming
routine [3, 4]. Molecular alterations were included in the
definition of the following entities: mucoepidermoid carci-
noma, adenoid cystic carcinoma, secretory carcinoma, poly-
morphous adenocarcinoma, hyalinizing clear cell carcinoma,
mucinous adenocarcinoma, and microsecretory adenocarci-
noma [1].
Cytological findings have been included in most sections,
in recognition of the importance of fine needle aspiration
(FNA) as an initial diagnostic approach, and the Milan sys-
tem is recommended [5]. While FNA has emerged as an
important component in the diagnostic workup of salivary
gland tumors, core needle biopsies are still performed occa-
sionally, especially after non-diagnostic aspirates. While
offering more architectural information than FNAs, most
core biopsies do not allow for assessment of the interface
between the tumor and surrounding tissues, and thus are
insufficient in distinguishing between benign tumors and low
grade malignancies (i.e. myoepithelioma vs myoepithelial
carcinoma). Only fully resected tumor specimens allow for
diagnostic clarity in such cases.
Histologic grading of salivary gland carcinomas has been
shown to be an independent predictor of behavior and plays
a role in optimizing therapy. Still, most salivary gland car-
cinomas have an intrinsic biologic behavior, and attempts to
apply universal grading schemes are not recommended [6,
7]. Carcinoma types for which validated grading systems
exist include adenoid cystic carcinoma, mucoepidermoid
carcinoma, and adenocarcinoma, not otherwise specified
[8]. High-grade transformation (HGT) has been shown to
be an important concept in tumor progression in salivary
gland carcinomas [9]. Tumors demonstrating HGT show an
aggressive clinical course that differs significantly from the
usual behavior of a given tumor type. Therefore the phenom-
enon of HGT is included in the description of the appropri-
ate entities [1].
The following controversial issues remain unresolved in
the new edition of the WHO Blue Book [1]:
• Mucinous adenocarcinoma (MA) subdivided into papil-
lary, colloid, signet ring, and mixed subtypes is charac-
terized by recurrent AKT1 E17K mutations across the
various patterns suggesting that mucin-producing sali-
vary adenocarcinomas represent a histologically diverse
single entity [10]. Intraductal papillary mucinous neo-
plasm (IPMN) is an emerging entity comprising duct-
centric tumors with low-grade mucinous morphology;
they share with MA frequent occurrence of AKT1 muta-
tions [11]. It is still not established whether IPMN should
be classified separately or within the MA spectrum as a
potential precursor [12, 13].
• Intraductal carcinoma (IC) is a salivary gland malig-
nancy characterized by papillary, cribriform, and solid
proliferations that are entirely or predominantly intra-
ductal. Despite the name „intraductal“, frank invasive
growth with loss of myoepithelial cells can be seen occa-
sionally in IC [14, 15]. Moreover, one recent study has
shown that the layer of myoepithelial cells is part of the
tumor and so ICs may actually be biphasic neoplasms
rather than truly in-situ neoplasms [16].
• There is no consensus whether oncocytic carcinoma
exists. Oncocytic appearance is a common change
encountered in many different salivary gland tumors.
In the past, carcinomas consisting entirely of oncocytes
were frequently diagnosed as oncocytic carcinoma.
Molecular studies have now shown that many such
tumors are oncocytic variants of other salivary carcino-
mas [17–19] and it is uncertain if any purely oncocytic
carcinomas exist that are not morphologic variants of
other carcinomas. For this reason, oncocytic carcinoma
has been moved into the emerging entities chapter.
• Carcinosarcoma has remained as a separate entity in
this edition, but it is not clear whether the sarcomatous
component represents a true sarcoma or a result of an
epithelial-mesenchymal transition.
New Entries Included in the 5th Edition WHO
Sclerosing Polycystic Adenoma
Sclerosing polycystic adenoma (SPA) is a rare sclerosing
tumor of salivary glands with a characteristic combination
of histological features, somewhat reminiscent of fibro-
cystic changes, sclerosing adenosis and adenosis tumor of
the breast. The histologic findings in SPA include fibrosis,
cystic alterations, apocrine metaplasia, and proliferations of
ducts, acini composed of the cells with abundant eosino-
philic cytoplasmic granules, and myoepithelial cells in vari-
able proportions (Fig. 1A–G) [20]. Recurrent mutations in
the PI3 kinase pathway, most frequently PTEN, confirm its
neoplastic nature and suggest links with apocrine intraductal
carcinoma (IC) and salivary duct carcinoma (SDC) [21–24].
