The Role of Molecular Testing in The Differential Diagnosis of Salivary Gland Carcinomas

SPECIAL ARTICLE
The Role of Molecular Testing in the Differential

Diagnosis of Salivary Gland Carcinomas
Alena Skálová, MD, PhD,* Göran Stenman, MD, PhD,†‡
Roderick H.W. Simpson, MD, ChB, FRCPath,§ Henrik Hellquist, MD, PhD, FRCPath,∥
David Slouka, MD, PhD,¶ Tomas Svoboda, MD, PhD,# Justin A. Bishop, MD,**
Jennifer L. Hunt, MD, MEd,†† Ken-Ichi Nibu, MD, PhD,‡‡
Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, F,§§
Vincent Vander Poorten, MD, MSc, PhD,§∥∥¶¶
Kenneth O. Devaney, MD, JD, FCAP,## Petr Steiner, Mgr,****
and Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glas)†††
translocation, is now known to be a feature of both low-grade

Abstract: Salivary gland neoplasms are a morphologically and high-grade mucoepidermoid carcinomas associated with
heterogenous group of lesions that are often diagnostically improved survival. A t(6;9)(q22-23;p23-34) translocation result-
challenging. In recent years, considerable progress in salivary ing in a MYB-NFIB gene fusion has been identified in the ma-
gland taxonomy has been reached by the discovery of tumor jority of adenoid cystic carcinomas. Polymorphous (low-grade)
type-specific fusion oncogenes generated by chromosome trans- adenocarcinoma and cribriform adenocarcinoma of (minor)
locations. This review describes the clinicopathologic features of salivary gland origin are related entities with partly differing
a selected group of salivary gland carcinomas with a focus clinicopathologic and genomic profiles; they are the subject of an
on their distinctive genomic characteristics. Mammary analog ongoing taxonomic debate. Polymorphous (low-grade) ad-
secretory carcinoma is a recently described entity characte- enocarcinomas are characterized by hot spot point E710D mu-
rized by a t(12;15)(p13;q25) translocation resulting in an tations in the PRKD1 gene, whereas cribriform adenocarcinoma
ETV6-NTRK3 fusion. Hyalinizing clear cell carcinoma is a of (minor) salivary glands origin are characterized by trans-
low-grade tumor with infrequent nodal and distant metastasis, locations involving the PRKD1-3 genes. Salivary duct carcinoma
recently shown to harbor an EWSR1-ATF1 gene fusion. The (SDC) is a high-grade adenocarcinoma with morphologic and
CRTC1-MAML2 fusion gene resulting from a t(11;19)(q21;p13) molecular features akin to invasive ductal carcinoma of the
breast, including HER2 gene amplification, mutations of TP53,
From the Departments of *Pathology; ¶Otorhinolaryngology; #Depart- PIK3CA, and HRAS and loss or mutation of PTEN. Notably, a
ment of Oncology and Radiotherapy, Oncological Clinic, Faculty of recurrent NCOA4-RET fusion has also been found in SDC. A
Medicine in Plzen, Charles University; ***Molecular and Genetic subset of SDC with apocrine morphology is associated with
Laboratory, Biopticka Lab Ltd, Plzen, Czech Republic; †Department
of Pathology and Genetics, Sahlgrenska Cancer Center, University of overexpression of androgen receptors. As these genetic aberra-
Gothenburg, Gothenburg, Sweden; §Department of Anatomical tions are recurrent they serve as powerful diagnostic tools in
Pathology, University of Calgary, Foothills Medical Centre, Calgary, salivary gland tumor diagnosis, and therefore also in refinement
AB, Canada; ‡European Salivary Gland Society, Geneva, Switzer- of salivary gland cancer classification. Moreover, they are
land; ∥Department of Biomedical Sciences and Medicine, Centre for
promising as prognostic biomarkers and targets of therapy.
Biomedical Research (CBMR), University of Algarve, Faro, Portu-
gal; **Department of Pathology, University of Texas Southwestern Key Words: salivary gland carcinoma, mammary analog secretory
Medical Center, Dallas, TX; ††Department of Pathology, University
of Arkansas for Medical Sciences, Little Rock, AR; ##Department carcinoma, mucoepidermoid carcinoma, hyalinizing clear cell
of Pathology, Allegiance Health, Jackson, MI; ‡‡Department of carcinoma, adenoid cystic carcinoma, salivary duct carcinoma,
Otolarygology-Head and Neck Surgery, Kobe University Graduate polymorphous adenocarcinoma, cribriform adenocarcinoma,
School of Medicine, Kobe, Japan; §§University of Udine School of fusion oncogenes, molecular testing
Medicine, Udine, Italy; †††Coordinator of the International Head
and Neck Scientific Group, Padua, Italy; ∥∥Otorhinolaryngology- (Am J Surg Pathol 2017;00:000–000)
Head and Neck Surgery, University Hospitals Leuven; and
¶¶Department of Oncology, Section Head and Neck Oncology, KU
Leuven, Leuven, Belgium.
Conflicts of Interest and Source of Funding: The authors have disclosed
that they have no significant relationships with, or financial interest
in, any commercial companies pertaining to this article.
S alivary gland tumors are relatively uncommon and
morphologically highly diverse. Thus, the significant
histologic overlap between tumor types with different bi-
Correspondence: Alena Skálová, MD, PhD, Sikl’s Department of Pathology,
Faculty of Medicine, Charles University, Faculty Hospital, E. Benese 13, ological behavior not only poses diagnostic challenges, but
305 99 Plzen, Czech Republic (e-mail: [email protected]). also continues to stimulate pathologists to look for new
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ancillary tests using immunohistochemistry (IHC) and
Am J Surg Pathol Volume 00, Number 00, ’’ 2017 www.ajsp.com |1
Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Skalova et al Am J Surg Pathol Volume 00, Number 00, ’’ 2017
molecular techniques. IHC markers are useful supple-

TABLE 1. Key Molecular Alterations in Selected Salivary Gland
mentary aides for visualization of cell compartments and Carcinomas
cell populations, thus contributing to improved salivary
Tumor Chromosomal Gene Fusion/ Prevalence
gland tumor classification.1,2 Moreover, IHC also has
Type Alteration Rearrangement (%)
an expanding role as surrogate markers of molecular
alterations.3,4 MASC t(12;15)(p13;q25) ETV6-NTRK3 95-98
t(12;X) ETV6-RET 2-5
Until recently, translocations and their resulting fusion MEC t(11;19)(q21;p13) CRTC1-MAML2 40-80
oncogenes were thought to be rare in epithelial tumors. t(11;15)(q21;q26) CRTC3-MAML2 5
Typically, these somatic genetic aberrations were found in HCCC t(12;22)(q21;q12) EWSR1-ATF1 80-90
hematological and soft tissue neoplasms and thought to be AdCC t(6;9)(q22-23;p23-24) MYB-NFIB 25-80
rare or even absent in other tumor lineages.5–7 Recently, t(8;9) MYBL1-NFIB 10-20
PLGA 14q12 Hotspot activating 20
however, the discovery of key molecular alterations in a PRKD1 somatic
variety of salivary gland tumors has significantly increased point mutation
our knowledge about their molecular pathology and im- (E710D)
proved the classification of salivary gland neoplasms and CAS- t(1;14)(p36.11;q12) ARID1A-PRKD1 24
Gs t(X;14)(p11.4;q12) DDX3X-PRKD1 13
also changed the way diagnoses are made.8–11 Consequently, PRKD2 and PRKD3 16
some existing tumor types have become more refined, and a rearrangements
few new salivary tumor entities have been characterized,12,13 SDC 17q21.1 HER2 amplification 20-40
some of which have already been adopted in the new World 3q26.32 PIK3CA mutation 20
Health Organization (WHO) Classification of Head and inv(10)(q11.21q11.22) NCOA4-RET <5
Neck Tumors.14
These genomic aberrations are recurrent and tumor
type specific and may serve as powerful diagnostic tools in been categorized as either unusual variants of salivary acinic
salivary gland diagnosis and classification. They also show cell carcinoma (AciCC) or cystadenocarcinoma not otherwise
promise as prognostic biomarkers and as new targets for specified.20
therapy.15 Some of these fusions have been found also in Skalova et al20 initially recognized MASC as an
other tumor types that show little or no overlap with their entity different from AciCC on the basis of 3 major find-
salivary gland counterparts, but effectively they are spe- ings. First, MASC showed no basophilia in the cytoplasm