Although no patient with SPA has developed metastases
or died of disease, reports indicate that at least three patients
had invasive carcinoma with apocrine ductal phenotype aris-
ing from SPA [23–25]. In a recent study, a unique case of
a parotid gland tumor composed of SPA, apocrine IC and
high grade SDC harbored an identical mutation in PI3K/

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Table 1 Selected genetic alterations in salivary tumors (Adapted from Andreasen, et al., ref. No. [53])
Tumor type Chromosomal region Gene and mechanism Prevalence
Pleomorphic adenoma 8q12 PLAG1 fusions/amplification >50%
12q13-15 HMGA2 fusions/amplification 10–20%
Basal cell adenoma 3p22.1 CTNNB1 mutations 37–80%
16q12.1 CYLD mutations 36%
16p13.3 AXIN1 mutations 9%
5q22.2 APC mutations 3%
Myoepithelioma, oncocytic subtype 8q12 PLAG1 fusions 40%
Sialadenoma papilliferum 7q34 BRAF V600E mutations 50%-100%
Sclerosing polycystic adenoma 3q26.32 PIK3CA mutation high
Mucoepidermoid carcinoma t(11;19) (q21;p13) CRTC1-MAML2 40–90%
t(11;15) (q21;q26) CRTC3-MAML2 6%
9p21.3 CDKN2A deletion 25%
Adenoid cystic carcinoma 6q22-23 MYB fusion/activation/amplification ~80%
8q13 MYBL1 fusion/activation/amplification ~10%
9q34.3 NOTCH mutations 14%
Acinic cell carcinoma 9q31 NR4A3 fusion/activation 86%
19q31.1 MSANTD3 fusion/amplification 4%
Secretory carcinoma t(12;15) (p13;q25) ETV6-NTRK3 fusion >90%
t(12;10) (p13;q11) ETV6-RET fusion 2–5%
t(12;7) (p13;q31) ETV6-MET fusion <1%
t(12;4) (p13;q31) ETV6-MAML3 fusion <1%
t(10;10) (p13;q11) VIM-RET fusion <1%
Microsecretory adenocarcinoma t(5q14.3) (18q11.2) MEF2C-SS18 fusion >90%
Polymorphous adenocarcinoma
Classic subtype 14q12 PRKD1 mutations 73%
Cribriform subtype 14q12 PRKD1 fusions 38%
19q13.2 PRKD2 fusions 14%
2p22.2 PRKD3 fusions 19%
Hyalinizing clear cell carcinoma t(12;22) (q21;q12) EWSR1-ATF1 fusions 93%
EWSR1-CREM fusions <5%
Basal cell adenocarcinoma 16q12.1 CYLD mutations 29%
Intraductal carcinoma
Intercalated duct subtype 10q11.21 RET fusions 47%
Apocrine subtype 3q26.32 PIK3CA mutations High
11p15.5 HRAS mutations High
Salivary duct carcinoma 17q21.1 HER2 amplification 31%
8p11.23 FGFR1 amplification 10%
17p13.1 TP53 mutation 56%
3q26.32 PIK3CA mutation 33%
11p15.5 HRAS mutation 33%
Xq12 AR copy gain 35%
10q23.31 PTEN loss 38%
9p21.3 CDKN2A loss 10%
Myoepithelial carcinoma 8q12 PLAG1 fusions 38%
t(12, 22) (q21;q12) EWSR1 rearrangement 13%
Epithelial-myoepithelial carcinoma 11p15.5 HRAS mutations 78%
Mucinous adenocarcinoma 14q32.33 AKT1 E17K mutations 100%
17p13.1 TP53 mutations 88%
Sclerosing microcystic adenocarcinoma 1p36.33 CDK11B mutation 1 case
Carcinoma ex pleomorphic adenoma 8q12 PLAG1 fusions/amplification 73%

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Akt pathway in all tumor three components [25] (Fig. 1H-
J). Taken together, recent findings not only strongly support
that SPA is a neoplastic disease, but suggest a close rela-
tionship between SPA, apocrine IC and high-grade invasive
SDC. In fact, SPA may represent a precursor lesion for the
development of apocrine IC and occasionally even invasive
SDC [25].
Keratocystoma
Keratocystoma is a benign salivary gland tumor character-
ized by multicystic spaces, lined by stratified squamous
epithelium, containing keratotic lamellae and focal solid
epithelial nests [26]. Essential diagnostic criteria include a
bland stratified squamous epithelial lining without a granu-
lar layer within the multicystic structures and the presence
of sharply defined solid squamous epithelial cell islands
(Fig. 2). All reported tumors arose in the parotid gland. Dif-
ferential diagnosis includes primary and metastatic squa-
mous cell carcinoma, mucoepidermoid carcinoma, meta-
plastic Warthin tumor, and necrotizing sialometaplasia. The
absence of necrosis, invasion, and cytologic atypia speaks
against malignancy.
Intercalated Duct Adenoma
Intercalated duct adenoma (IDA) is a benign proliferation of
bilayered ducts with a cytological appearance and immuno-
profile of normal intercalated ducts (Fig. 3A, B) [27]. IDAs
are part of intercalated duct lesion (IDL) spectrum together
with intercalated duct hyperplasia (IDH) [27]. Both IDHs
and IDAs show proliferation of small ducts with eosinophilic
to amphophilic cytoplasm and small bland nuclei. Although
myoepithelial cells can be shown to be present using immu-
nohistochemistry for myoepithelial markers, they are usually
not conspicuous on routine H&E slides. The ductal cells
show diffuse staining for cytokeratin 7, focal positivity for
lysozyme and estrogen receptor, and diffuse staining for
S100 in the majority of cases [27]. Occasional acinic cells
can be seen within the lesions. The distinction of IDA from
IDH was proposed to be based on the presence of a discrete,
well-defined, partially or completely encapsulated tumor
which does not respect the pre-existing lobular architecture
of the background salivary parenchyma [27]. Although inter-
calated duct lesions tend to be small and are frequently found
incidentally in resections of other lesions, IDAs can reach
sizes that bring them to direct clinical attention. The associa-
tion of IDLs with other salivary neoplasms such as epithe-
lial-myoepithelial carcinomas, basal cell adenomas, basal
cell adenocarcinomas and others, has lead some authors to
propose that IDL may in fact be a precursor lesion for other
neoplasms [27, 28]. This hypothesis is supported by pub-
lished cases of hybrid tumors showing and IDL component
next to a morphologically distinct tumour such as basal cell
adenoma or epithelial-myoepithelial carcinoma [27, 28]. The
main differential diagnosis of IDA is basal cell adenoma,
which tends to be larger (typically over >10 mm) show-
ing obvious bilayering, prominent spindle cell stroma, and
a prominent S100 expression in the stromal spindle cells,
while in the luminal cells it is weak and patchy [27].
Striated Duct Adenoma
Striated duct adenoma is a rare benign tumor composed of
ducts lined by a monolayer of cells with cytological appear-
ance resembling normal striated ducts (Fig. 3C, D) [29].
Unlike the intercalated duct adenomas, striated duct adeno-
mas do not contain myoepithelial or basal cells. The tumors
are encapsulated and composed of closely apposed ducts
with little or no stroma. Some ducts show cystic dilation up
to 0.1 cm. The cells have eosinophilic cytoplasm and promi-
nent cell membranes resembling striations seen in normal
striated ducts. Immunoprofile is positive for S100, cytokera-
tin 7, and cytokeratin 5, and negative for smooth muscle
actin. The p63 staining may show single positive cells.
Occasional tumors may show nuclear grooves and intranu-
clear pseudoinclusions, mimicking the nuclear features of
papillary thyroid carcinoma [30]. Given the oncocytic cyto-
plasm and the ductal architecture, the differential diagnosis
of striated duct adenoma includes oncocytoma, intercalated
duct adenoma, basal cell adenoma, and canalicular adenoma.
Lack of bilayering, basophilic cytoplasm, and basement
membrane connective tissue distinguishes striated duct ade-
noma from basal cell adenoma. Canalicular adenomas show
a beading pattern of anastomosing cords of cells, which stri-
ated duct adenomas lack. The cells of oncocytoma show
more prominent oncocytic cytoplasm while forming fewer
ducts and more solid islands than striated duct adenoma.