cific within the salivary gland.16–19 in any of the constituent cells, which is the hallmark of the
In this review salivary carcinomas currently known serous acinar cells of AciCC resulting from the presence of
to harbor translocations will be discussed, namely secre- cytoplasmic zymogen granules. Second, these neoplasms
tory carcinoma (SC) (also known as mammary analog had a completely different immunohistochemical profile,
secretory carcinoma [MASC]), hyalinizing clear cell car- almost always expressing S100 protein, mammaglobin,
cinoma (HCCC), mucoepidermoid carcinoma (MEC), vimentin, STAT5, and MUC4, all of which were rarely
adenoid cystic carcinoma (AdCC), and 2 related low- expressed in AciCC. Finally, unlike AciCC, most cases
grade salivary gland adenocarcinomas, namely poly- were found to harbor an ETV6-NTRK3 fusion gene due to
morphous (low-grade) adenocarcinoma (PLGA/PAC) and a t(12;15)(p13;q25), a finding identical to SC of the
cribriform adenocarcinoma of (minor) salivary gland ori- breast.21 Because of the morphologic and genomic sim-
gin (CASG). Finally, we will also discuss salivary duct ilarities, Skalova et al,20 proposed the designation
carcinoma (SDC) (Table 1). “mammary analog secretory carcinoma (MASC) of sali-
vary gland.” The most recent version of the WHO Clas-
sification of Head and Neck Tumors, however, utilizes the
MAMMARY ANALOG SECRETORY CARCINOMA terminology “secretory carcinoma,”23 for consistency and
MASC of salivary gland origin is a recently because SCs have been recently described at other sites,
described tumor that harbors a characteristic balanced such as thyroid gland and skin.24–26
t(12;15)(p13;q25) chromosomal translocation resulting in The near 100% rate of ETV6 gene rearrangements
an ETV6-NTRK3 fusion20 identical to that commonly in MASC has been subsequently confirmed by many other
found in SC of the breast.21 The Etv6-NTRK3 fusion gene studies.27–30 Detection of ETV6 rearrangements by fluo-
encodes a chimeric tyrosine kinase with transforming ac- rescence in situ hybridization (Fig. 1B) or ETV6-NTRK3
tivity in epithelial and myoepithelial cells in the mouse fusion by reverse transcription polymerase chain reaction
mammary gland.22 in formalin-fixed paraffin-embedded material (Fig. 1C) is
Over many years Skalova et al20 began to identify technically straightforward, and > 250 cases of MASC
a distinctive hitherto unrecognized neoplasm arising in have been published since its original description in 2010.20
the salivary glands characterized by morphologic and The presence of the ETV6-NTRK3 fusion gene has
immunohistochemical features strongly reminiscent of those not been demonstrated in any other salivary gland
of SC of the breast. These salivary carcinomas are composed tumor. However, the same fusion is found not only in SC
of microcystic and solid areas with abundant vacuolated of the breast,21 but also in infantile fibrosarcoma,31
colloid-like periodic acid Schiff-positive secretory material congenital mesoblastic nephroma,32 certain hematopoietic
within the microcystic spaces (Fig. 1A). They had previously malignancies,33 ALK-negative inflammatory myofibroblastic
2 | www.ajsp.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Am J Surg Pathol Volume 00, Number 00, ’’ 2017 Molecular Testing in Salivary Gland Carcinomas
FIGURE 1. MASC of salivary gland. A, MASC is composed of microcystic and solid areas with abundant vacuolated colloid-like PAS-positive
secretory material within the microcystic spaces. B, FISH analysis of ETV6 gene. C, Part of the ETV6-NTRK3 fusion transcript sequence. FISH
indicates fluorescence in situ hybridization; PAS, periodic acid Schiff.
tumors,34 and in radiation-induced papillary thyroid favorable clinical outcomes.41,42 In addition, MASCs with
carcinomas.35 MASCs of the thyroid gland have recently ETV6-X gene fusion and other atypical fusion transcripts
been reported also in patients without history of radiation often demonstrate abundant fibrosclerotic stroma and
exposure.36–38 Moreover, ETV6-rearranged carcinomas with particularly prominent, thick hyalinized fibrous septa.41,42
secretory features have been reported in the skin26,39 and The neoplastic cells may be embedded in a completely
sinonasal mucosa.40 hyalinized central part of the tumor. Recently, next-generation
A small subset of MASCs show ETV6 rearrange- sequencing using the ArcherDX analysis platform detected a
ments with an as yet unknown partner(s) or may have novel ETV6-RET fusion transcript joining exon 6 of ETV6
atypical ETV6-NTRK3 exon fusion junctions.41 These gene and exon 12 of RET gene in 10 cases of salivary gland
atypical molecular features may be associated with more tumors displaying histologic and immunohistochemical
infiltrative histologic characteristics of MASC, and less features typical of SC (Figs. 2A–C).43
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.ajsp.com |3
FIGURE 2. MASC of salivary gland. A, MASC has a prominent fibrosclerotic stroma with isolated tumor cells in small islands or
trabeculae were seen in central part of the tumor. B, MASC is characterized by solid and microcystic growth with a multilobular
structure. The cysts are lined by a double layer of cells with prominent apocrine features. C, MASC is well circumscribed and
surrounded by a thick fibrous capsule enclosing predominantly multicystic growth pattern with multiple mural nodules.
Differential Diagnosis translocation, that is a t(11;19) resulting in a CRTC1-

The major differential diagnostic consideration is MAML2 fusion.46,47
AciCC. The architectural patterns of MASC (ie, micro-
cystic, papillary-cystic, follicular, and solid) overlap with Clinical Features and Prognosis
those of AciCC. However, the large serous acinar cells MASC usually behaves indolently, but like other
with cytoplasmic periodic acid Schiff-positive zymogen- low-grade salivary gland carcinomas, there is some
like granules typical of AciCC are completely absent capacity for aggressive behavior including locoregional
in MASC.20 Intraductal carcinoma, previously called recurrence and distant metastasis. Particularly important
“low-grade salivary duct carcinoma” is characterized by a is the rare occurrence of high-grade transformation (HGT)
prominent cystic tumor component associated with pro- that may result in tumor-related death.48,49
liferation of bland eosinophilic ductal cells, frequent in- The treatment of MASC has varied, ranging from
traluminal secretions, and expression of S100 protein and simple excision to radical resection, neck dissection, adjuvant
mammaglobin, features that overlap with MASC.36,44,45 radiotherapy, and/or adjuvant systemic chemotherapy.20,45,50
In contrast to MASC, the epithelial structures of intra- Recognizing MASC and testing for ETV6 rearrangements
ductal carcinoma are characteristically surrounded by an may be of potential value in treatment decisions, because the
intact layer of p63-positive myoepithelial cells. Low-grade ETV6-NTRK3 fusion may serve as a target for treatment of
MEC is another potential consideration in the differential tumors with this fusion at multiple anatomic sites, including
diagnosis of MASC because both tumor types can have a the parotid gland.51–53
prominent cystic component, variable mucicarmine pos-
itivity together with cytologically bland cells that can be Application of Molecular Testing
eosinophilic, clear, or vacuolated.29 In contrast to MASC, For patients presenting with a locally advanced, re-
MEC is consistently positive for p63 in the epidermoid current, or metastatic MASC cases, the treatment options
foci and is negative for S100 and mammaglobin. In ad- are currently limited and mainly palliative. Therefore,
dition, low-grade MECs harbor a different chromosomal testing for ETV6 rearrangements may be of potential
FIGURE 3. HCCC. A, The tumor is composed of cords and nests of clear cells in a hyalinized and myxoid stroma. B, Part of
EWSR1-ATF1 transcript fusion sequence.
value in treatment decisions, because the ETV6-NTRK3 detected in myoepithelioma, PLGA, MEC, or epithelial-
and ETV6-RET fusions may serve as a target for therapy. myoepithelial carcinoma (EMCA).54,55
MASC with ETV6-RET fusion must be clearly dis- EWSR1 rearrangements are also seen in a variety of
tinguished from MASCs with ETV6-NTRK3 trans- epithelial and soft tissue tumors, including soft tissue
location, because drugs effective with various tumors myoepithelioma; however, the fusion partner genes that
driven with RET gene alterations, are being tested for the are common in myoepithelioma (FUS, POU5F1, PBX1,
treatment. MASCs with ETV6-RET translocation might and ZNF444) does not seem to be involved in HCCC.54,56
respond much better to these drugs, whereas entrectinib EWSR1-ATF1, which originally was identified in soft
and similar inhibitors of tyrosine kinases TRKA/B/C will tissue clear cell sarcomas,57 has also been described in 1
probably be ineffective. case of soft tissue myoepithelioma of the pelvis58 and in
angiomatoid fibrous histiocytoma.59
Initial studies failed to identify EWSR1 rearrange-
HYALINIZING CLEAR CELL CARCINOMA ments in other classic salivary gland tumors,54 but more
HCCC is a rare salivary gland malignancy with recently, Skalova et al60 reported EWSR1 rearrangements
squamous differentiation and prominent clear cell mor- in 25 of 72 (34.7%) clear cell myoepithelial carcinomas (de
phology (Fig. 3A). Recently, it was discovered that most novo and ex-pleomorphic adenoma [PA]) as well as in 1 of
HCCCs have a recurrent t(12;22)(q13;q12) chromosomal 11 (9%) EMCAs. Cases of EWSR1-rearranged my-
translocation, leading to fusion of the EWSR1 and ATF1 oepithelial carcinoma commonly had at least focal areas
genes (Fig. 3B). Notably, this rearrangement was not of necrosis, squamous pearls, and significant nuclear
pleomorphism. In cases where the differential diagnosis MEC is associated with one of the most clinically
includes EWSR1-rearranged myoepithelial carcinoma and useful translocations, involving the MAML2 and CRTC1 or
HCCC, the diagnosis depends more heavily on morphol- CRTC3 genes (Fig. 4B). A recurrent t(11;19)(q21;p13)
ogy and immunophenotypic markers because HCCC only translocation, resulting in a CRTC1-MAML2 fusion, was
infrequently shows focal myoepithelial differentiation with first described in MEC in 2003.65,66 Later studies revealed
S100 positivity. that a small subset of MECs instead has t(11;15)(q21;q26)
translocations generating molecularly similar CRTC3-
Differential Diagnosis MAML2 fusions.67,68 The use of MAML2 FISH has been
Although the finding of infiltrative nests of low- proposed as a useful ancillary test in the routine clinical
grade clear tumor cells with hyalinized and cellular fibrous diagnosis of salivary gland tumors in which MEC enters the
stroma is quite characteristic of HCCC, several other tu- differential diagnosis.69 Recently, detection of AREG
mor types, such as myoepithelial carcinoma, EMCA, and expression (downstream target of the CRTC1-MAML2
MEC, can enter into the differential diagnosis. In most fusion) has been reported to be useful for identifying
instances the diagnosis is readily apparent, but cases with CRTC1-MAML2-positive MECs and as a marker of
limited biopsy material or with only focal clear cell dif- favorable prognosis.70
ferentiation often require additional ancillary testing. In The mutational profile of MEC is only partly
such cases, EWSR1 FISH testing may be of great value. known. TP53 was the most commonly mutated gene in a
The current recommendation is that EWSR1 FISH is not whole-exome study of 18 MECs.71 Other recurrently
necessary in classic mucin-negative cases of HCCC. mutated genes were POU6F2 (only seen in low-grade tu-
However, when abundant mucin is present or when there mors), IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL,
is minimal clear cell differentiation or hyalinization, con- KMT2C, and OBSCN. These observations were partly
firmation can be useful. MECs showing similar features confirmed in a targeted resequencing study of 315 genes in
will generally have a higher grade than HCCC and po- 48 MECs identifying TP53 as the most frequently mutated
tentially different treatment.54,61 This is because most gene (41.7%). Recurrent genomic alterations were also
HCCCs lack cystic features, have highly infiltrative tumor found in PI3KCA, BAP1, BRCA1/2, and ERBB2 (gene
fronts, and often show perineural invasion. With muci- amplification).72 Recurrent deletions of the tumor sup-
nous differentiation, these would be considered at least pressor gene CDKN2A is also a characteristic feature of
intermediate-grade, or even high-grade when using most high-grade MECs.72,73
traditional MEC grading schemes.54,61
Differential Diagnosis
Clinical Features and Prognosis Clinically, detection of a MAML2 rearrangement
Although often indolent, HCCC shows occasional using break-apart FISH probes is helpful in several sit-
recurrences and/or metastases to lymph nodes in the uations. In cases of low-grade MEC, differential diag-
neck.54,62 They have a tendency to invade bone and show nostic considerations can often include benign entities,
prominent perineural invasion in about half of the cases54 such as metaplastic variant of Warthin tumor (WT),74 or
and this can occasionally lead to pain or muscle atrophy.61 more rare lesions such as lymphadenoma. In such cases,
Very rare examples of distant metastasis have been re- detection of MAML2 rearrangement confirms the diag-
ported and occasional deaths due to the disease have been nosis of MEC. Although some authors have reported
described.55,61,63 These rates of morbidity and mortality MAML2 translocations in WT75 some even suggest that
are probably comparable with most other low-grade sali- MEC can arise from WT,76 others argue these cases may
vary gland carcinomas. represent low-grade MEC mimicking WT, and most
consider the finding of a MAML2 rearrangement to
Application of Molecular Testing strongly favor a diagnosis of MEC over WT.77–83
Detection of EWSR1 rearrangements in salivary A particular scenario in which MAML2 FISH can
gland tumors currently has no prognostic or predictive be extremely useful is the oncocytic variant of MEC, in
value but serves as good differential diagnostic tool and in which the prominent oncocytic morphology can mask the
refining classification criteria. epidermoid phenotype, and mimic WT, oncocytic cys-
tadenoma, or AciCC. Although p63 reactivity can be
MUCOEPIDERMOID CARCINOMA useful in many cases to suggest a diagnosis of MEC, de-
MEC is the most common salivary gland carcinoma tection of MAML2 rearrangements confirms a diagnosis
and occurs approximately equally at major and minor of MEC.74,84,85 Although many of the oncocytic MECs
salivary gland sites.64 MEC is composed of 3 cell types: that enter the differential diagnosis with benign mimickers
mucinous cells, often large and goblet like, which often (WT and oncocytic cystadenoma) will be low grade and
line cystic spaces, epidermoid cells that are non- unlikely to metastasize, the diagnosis of malignancy may
keratinizing and may even look frankly squamous, and nevertheless be important in highlighting the potential for
finally intermediate cells which are more basal or cuboidal more frequent recurrence.