Finally, intercalated duct adenomas have basophilic cyto-
plasm and a myoepithelial layer on immunohistochemistry,
Table 1 (continued)
Tumor type Chromosomal region Gene and mechanism Prevalence
12q13-15 HMGA2 fusions/amplification 14%
17p13.1 TP53 mutations 60%
Sebaceous adenocarcinoma 2p21 MSH2 loss 10%

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both of which lack in striated duct adenoma. Fewer than ten
cases of striated duct adenomas have been published to-date,
highlighting its rarity. Lack of recognition may also contrib-
ute to its low incidence, whereby inclusion of striated duct
adenoma in the 5th edition of World Health Organization
Classification of Head and Neck Tumours, may inspire more
pathologists to report it.
Microsecretory Adenocarcinoma
Microsecretory adenocarcinoma (MSA) is a newly identified
low-grade salivary adenocarcinoma characterized by distinc-
tive morphology and a specific MEF2C::SS18 fusion [31].
Its discovery stemmed from efforts to further subclassify
the heterogeneous group of salivary carcinomas collec-
tively termed as “adenocarcinoma, not otherwise specified”
(NOS). Next generation sequencing of such adenocarcino-
mas showed a recurrent MEF2C::SS18 gene fusion in a sub-
set of tumors with consistent morphologic features, includ-
ing small tubules and microcysts lined by flat intercalated
duct-like cells, and containing abundant basophilic luminal
secretions (Fig. 4) [32]. The nuclei are uniform, oval, and
lack prominent nucleoli. MSAs lack myoepithelial and basal
cells placing them within the group of monophasic salivary
tumors. Despite a fairly good circumscription within a myx-
ohyaline stroma, these tumors lack a capsule and tend to
show focal infiltration into surrounding tissues, leading to
their classification as carcinomas. Despite this, none of the
24 cases identified to-date has shown recurrence, or locore-
gional or distant metastasis [31]. The SS18 gene rearrange-
ment is so far unique among salivary gland tumors and it
can be demonstrated by fluorescence in situ hybridization
(FISH). The SS18 FISH is available in many laboratories,
since the same gene is rearranged in synovial sarcomas,
albeit with different partners [33]. Alternative testing strat-
egies include next generation sequencing (NGS) and poly-
merase chain reaction (PCR) [31]. Tumor cells show diffuse
positivity for S100, SOX10, and p63, but are negative for
p40, calponin, SMA, and mammaglobin [31]. Differential
diagnosis includes adenoid cystic carcinoma, secretory car-
cinoma, polymorphous adenocarcinoma, secretory variant
of myoepithelial carcinoma, and adenocarcinoma, NOS.
Adenoid cystic carcinoma is a biphasic neoplasm, which can
be demonstrated by immunohistochemistry for myoepithe-
lial markers, CEA and EMA. Secretory carcinoma lacks the
myxoid stroma and shows strong mammaglobin positivity.
Polymorphous adenocarcinoma tends to lack the microse-
cretory pattern and the myxoid stroma and its cells show
much more abundant cytoplasm. Myoepithelial carcinoma
shows positivity for myoepithelial markers such as calponin,
smooth muscle actin and p40, which are absent in MSA.
Finally, all these tumors lack the MEF2C::SS18 gene fusion.
Sclerosing Microcystic Adenocarcinoma
Sclerosing microcystic adenocarcinoma (SMA) is a rare
malignancy occurring in salivary glands with character-
istic morphology resembling the cutaneous microcystic
adnexal carcinoma. Reports of such tumors occurring in
the oral cavity and other mucosal H&N sites [34–36] led
to proposals for recognition of SMA as a new type of sali-
vary carcinoma rather than simply a microcystic adnexal
carcinoma occurring in extracutaneous sites [36, 37]. The
name sclerosing microcystic adenocarcinoma highlights its
key morphological features, and “adnexal” was removed as
adnexal structures are absent from mucosal sites where these
tumors occur [37]. SMA has so far been described in minor
salivary glands only, and unlike its cutaneous counterpart,
the salivary tumor has a good outcome with no documented
local recurrence or distant metastasis [37, 38].
SMAs consist of small infiltrative cords and nests embed-
ded in thick fibrous or desmoplastic stroma, which tends
to dominate the tumor volume. The tumor is biphasic with
bland luminal cuboidal ductal cells with eosinophilic or
clear cytoplasm, and flat peripheral myoepithelial cells. The
nuclei are bland, round to oval, with occasional nucleoli.