(Fig. 4A). Atypia is unusual and the epidermoid/squamoid At the other end of the spectrum, high-grade MEC
cells tend to be very bland akin to normal mucosal can mimic a variety of other high-grade cancers, including
epithelium.64 metastatic squamous cell carcinoma, adenosquamous
FIGURE 4. MEC. A, MEC is composed of large mucinous cells, epidermoid, and intermediate cells. B, Part of CRTC1-MAML2 and
CRTC3-MAML2 transcript fusion sequence.
carcinoma, and SDC. In these instances, identification of a such tumors include SDC, adenosquamous carcinoma,
MAML2-rearrangement is diagnostic for MEC, which and even squamous cell carcinoma; all of which, in gen-
can be important because, in the parotid gland, this ex- eral, have a poorer prognosis than high-grade MEC. SDC
cludes the possibility of a metastasis. High-grade MECs frequently stains positive for androgen receptor (AR) and
are less likely to have MAML2 rearrangements, hence the is p63 negative, which contrasts with MEC, which is
absence of a rearrangement does not rule out a diagnosis usually AR-negative and has at least focal reactivity for
of MEC.80,86,87 Differential diagnostic considerations for p63. Adenosquamous and squamous cell carcinoma are
generally considered to arise from surface epithelium, in solid component constitute grade 3.101 AdCC with HGT is
contrast to MEC, which does not have a surface in situ characterized by an overgrowth of the ductal component
component. The presence of more than just focal kerati- into a pleomorphic high-grade or undifferentiated
nization favors a diagnosis of squamous cell carcinoma adenocarcinoma.102–104
over MEC. The most significant advance in the understanding of
In addition to salivary gland MEC, MAML2 re- the molecular pathology of AdCC is the discovery and
arrangement can also be detected in central (intraosseous) characterization of the t(6;9)(q22-23;p23-24) translocation
MEC88 and MEC of the lacrimal gland,89 thyroid,90 (Fig. 5C).105,106 The translocation results in an MYB-
thymus,91 lung,92,93 and cervix.94 CRTC1-MAML2 fusion NFIB gene fusion which is the main genomic hallmark of
has also been identified in cases of cutaneous clear cell AdCC.11,15,107 The fusion is an oncogenic driver which
hidradenoma.95 MAML2 can fuse with KMT2A (pre- activates several critical downstream targets with
viously MLL) in some cases of acute myelogenous transforming potential.15 Activation of the MYB
leukemia.96 MAML2-rearrangements are not detected in oncogene by gene fusion or other mechanisms (eg,
glandular odontogenic cysts, which can enter the differ- enhancer hijacking) has been shown by break-apart or
ential diagnosis, especially for a central (intraosseous) fusion FISH or fusion transcript reverse transcription
MEC.97 polymerase chain reaction in up to 80% of AdCCs.108–110
Recently, a small subset of MYB-NFIB negative cases
Clinical Features and Prognosis were shown to have t(8;9) translocations resulting in
The presence of MAML2 rearrangement correlates closely related MYBL1-NFIB fusions.111,112
with prognosis and stage because tumors with this re- Other genomic alterations in AdCC are variable with
arrangement tend to be less aggressive and of lower his- solid tumors showing a higher number of copy number
tologic grade.75,76,80,98 This statement only seems to hold alterations, including chromosomal losses involving 1p and
in the absence of deletions inactivating the tumor sup- 6q.113 Interestingly, there is some evidence to suggest that
pressor gene CDKN2A.99 MAML2 rearrangements have 1p deletion correlates with poor prognosis.114 Studies of the
been detected in up to three quarters of low-grade and mutational landscape of > 100 AdCCs have revealed a
intermediate-grade MECs, but fewer than one half of low exonic mutation rate and a wide mutational
high-grade MECs seem to be fusion-positive. Among spectrum.107,114,115 Although the frequency of mutations in
high-grade MECs there is recent evidence that fusion- individual genes seems to be very low, the mutations
negative tumors behave much more aggressively than fu- preferentially cluster in certain pathways, including those
sion-positive ones. It has been proposed that involved in chromatin regulation, DNA-damage/check-
CRTC1-MAML2 fusion-negative high-grade carcinomas point signaling, FGF-IGF-PI3K-signaling and NOTCH-
with MEC-like morphologic features and scanty mucin signaling, and axonal guidance. Interestingly, several
content actually represent a heterogenous group of other of these are actionable mutations, calling for genetic testing
high-grade carcinomas which could relate to their more of patients with AdCC to individualize and optimize the
aggressive behavior.73 treatment.
Application of Molecular Testing Differential Diagnosis
The CRTC1 and CRTC3-MAML2 were originally AdCC is a biphasic salivary gland neoplasm con-
considered prognostic markers in MEC,68,78,98 however, sisting of a variety of architectural patterns. The ablumi-
more recent studies fail to show this, and in fact the nal myoepithelial cells often secrete a basement
original prognostic value may have been an artifact of membrane-like material which is deposited in character-
misclassification of high-grade tumors. Detection of a istic extracellular pseudocystic/cribriform myxoid and
MAML2 rearrangement using break-apart FISH probes is hyalinized extracellular matrix deposits. Although this
helpful in differential diagnosis. might be a useful diagnostic clue, identical extracellular
matrix deposits can be produced also by other biphasic
ADENOID CYSTIC CARCINOMA salivary gland neoplasms, including PA, EMCA, basal cell
AdCC is a common salivary gland carcinoma of adenoma/adenocarcinoma, and PLGA/PAC.14 Dis-
both minor and major glands and the sinonasal mucosa. tinguishing AdCC from its histomorphologic mimics is
AdCC is characterized by its slow but relentless clinical crucial for optimal treatment decisions.
progression. It is a morphologically bland but highly in- The tumor border is important as pleomorphic and
filtrative and aggressive biphasic basaloid tumor com- basal cell adenomas have well demarcated or even en-
posed of abluminal myoepithelial and luminal ductal cells capsulated edges, whereas basal cell adenocarcinoma and
arranged in tubular, cribriform, and solid growth patterns. EMCA are multinodular, in sharp contrast to AdCC
The cells tend to have scant cytoplasm and angulated which is almost always frankly invasive. However, tumor
hyperchromatic nuclei (Figs. 5A, B). Perineural invasion is borders are not apparent in small biopsies. In such cases,
almost invariably present with adequate sampling.100 important clues to the diagnosis of AdCC are angulated
Conventional AdCC is typically composed of all growth hyperchromatic nuclei, as well as frequent mitotic figures
patterns in variable proportions, and is graded based on and a Ki-67 index usually above 10%.116 In addition,
the extent of any solid growth component; > 30% to 50% MYB protein expression by IHC shows strong nuclear
FIGURE 5. AdCC. A, AdCC is morphologically bland but highly infiltrative biphasic basaloid tumor, composed of abluminal
myoepithelial and luminal ductal cells arranged in tubular, cribriform, and solid growth patterns. B, Nuclear expression of MYB
antibody is seen in most cells of AdCC. C, Part of MYB-NFIB transcript fusion sequence.
staining in ≈90% of AdCCs irrespective of the mechanism patients. Local recurrences and distant metastases are
of activation of MYB.108 Although focal weak staining common but nodal disease is relatively rare in conventional
may occasionally be seen in other salivary gland tumors, AdCC,100 especially for parotid gland primaries. The risk
MYB protein expression may still have utility in the for nodal disease in AdCC is, however, distinctly higher in
diagnosis of difficult cases of AdCC. cases of AdCC with HGT.103,104 HGT is an uncommon
phenomenon among salivary carcinomas and is associated
Clinical Features and Prognosis with increased tumor aggressiveness.103 In AdCC with
AdCC is characterized by its slow but relentless clin- HGT, the clinical course tends to be accelerated, with a high
ical progression with ultimate poor clinical outcome in most propensity for lymph node metastasis.104
Because of the historically low incidence of occult

nodal metastasis, neck dissection is only performed in case
of clinically positive lymph nodes. Clinically obvious
lymph node metastasis is not frequent in AdCC, especially
not for parotid gland primaries.117 However, for minor
salivary gland subsites the incidence of lymph node in-
volvement seems to be higher. Min et al118 described a
general incidence of lymph node metastases in AdCCs of
the head and neck of almost 10%, which was mainly at-
tributed to tumor sites such as base of tongue, mobile
tongue, and floor of the mouth.118 They also noted that
primary tumor site and peritumoral lymphovascular in-
vasion were significantly associated with cervical lymph
node metastasis.
Recent rigorous reviews of the world literature by FIGURE 7. CASGs has a prominent solid growth often divided
by fibrous septa into irregularly shaped and sized nodules
the International Head and Neck Scientific Group re-
composed of solid, cribriform, microcystic, and especially glo-
vealed high prevalence of lymph node metastasis in AdCC meruloid structures in variable proportions. The nuclei often
originating in the parotid (14.5%) the submandibular overlap with one another, and are optically clear and vesicular
(23%), the sublingual glands (25%),119 as well as in over with a ground glass appearance, strongly resembling those in
20% of AdCC arising in the minor salivary glands of the papillary thyroid carcinoma.
oral cavity and oropharynx.120
Treatment of AdCC includes surgery as well as ra- CASG was described (Fig. 7).122,123 There is currently an
diation. Selective neck dissection should be considered for ongoing taxonomic debate as to whether these 2 are
AdCC arising in minor salivary glands showing lympho- distinct entities or represent different ends of a
vascular invasion. AdCCs are usually resistent to chemo- morphologic spectrum. The most recent edition of the
therapy and targeted therapies.121 WHO Classification of Head and Neck Tumors prefers a
designation “polymorphous adenocarcinoma” (PAC) for
Application of Molecular Testing both tumor entities, referring to CASG as the “cribriform
MYB-status has not been shown consistently to variant of PAC.”124
correlate with prognosis or other clinicopathologic fea- However, CASG does have differences both mor-
tures, but the use of MYB-testing serves as robust ancil- phologically and behaviorally from classic PAC. Unlike
lary test in the routine clinical diagnosis of salivary gland classic PAC, CASGs are more frequently extrapalatal,
tumors in which AdCC enters the differential diagnosis. commonly at base of tongue, and have a higher propensity
for nodal metastasis. Histologically they have more pro-
POLYMORPHOUS (LOW-GRADE) nounced vesicular nuclei and tend to have a papillary,
ADENOCARCINOMA AND CRIBRIFORM glomeruloid, and cribriform growth rather than a targe-
ADENOCARCINOMA OF (MINOR) SALIVARY toid fascicular pattern seen in classic PAC.123 They tend to
GLAND ORIGIN demonstrate translocations involving the PRKD family of
PAC occurs most commonly in minor salivary genes,125 rather than the PRKD1 point mutations 126,127
glands, particularly in the palate, and displays a diversity seen in classic PAC. Table 2 shows the key distinguishing
of architectural growth patterns composed of monotonous features of PLGA/PAC and CASG.
tumor cells (Fig. 6). Recently, a similar tumor termed
Differential Diagnosis
The most important entity in the differential diag-
nosis of CASG is classic PAC.124 PAC typically has a wide
range of architectural appearances, including tubule and
fascicle formation, as well as solid, cribriform, and
sometimes small papillary structures. A prominent feature
of PAC is the occurrence of streaming columns of single
file or narrow trabeculae of cells forming concentric
whorls, thereby creating a target-like (or “eye of storm”)
appearance. Perineural invasion is often seen, but does not
indicate more aggressive behavior. The most striking
feature of CASG is pronounced nuclear similarity to
papillary carcinoma of the thyroid, and this is not seen to
any great extent in PAC.
The main controversy in differentiating classic PAC
FIGURE 6. PLGA/PAC. PLGA displays a diversity of architectural (originally PLGA) from CASG has been stimulated by the
growth patterns composed of monotonous tumor cells. approach of the editors of the recent issue of the WHO
TABLE 2. Comparison of PAC, Classic Variant (Originally Called PLGA) and CASGs
CASG PAC Classic Variant
Site Minor salivary glands, base of tongue predominant Minor salivary glands, palate, and buccal mucosa predominant
Growth Cribriform and glomeruloid structures predominant, Streaming columns of single file or narrow trabeculae of cells forming
tubular, solid concentric whorls, target-like appearance, predominant, tubular,
trabecular, papillary, solid, and cribriform
Nuclear features Optically clear and vesicular with a ground glass Vesicular and ovoid nuclei
appearance, papillary thyroid cancer-like nuclei
Clinical features Early cervical lymph node metastasis very common, Cervical lymph node metastasis only very rarely
occasionally bilaterally, no distant metastasis
Molecular PRKD1-3 translocations, ARID1A and DDX3X Hotspot activating PRKD1 somatic point mutation (E710D)
alterations partner genes
Tissue invasion Higher propensity for lymphatic invasion Perineural invasion
Blue book who merged both entities to 1 single tumor type men and about half of the cases arise from preexisting
designated as PAC.124 On the basis of clinical, morpho- PAs.138 Morphologic variants are rare, including
logic, and molecular differences, however, many pathol- sarcomatoid, colloid (mucinous), basaloid, papillary, and
ogists and clinicians still advocate for separation of CASG micropapillary.19,139 There is no role for grading in SDC
into a distinct entity.122,123,128–136 There is, however, an because aggressive behavior is seen in most cases. When
ongoing discussion and controversy related to the defined as a high-grade adenocarcinoma with apocrine
morphologic and immunophenotypic overlap between phenotype, SDC almost uniformly expresses ARs,140
these entities indicating that, the ultimate decision on although other large studies allow a broader
separation of CASG and classic PAC will likely require morphologic phenotype in which AR positivity is seen in
additional studies.2–4,12,13,124,137 67% to 83%.141–144 The similarities between SDC and
ductal breast carcinoma also include HER2 (ERBB2) gene
Clinical Features and Prognosis amplification. Amplification determined by FISH is found
CASG is a rare tumor; about 60 cases have been in 20% to 30% of SDCs.141,143,145
reported in the literature so far. Most CASGs are indolent Additional common molecular alterations in SDC
neoplasms, but the local recurrence rates is 10% to 30%. include mutations in TP53, PIK3CA, and HRAS, and loss
Most importantly, about 70% of patients experience or mutation of PTEN.4,146–148 BRAF, FBXW7, ATM, and
regional lymph node metastases often at the time of NF1 mutations are also found in a small number of
diagnosis. Nevertheless, there are no reported distant cases.4,149–151 The majority of SDCs (74%) have alter-
metastases and the only tumor-related deaths were due to ations in either the MAPK pathway (BRAF, HRAS, and
late presentation and extensive local disease.123,137 NF1) or in ERBB2, indicating that MAPK pathway
activation and ERBB2 amplification are the major
Application of Molecular Testing oncogenic drivers in SDC.149 Notably, recent studies using
Although CASG and classic PAC have molecular RNA sequencing have revealed that also SDC may be
alterations affecting the same gene loci, there are notable added to the growing list of gene fusion-positive salivary
differences.125–127 Molecular alterations of the PRKD carcinomas. Thus, NCOA4-RET fusions have been found
gene family have been described in both entities. Weinreb in 2 SDCs150 and there are also single cases of SDCs
et al125 discovered recurrent translocations involving the reported with ETV6-NTRK3, BCL6-TRADD, and
PRKD genes in a series of 60 PAC and CASG cases, of ABL1-PPP2R2C gene fusions.149
which nearly one half showed a rearrangement of one of Gene fusions involving the PLAG1 and HMGA2
these genes, most commonly PRKD1. The fusion partner oncogenes are specific for benign PAs9,152 and as such
genes included ARID1A and DDX3X. Most cases with have been used in differentiating PA from AdCC in fine
rearrangements were blindly classified as CASG or were needle aspiration cytology153 and in differentiating carcino-
judged to have indeterminate morphology, whereas only 1 ma ex-PA from other de novo carcinomas.154,155 Recently,
case categorized as PAC showed rearrangement of PLAG1 and HMGA2 alterations have been described also
PRKD2.125 Hotspot activating E710D point mutations in in SDC (SDC-ex-PA) (Fig. 8B).149,156 PLAG1 positivity,
PRKD1 were also recently reported in nearly 3 quarters of as determined by IHC, has also been encountered in
PAC cases.126 Mutations in PRKD2 and PRKD3 were not 2 PLGAs.157 The significance of this observation is
found in PAC.127 unclear.
SALIVARY DUCT CARCINOMA Differential Diagnosis

SDC is a primary, high-grade salivary gland ad- The histopathologic differential diagnosis of SDC
enocarcinoma, characterized by morphologic features includes primary oncocytic carcinoma, MEC, and my-
akin to high-grade ductal carcinoma of the breast oepithelial carcinomas as well as metastatic melanoma,
(Fig. 8A). SDCs are most commonly encountered in older squamous, breast, and prostate carcinomas.139
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.ajsp.com | 11
FIGURE 8. SDC. A, SDC is high-grade salivary gland carcinoma, characterized by morphologic features akin to high-grade ductal
carcinoma of the breast. B, PLAG1 is expressed in residual structures of original PA and absent in most tumor cells of SDC. C, Strong
nuclear expression of AR in SDC.