The ducts contain focal eosinophilic secretions. Perineural
invasion is common while mitoses are rare (Fig. 5). Immu-
nohistochemistry shows that the luminal cells are positive
for cytokeratin 7 while the abluminal myoepithelial cells
are positive for smooth muscle actin, S100, p63, and p40.
The differential diagnosis includes squamous cell carcinoma
(SCC), hyalinizing clear cell carcinoma, adenoid cystic car-
cinoma and myoepithelial carcinoma. Lack of keratinization,
low grade cytology and biphasic architecture distinguish
SMA from SCC. Hyalinizing clear cell carcinoma shares
the dense connective tissue stroma and trabecular architec-
ture, but it lacks lumina, secretions, and myoepithelial cells.
Myoepithelial carcinoma is a monophasic neoplasm with-
out the ductal component. Adenoid cystic carcinoma shares
the biphasic nature and the propensity for perineural inva-
sion; however, in typical cases the myoepithelial component
dominates and is easily seen. It also tends to lack the dense
connective tissue deposition. In difficult cases, molecular
testing for the MYB gene rearrangement may be helpful.
New concepts, Variant Morphologies,
Controversial Issues, and Emerging Entities
Intraductal Carcinoma
In the 2017 World Health Organization Classification of
Head and Neck Tumours [39], the tumor entity originally
described as “low-grade salivary duct carcinoma” [40] and
later called “low-grade cribriform cystadenocarcinoma”

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[41] was renamed as intraductal carcinoma (IC). IC is a
rare low-grade salivary gland malignancy with histomor-
phologic features reminiscent of atypical ductal hyperplasia
or ductal carcinoma in situ of the breast. The tumor is, in
typical cases, characterized by intraductal and intracystic
proliferation of luminal ductal cells exhibiting solid, cribri-
form, and papillary patterns. Its in situ intraductal nature is
demonstrated by an intact surrounding myoepithelial cell
layer highlighted by antibodies to p63 protein, calponin, and/
or cytokeratin 14. IC typically shows an intercalated duct
phenotype demonstrating S100 protein and SOX10 positiv-
ity of luminal cells (Fig. 6A, B), while a subset of IC shows
apocrine morphology supported by androgen receptor (AR)
positivity (Fig. 6C, D) [42]. Most ICs harbor recurrent RET
gene rearrangements. NCOA4::RET fusion has been identi-
fied in 47% of intercalated duct type ICs [14, 43], while
TRIM27::RET fusion is often observed in an apocrine type
or hybrid type IC [15, 43]. Recently, novel TUT1::ETV5,
KIAA1217::RET [15], and STRN::ALK [44] fusions have
been identified in rare cases of IC with invasive growth pat-
tern. A recent report proposed that oncocytic ICs that har-
bor BRAF V600E mutations and TRIM33::RET fusion are a
fourth distinct subtype of IC [45].
It remains a controversial issue how to classify a tumor
which has morphology, immunoprofile and molecular sig-
nature typical of IC, but if there is also invasive growth [14,
15]. Moreover, one recent study reported that the myoepithe-
lial and ductal cells of IC harbor the same fusion, thus indi-
cating that the myoepithelial cell layer is part of the tumor,
and consequently ICs may be biphasic, occasionally invasive
neoplasms rather than true in-situ neoplasms [16].
Polymorphous Adenocarcinoma and Cribriform
Adenocarcinoma
Polymorhous adenocarcinoma (PAC), (previously known as
polymorphous low-grade adenocarcinoma), is a malignant
epithelial tumor characterized by cytological uniformity,
morphological diversity, and an infiltrative growth pattern,
and it is predominantly seen in minor salivary glands [1].