The oncocytic variant of SDC probably accounts for in the absence of sialodochodysplasia, the presence of
many cases previously diagnosed as oncocytic carcinoma, which would support a primary salivary malignancy.
which is a rare and usually high-grade malignancy, un- Detection of AR expression by IHC is a useful diagnostic
likely to represent a single entity. High-grade MEC is also aid in resolving the differential diagnosis with other high-
invasive and displays nuclear pleomorphism and increased grade carcinomas (Fig. 8C).139
mitotic activity. It is composed of mucinous goblet cells
and cells with epidermoid and intermediate differ- Clinical Features and Prognosis
entiation. In myoepithelial carcinoma, neoplastic lobules SDC is one of the most aggressive salivary malig-
with central necrosis can bear a superficial resemblance to nancies. At present, death occurs in 60% to 80% of the
the ductal carcinoma in situ lesions of SDC, but these cases, usually within 5 years, with patients often devel-
areas usually contain increased amounts of hyaline stro- oping distant metastases to the lungs, bone, liver, brain,
mal material. The IHC profile is also very different. and skin. The current standard treatment is complete
Metastatic melanoma with an epithelioid pattern can surgical excision with radical neck dissection followed
mimic a predominantly solid SDC, but can be excluded by by radiotherapy to the tumor bed and possibly
appropriate immunomarkers. Metastatic squamous chemotherapy.158 Several studies have shown benefit with
(poorly differentiated, nonkeratinizing), prostate or breast androgen-deprivation therapy alone or in combination
carcinoma all have the appearance of a high-grade sali- with conventional radiotherapy in some patients.159,160
vary carcinoma. Squamous carcinoma lacks an infiltrating Because of the rarity of this carcinoma and the limited
cribriform pattern and displays evidence of epidermoid experience with androgen-deprivation therapy, correlation
differentiation such as intercellular bridges. Metastatic between the intensity of AR expression and response has
breast carcinoma is microscopically very similar to in- not been determined and there is currently no accepted
vasive SDC and differentiation can only be made on threshold to define AR positivity.
clinical grounds, although estrogen/progesterone receptor Treatment with anti-HER2 therapy in combination
positivity would strongly favor a metastasis, particularly with bevacizumab and chemoradiation has resulted in
objective tumor response in some patients.161,162 However, Notably, an important number of salivary gland
complete response to anti-HER2 therapy is rare in SDC malignancies are still included in the group of ad-
and there is evidence that additional mutations involving enocarcinomas not otherwise specified. We believe that
TP53, HRAS, or loss of PTEN may decrease the efficacy detailed genomic and proteomic profiling and next-gen-
of HER2 blockade.4,146–148 eration sequencing of a large cohort of these unspecified
neoplasms may lead to the identification of novel gene
Application of Molecular Testing fusions and driver mutations characterizing new clinically
SDC is a high-grade adenocarcinoma with mor- relevant subgroups of salivary gland carcinomas. There-
phologic and molecular features akin to invasive ductal fore, further molecular analyses of salivary gland tumors
carcinoma of the breast, including HER2 gene amplifica- are warranted and deserve special attention.
tion, mutations in TP53, PIK3CA, and HRAS and loss or
mutation of PTEN. A subset of SDC with apocrine
REFERENCES
morphology is associated with overexpression of ARs. 1. Zhu S, Schuerch C, Hunt J. Review and updates of immunohis-
Molecular testing of SDC might provide information that tochemistry in selected salivary gland and head and neck tumors.
leads to advances in personalized therapy for SDC. Arch Pathol Lab Med. 2015;139:55–66.
2. Griffith CC, Schmitt AC, Little JL, et al. New developments in
salivary gland pathology. Clinically useful ancillary testing and new
CONCLUSIONS potentiall targetable molecular alterations. Arch Pathol Lab Med.
Molecular examination in salivary gland pathology 2017;141:381–395.
is becoming more common and can provide differential 3. Seethala RR. Salivary gland tumors. Current concepts and
diagnostic, therapeutic, and prognostic information im- controversies. Surg Pathol. 2017;10:155–176.
4. Seethala RR, Griffiths CC. Molecular pathology. Predictive,
portant not only for the purpose of classification of tumors prognostic, and diagnostic markers in salivary gland tumors. Surg
but also for the management of patients with salivary Pathol. 2016;9:339–352.
gland carcinomas. The primary treatment of salivary 5. Mitelman F, Johansson B, Mertens F. Mitelman database of
gland neoplasms is surgical resection with or without chromosome aberrations and gene fusions in cancer. 2013.
postoperative radiotherapy. For patients presenting with Available at: http://cgap.nci.nih.gov/Chromosomes/Mitelman.
6. Mitelman F, Johansson B, Mertens F. The impact of translocations
locally advanced, recurrent, or metastatic disease the and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:
treatment options are currently limited and mainly pal- 233–245.
liative. However, the recent discovery of key molecular 7. Aman P. Fusion oncogenes in tumor development. Semin Cancer
alterations in a variety of salivary gland tumor types has Biol. 2005;15:236–243.
8. Stenman G. Fusion oncogenes and tumor type specificity—insight
significantly increased our knowledge about their molec- from salivary gland tumors. Semin Cancer Biol. 2005;15:224–235.
ular pathology and improved the classification of salivary 9. Stenman G. Fusion oncogenes in salivary gland tumors: molecular
gland tumors. As these genetic alterations are recurrent and clinical consequences. Head Neck Pathol. 2013;7(suppl 1):
they serve not only as powerful diagnostic tools, but also S12–S19.
as promising prognostic biomarkers and new targets of 10. Stenman G, Persson F, Andersson MK. Diagnostic and therapeutic
implications of new molecular biomarkers in salivary gland cancers.
therapy. Oral Oncol. 2014;50:683–690.
In this review we describe the clinicopathologic 11. Andersson MK, Stenman G. The landscape of gene fusions and
features of a selected group of salivary gland carcinomas somatic mutations in salivary gland neoplasms—implications for
with a focus on their distinctive molecular genetic char- diagnosis and therapy. Oral Oncol. 2016;57:63–69.
12. Skalova A, Michal M, Simpson RHW. Newly described salivary
acteristics. Importantly, we summarize the evidence and gland tumors. Mod Pathol. 2017;30:S27–S43.
clinical utility of a tumor type-specific network of chro- 13. Skalova A, Gnepp DR, Lewis JS Jr, et al. Newly described
mosome translocations and gene fusions in this group of entities in salivary gland pathology. Am J Surg Pathol. 2017;41:
diagnostically challenging carcinomas. We also discuss the e33–e47.
14. El-Naggar AK, Chan JKC, Grandis JR, et al. WHO Classification
clinical significance of the emerging landscape of onco- of Head and Neck Tumours, 4th ed. Lyon, France: IARC; 2017.
genic driver mutations in these carcinomas. Thus, MASC 15. Andersson MK, Afshar MK, Andrén Y, et al. Targeting the
is characterized by ETV6-NTRK3 fusions, HCCC by oncogenic transcriptional regulator MYB in adenoid cystic
EWSR1-ATF1 fusions, MEC by CRTC1-MAML2 fu- carcinoma by inhibition of IGF1R-AKT signaling. J Natl Cancer
sions, and AdCC by MYB-NFIB fusions. PLGA/PAC and Inst. 2017;109:djx017. Doi:10.1093/ jnci/djx017.
16. McCord C, Weinreb I, Perez-Ordonez B. Progress in salivary gland
CASG are related entities with partly differing clin- pathology: new entities and selected molecular features. Diagn
icopathologic and genomic profiles; they are the subject of Histopathol. 2012;18:253–260.
an ongoing taxonomic debate. PLGA/PACs are charac- 17. Skalova A, Vanecek T, Simpson RHW, et al. Molecular advances
terized by hot spot point E710D PRKD1 mutations, in salivary gland pathology and their practical application. Diagn
Histopathol. 2012;18:388–396.
whereas CASGs have translocations involving the 18. Weinreb I. Translocation-associated salivary gland tumors: a review
PRKD1-3 genes. SDC is a high-grade adenocarcinoma and update. Adv Anat Pathol. 2013;20:367–376.
with morphologic and molecular features akin to invasive 19. Simpson RHW, Skálová A, Di Palma S, et al. Recent advances in
ductal carcinoma of the breast, including HER2 gene the diagnostic pathology of salivary glands. Virchows Arch. 2014;
amplification, mutations in TP53, PIK3CA, and HRAS 465:371–384.