Polymorphous adenocarcinoma, cribriform subtype (cri-
briform adenocarcinoma of salivary glands; CASG) was
initially reported at the base of the tongue [46] and later in
other minor salivary gland sites [47]. CASG is character-
ized by a multinodular growth pattern separated by fibrous
septa, relatively uniform solid, cribriform and microcystic
architecture, and optically clear nuclei. Glomeruloid and
papillary structures, peripheral palisading and clefting may
be observed (Fig. 7). Compared with classic PAC, CASG
is associated with a propensity to base of the tongue loca-
tion and a higher risk of lymph node metastasis. Activating
protein kinase D1 (PRKD1) gene point mutations have been
identified in more than 70% of the classic variant of PACs
[48, 49]. Rearrangements in PRKD1, PRKD2, or PRKD3
genes rather than point mutations have been noted in about
80% of the CASG subtype of PACs [50]. The PRKD1 E710D
hotspot mutation and PRKD1/2/3 gene rearrangements are
useful as an ancillary diagnostic markers to differentiate
PACs from other salivary gland tumors, such as adenoid
cystic carcinoma, the rare SC and canalicular adenoma
[48, 51]. The classic subtype of PACs most often exhibit
a PRKD1 point mutation, whereas the CASG subtype of
PACs mostly exhibit PRKD1/2/3 translocations. The PRKD1
E710D hotspot mutation and the gene fusions involving the
PRKD1/2/3 genes are mutually exclusive [48].
Whether CASG is a different diagnostic category or a
variant of PAC is still controversial, and currently PAC is
defined as a histologically and molecularly heterogene-
ous disease group [48]. Our knowledge of the relationship
between PRKD gene changes and prognosis is limited. The
PRKD1 E710D hotspot mutation may be associated with
good, metastasis-free survival, while the fusion-positive
CASGs, however, appear to be more aggressive clinically.
CASGs are usually located in the base of the tongue, and
they have a high risk of nodal metastasis, and may require
additional treatments (e.g., neck dissection) [52].
Mucinous Adenocarcinoma Versus Intraductal
Papillary Mucinous Neoplasm (IPMN)
Mucinous adenocarcinoma (MA) is a primary salivary
adenocarcinoma that displays prominent intracellular
and/or extracellular mucin and lacks diagnostic features
of other salivary carcinomas. A variety of patterns have
been observed including papillary, signet ring, colloid, and
mixed subtypes. MA occurs typically in oral minor salivary
glands. Molecular profiling has shown a recurrent AKT1
E17K mutation in MA regardless of the pattern [10]. The
same mutation has been reported in low grade prolifera-
tions of intraductal epithelium with mucinous component,
for which a collective term “intraductal papillary mucinous
Fig. 1 Sclerosing polycystic adenoma (SPA). SPA is well circum-
scribed and encapsulated tumor composed of proliferations of ducts
and acini within fibrotic stroma sometimes intermixed with foci of
mature adipose tissue (Fig. 1A). The halmark of SPA is a presence
acinic cells with abundant large eosinophilic cytoplasmic granules
(Fig. 1B). Ductal structures are surrounded by periductal concentric
layers of stromal hyalinization (Fig. 1C). SPA frequently harbors
intraductal epithelial proliferations with variable degree of atypia.
Low-grade atypia is composed of intercalated duct-like epithelium
positive for SOX10 (Fig. 1D, E) and high-grade atypia with atypical
nuclear features and complex growth pattern of micropapillary struc-
tures with luminal apocrine epithelium positive for AR (Fig. 1F, G).
Invasive carcinoma arising in SPA is presented in Fig. 1H–J. Well cir-
cumscribed predominantly polycystic SPA divided from parotid gland
by fibrous pseudocapsule is seen in the left upper part of the picture
(Fig. 1H) while Figs. 1I andJ show invasive salivary duct carcinoma
and apocrine intraductal carcinoma, respectively
◂

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neoplasm” (IPMN) has been proposed in analogy with the
pancreatic duct mucinous lesions [11]. IPMN is an emerging
entity whose place in the classification of salivary tumors is
uncertain at this time, although a recent study showed that
IPMN may be distinct from sialadenoma papilliferum, with
the former harboring AKT1 E17K mutation and the latter
BRAF V600E mutation [13]. Nevertheless, it is currently
unknown whether IPMN is (1) a separate entity from MA,
possibly related to ductal papilloma; (2) a precursor lesion
to MA analogous to pancreatic IPMN, or (3) an intraductal
variant of MA. Additional studies are needed to clarify these
questions.