20. Skalova A, Vanecek T, Sima R, et al. Mammary analogue secretory
and loss or mutation of PTEN. A subset of SDC with carcinoma of salivary glands, containing the ETV6-NTRK3 fusion
apocrine morphology is associated with overexpression gene: a hitherto undescribed salivary gland tumor entity. Am J Surg
of ARs. Pathol. 2010;34:599–608.
21. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the 41. Skalova A, Vanecek T, Simpson RHW, et al. Mammary analogue
ETV6-NTRK3 gene fusion as a primary event in human secretory secretory carcinoma of salivary glands. Molecular analysis of 25
breast carcinoma. Cancer Cell. 2002;2:367–376. ETV6 gene rearranged tumors with lack of detection of classical
22. Li Z, Tognon CE, Godinho FJ, et al. ETV6-NTRK3 fusion ETV6-NTRK3 fusion transcript by standard rt-pcr: report of 4 cases
oncogene initiates breast cancer from committed mammary harboring ETV6-X gene fusion. Am J Surg Pathol. 2016;40:3–13.
progenitors via activation of AP1 complex. Cancer Cell. 2007;12: 42. Ito Y, Ishibashi K, Masaki A, et al. Mammary analogue secretory
542–558. carcinoma of salivary glands: a clinicopathological and molecular
23. Skálová A, Bell D, Bishop JA, et al. Secretory carcinoma. In: study including 2 cases harboring ETV6-X fusion. Am J Surg
El-Naggar A, Chan JKC, Grandis JR, Takata T, Slootweg PJ, Pathol. 2015;39:602–610.
eds. World Health Organization (WHO) Classification of Head 43. Skalova A, Vanecek T, Martinek P, et al. Molecular profiling of
and Neck Tumours, 4th ed. Lyon, France: IARC Press; 2017: mammary analogue secretory carcinoma revealed a subset of
177–178. tumors harboring a novel ETV6-RET translocation: report of 10
24. Dogan S, Wang L, Ptashkin RN, et al. Mammary analog secretory cases. Am J Surg Pathol. 2017. In press.
carcinoma of the thyroid gland: a primary thyroid adenocarcinoma 44. Majewska H, Skálová A, Stodulski D, et al. Mammary analogue
harboring ETV6-NTRK3 fusion. Mod Pathol. 2016;29:985–995. secretory carcinoma of salivary glands: first retrospective study of a
25. Reynolds S, Shaheen M, Olson G, et al. A case of primary new entity in Poland with special reference to ETV6 gene
mammary analog secretory carcinoma (MASC) of the thyroid rearrangement. Virchows Arch. 2015;466:245–254.
masquerading as papillary thyroid carcinoma: potentially more 45. Pinto A, Nosé V, Rojas C, et al. Searching for mammary analogue
than a one off. Head Neck Pathol. 2016;10:405–413. secretory carcinoma among their mimicks. Mod Pathol. 2014;27:
26. Bishop JA, Taube JM, Su A, et al. Secretory carcinoma of the skin 30–37.
harboring ETV6 gene fusions. A cutaneous analogue to secretory 46. Tonon G, Modi S, Wu L, et al. t(11;19)(q21;p13) translocation in
carcinomas of the breast and salivary glands. Am J Surg Pathol. mucoepidermoid carcinoma creates a novel fusion product that
2017;41:62–66. disrupts a Notch signaling pathway. Nat Genet. 2003;33:208–213.
27. Griffith C, Seethala R, Chiosea SI. Mammary analogue secretory 47. Okumura Y, Miyabe S, Nakayama T, et al. Impact of CRTC1/3–
carcinoma: a new twist to the diagnostic dilemma of zymogen MAML2 fusions on histological classification and prognosis of
granule poor acinic cell carcinoma. Virchows Arch. 2011;459: mucoepidermoid carcinoma. Histopathology. 2011;59:90–97.
117–118. 48. Skálová A, Vanecek T, Majewska H, et al. Mammary analogue
28. Fehr A, Loning T, Stenman G. Mammary analogue secretory secretory carcinoma of salivary glands with high-grade trans-
carcinoma of the salivary glands with ETV6-NTRK3 gene fusion. formation: report of 3 cases with the ETV6-NTRK3 gene fusion and
letter to the editor. Am J Surg Pathol. 2011;35:1600–1602. analysis of TP53, beta-catenin, EGFR, and CCND1 genes. Am J
29. Connor A, Perez-Ordoñez B, Shago M, et al. Mammary analog Surg Pathol. 2014;38:23–33.
secretory carcinoma of salivary gland origin with the ETV6 gene 49. Luo W, Lindley SW, Lindley PH, et al. Mammary analog secretory
rearrangement by FISH: expanded morphologic and immunohis- carcinoma of salivary gland with high-grade histology arising in
tochemical spectrum of a recently described entity. Am J Surg Pathol. palate, report of a case and review of literature. Int J Clin Exp
2012;36:27–34. Pathol. 2014;7:9008–9022.
30. Chiosea SI, Griffith C, Assad A, et al. The profile of acinic cell 50. Bishop JA. Unmasking MASC: bringing to light the unique
carcinoma after recognition of mammary analog secretory carci- morphologic, immunohistochemical and genetic features of the
noma. Am J Surg Pathol. 2012;36:343–350. newly recognized mammary analogue secretory carcinoma of
31. Rubin BP, Chen CJ, Morgan TW, et al. Congenital mesoblastic salivary glands. Head Neck Pathol. 2013;7:35–39.
nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: 51. Chi HT, Ly BT, Kano Y, et al. ETV6-NTRK3 as a therapeutic
cytogenetic and molecular relationship to congenital (infantile) target of small molecule inhibitor PKC412. Biochem Biophys Res
fibrosarcoma. Am J Pathol. 1998;153:1451–1458. Commun. 2012;429:87–92.
32. Knezevich SR, Garnett MJ, Pysher TJ, et al. ETV6- NTRK3 gene 52. Tognon CE, Somasiri AM, Evdokimova VE, et al. ETV6-NTRK3-
fusions and trisomy 11 establish a histogenetic link between mediated breast epithelial cell transformation is blocked by
mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. targeting the IGF1R signaling pathway. Cancer Res. 2011;71:
1998;15:5046–5048. 1060–1070.
33. Kralik JM, Kranewitter W, Boesmueller H, et al. Characterization 53. Drilon A, Li G, Dogan S, et al. What hides behind the MASC:
of a newly identified ETV6-NTRK3 fusion transcript in acute clinical response and acquired resistance to entrectinib after
myeloid leukemia. Diagn Pathol. 2011;6:19. ETV6-NTRK3 identification in a mammary analogue secretory
34. Alassiri AH, Ali RH, Shen Y, et al. ETV6-NTRK3 is expressed in a carcinoma (MASC). Ann Oncol. 2016;27:920–926.
subset of ALK-negative inflammatory myofibroblastic tumor. Am J 54. Antonescu CR, Katabi N, Zhang L, et al. EWSR1-ATF1 fusion is a
Surg Pathol. 2016;40:1051–1061. novel and consistent finding in hyalinizing clear-cell carcinoma of
35. Leeman-Neill RJ, Kelly LM, Liu P, et al. ETV6-NTRK3 is a salivary gland. Genes Chromosomes Cancer. 2011;50:559–570.
common chromosomal rearrangement in radiation-associated 55. Shah AA, LeGallo RD, van Zante A, et al. EWSR1 genetic
thyroid cancer. Cancer. 2014;120:799–807. rearrangements in salivary gland tumors: a specific and very
36. Stevens TM, Kovalovsky AO, Velosa C, et al. Mammary analog common feature of hyalinizing clear cell carcinoma. Am J Surg
secretory carcinoma, low-grade salivary duct carcinoma, and Pathol. 2013;37:571–578.
mimickers: a comparative study. Mod Pathol. 2015;28:1084–1100. 56. Antonescu CR, Zhang L, Chang NE, et al. EWSR1-POU5F1
37. Seethala RR, Chiosea SI, Liu CZ, et al. Clinical and morphological fusion in soft tissue myoepithelial tumors: a molecular analysis of
features of ETV6-NTRK3 translocated papillary thyroid carcinoma sixty-six cases, including soft tissue, bone, and visceral lesions,
in an adult population without radiation exposure. Am J Surg showing common involvement of the EWSR1 gene. Genes
Pathol. 2017;41:446–457. Chromosomes Cancer. 2010;49:1114–1124.