Fig. 2 Keratocystoma. Keratocystoma is composed of multicystic
spaces (Fig. 2A), lined by stratified squamous epithelium, containing
keratotic lamellae (Fig. 2B). Squamous epithelium shows a parakera-
totic or orthokeratotic surface, usually without a granular cell layer
(Fig. 2C). (courtesy of Dr. Toshitaka Nagao)

9. 48 Head and Neck Pathology (2022) 16:40–53
1 3
Oncocytic Neoplasms
There is no consensus on whether oncocytic carcinoma
exists. Oncocytic appearance is a common change encoun-
tered in many different salivary gland tumors. In the past,
carcinomas consisting entirely of oncocytes were frequently
diagnosed as oncocytic carcinoma. Molecular studies have
now shown that many such tumors represent oncocytic vari-
ants of other salivary carcinomas [17–19]. For this reason,
oncocytic carcinoma is not classified as an independent
entity, but it has been included in the category of emerging
entities [1].
Conclusions
Molecular pathology of salivary tumors has seen numerous
advances in recent years, and they have allowed for better
classification of the previously heterogenous categories of
adenocarcinoma, NOS and oncocytic carcinoma, and have
led to the discovery of novel tumor types such as secre-
tory carcinoma (mammary analogue) and microsecretory
adenocarcinoma. Additional neoplastic entities will almost
certainly be defined as characteristic molecular alterations
are discovered in tumors with reproducible morphologies.
Nevertheless, the synthesis of morphological patterns and
Fig. 3 Intercalated duct adenoma (IDA) (Fig. 3A, B) and striated
duct adenoma (SDA) (Fig. 3C, D). IDA is composed of bilayered
ducts with a cytological appearance and immunoprofile of normal
intercalated ducts (Fig. 3A). High power image shows spindle shaped
abluminal myoepithelial cell layer (Fig. 3B). SDA is composed of
ducts lined by a monolayer of cells resembling normal striated ducts
(Fig. 3C) and do not contain myoepithelial or basal cells. Only occa-
sional abluminal cells are decorated by smooth muscle actin (Fig. 3D)

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Head and Neck Pathology (2022) 16:40–53
1 3
Fig. 4 Microsecretory adenocarcinoma (MSA). MSA is small tubules
and microcysts lined by flat intercalated duct-like cells, and contain-
ing abundant basophilic luminal secretions (Fig. 4A, B). Tumor cells
show diffuse positivity for p63 (Fig. 4C), S100 protein (Fig. 4D)
and SOX10 (Fig. 4E). Next generation sequencing of MSA shows a
recurrent MEF2C::SS18 gene fusion (Fig. 4F). (courtesy of Dr. Justin
Bishop)

11. 50 Head and Neck Pathology (2022) 16:40–53
1 3
molecular alterations driving them is rarely straightfor-
ward. In addition to the issues discussed above, questions
remain concerning the classification of neoplasms with
morphologies matching known types but the tumors lack-
ing the recognized molecular alterations. Is mucoepider-
moid carcinoma without MAML2 gene rearrangement still
a mucoepidermoid carcinoma or a convincing mimic? Is
a secretory carcinoma with an atypical VIM::RET fusion
still a secretory carcinoma? As more molecular and clini-
cal data accumulates about these tumors, such questions
may be answered and the tumor classification adjusted
accordingly in future editions.
Fig. 5 Sclerosing microcystic adenocarcinoma (SMA). SMAs consist of small infiltrative cords and nests embedded in thick fibrous or desmo-
plastic stroma (Fig. 5A). Perineural invasion is common (Fig. 5B). (courtesy of Dr. Abbas Agaimy)
Fig. 6 Intraductal carcinoma (IC). IC typically shows an intercalated duct phenotype demonstrating SOX10 positivity of luminal cells (Fig. 6A,
B), while a subset of IC shows apocrine morphology supported by androgen receptor positivity (Fig. 6C, D)

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Head and Neck Pathology (2022) 16:40–53
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Acknowledgements Mrs. Elaheh Mosaieby, Tomas Vaněček, PhD and
Martina Baněčková, MD, PhD are acknowledged for expert technical
assistence.
Authors Contributions Conceptualization, literature search, data analy-
sis, writing original draft [AS, MH], review and editing [AS, IL].
Funding This work was supported by the grant from the Finnish Can-
cer Society, Helsinki [Ilmo Leivo].
Data Availability Data supporting the findings are available from the
corresponding author [A.S.], upon reasonable request.
Code Availability Not applicable.
Declarations
Conflict of interest The authors declare no conflict of interest.
Ethical Approval Not needed.
Consent to Participate Not applicable.
Consent for Publication Not applicable.
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