38. Dettloff J, Seethala RR, Stevens TM, et al. Mammary analog 57. Zucman J, Delattre O, Desmaze C, et al. EWS and ATF1 gene
aecretory aarcinoma (MASC) involving the thyroid gland: A report fusion induced by t(12;22) translocation in malignant melanoma of
of the first 3 cases. Head Neck Pathol. 2017;11:124–130. soft parts. Nat Genet. 1993;4:341–345.
39. Hyrcza MD, Ng T, Crawford RI. Detection of the ETV6-NTRK3 58. Flucke U, Mentzel T, Verdijk MA, et al. EWSR1-ATF1 chimeric
translocation in cutaneous mammary-analogue secretory carcino- transcript in a myoepithelial tumor of soft tissue: a case report. Hum
ma. Diagn Histopathol. 2015;21:481–484. Pathol. 2012;43:764–768.
40. Lurquin E, Jorissen M, Debiec-Rychter M, et al. Mammary 59. Chen G, Folpe AL, Colby TV, et al. Angiomatoid fibrous
analogue secretory carcinoma of the sinus ethmoidalis. Histopathol- histiocytoma: unusual sites and unusual morphology. Mod Pathol.
ogy. 2015;67:749–751. 2011;24:1560–1570.
60. Skalova A, Weinreb I, Hyrcza M, et al. Clear cell myoepithelial 81. Clauditz TS, Gontarewicz A, Wang CJ, et al. 11q21 rearrangement
carcinoma of salivary glands showing EWSR1 rearrangement: is a frequent and highly specific genetic alteration in mucoepider-
molecular analysis of 94 salivary gland carcinomas with prominent moid carcinoma. Diagn Mol Pathol. 2012;21:134–137.
clear cell component. Am J Surg Pathol. 2015;39:338–348. 82. Ishibashi K, Ito Y, Masaki A, et al. Warthin-like mucoepidermoid
61. Tanguay J, Weinreb I. What the EWSR1-ATF1 fusion has taught carcinoma: a combined study of fluorescence in situ hybridization
us about hyalinizing clear cell carcinoma. Head Neck Pathol. 2013;7: and wholeslide imaging. Am J Surg Pathol. 2015;39:1479–1487.
28–34. 83. Skalova A, Vanecek T, Simpson RHW, et al. CRTC1-MAML2 and
62. Solar AA, Schmidt BL, Jordan RC. Hyalinizing clear cell CRTC3-MAML2 fusions were not detected in metaplastic War-
carcinoma: case series and comprehensive review of the literature. thin’s tumor and metaplastic pleomorphic adenoma of salivary
Cancer. 2009;115:75–83. glands. Am J Surg Pathol. 2013;37:1743–1750.
63. O’Regan E, Shandilya M, Gnepp DR, et al. Hyalinizing clear cell 84. Garcıa JJ, Hunt JL, Weinreb I, et al. Fluorescence in situ
carcinoma of salivary gland: an aggressive variant. Oral Oncol. hybridization for detection of MAML2 rearrangements in oncocytic
2004;40:348–352. mucoepidermoid carcinomas: utility as a diagnostic test. Hum
64. Brandwein-Gensler M, Bell D, Inagaki H, et al. Mucoepidermoid Pathol. 2011;42:2001–2009.
carcinoma. In: El-Naggar A, Chan JKC, Grandis JR, Takata T, 85. Weinreb I, Seethala RR, Perez-Ordoñez B, et al. Oncocytic
Slootweg PJ, eds. World Health Organization (WHO) Classifica- mucoepidermoid carcinoma: clinicopathologic description in a
tion of Head and Neck Tumours, 4th ed. Lyon, France: IARC Press; series of 12 cases. Am J Surg Pathol. 2009;33:409–416.
2017:163–164. 86. Kass JI, Lee SC, Abberbock S, et al. Adenosquamous carcinoma of
65. Tonon G, Modi S, Wu L, et al. t(11;19)(q21;p13) translocation in the head and neck: molecular analysis using CRTC-MAML FISH
mucoepidermoid carcinoma creates a novel fusion product that and survival comparison with paired conventional squamous cell
disrupts a Notch signaling pathway (published correction appears in carcinoma. Laryngoscope. 2015;125:E371–E376.
Nat Genet 2003;33(3):430) (letter). Nat Genet. 2003;33:208–213. 87. Chenevert J, Barnes LE, Chiosea SI. Mucoepidermoid carcinoma: a
66. Enlund F, Behboudi A, Andrén Y, et al. Altered Notch signaling five decade journey. Virchows Arch. 2011;458:133–140.
resulting from expression of a WAMTP1-MAML2 gene fusion in 88. Khan HA, Loya A, Azhar R, et al. Central mucoepidermoid
mucoepidermoid carcinomas and benign Warthin’s tumors. Exp carcinoma, a case report with molecular analysis of the TORC1/
Cell Res. 2004;292:21–28. MAML2 gene fusion. Head Neck Pathol. 2010;4:261–264.
67. Fehr A, Roser K, Heidorn K, et al. A new type of MAML2 fusion 89. Von Holstein SL, Fehr A, Heegaard S, et al. CRTC1-MAML2 gene
in mucoepidermoid carcinoma. Genes Chromosomes Cancer. 2008; fusion in mucoepidermoid carcinoma of the lacrimal gland. Oncol
47:203–206. Rep. 2012;27:1413–1416.
68. Nakayama T, Miyabe S, Okabe M, et al. Clinicopathological 90. Shah AA, La Fortune K, Miller C, et al. Thyroid sclerosing
significance of the CRTC3-MAML2 fusion transcript in mucoepi- mucoepidermoid carcinoma with eosinophilia: a clinicopathologic and
dermoid carcinoma. Mod Pathol. 2009;22:1575–1581. molecular analysis of a distinct entity. Mod Pathol. 2017;30:329–339.
69. Chiosea SI, Dacic S, Nikiforova MN, et al. Prospective testing of 91. Roden AC, Erickson-Johnson MR, Yi ES, et al. Analysis of
mucoepidermoid carcinoma for the MAML2 translocation: clinical MAML2 rearrangement in mucoepidermoid carcinoma of the
implications. Laryngoscope. 2012;122:1690–1694. thymus. Hum Pathol. 2013;44:2799–2805.
70. Shinomiya H, Ito Y, Kubo M, et al. Expression of amphiregulin in 92. Serra A, Schackert HK, Mohr B, et al. t(11;19)(q21; p12~p13.11)
mucoepidermoid carcinoma of the major salivary glands: a molecular and MECT1-MAML2 fusion transcript expression as a prognostic
and clinicopathological study. Hum Pathol. 2016;57:37–44. marker in infantile lung mucoepidermoid carcinoma. J Pediatr
71. Kang H, Tan M, Bishop JA, et al. Whole-exome sequencing of Surg. 2007;42:E23–E29.
salivary gland mucoepidermoid carcinoma. Clin Cancer Res. 2017; 93. Achcar Rde O, Nikiforova MN, Dacic S, et al. Mammalian
23:283–288. mastermind like 2 11q21 gene rearrangement in bronchopulmonary
72. Wang K, McDermott JD, Schrock AB, et al. Comprehensive mucoepidermoid carcinoma. Hum Pathol. 2009;40:854–860.
genomic profiling of salivary mucoepidermoid carcinomas reveals 94. Lennerz JK, Perry A, Mills JC, et al. Mucoepidermoid carcinoma
frequent BAP1, PIK3CA, and other actionable genomic alterations. of the cervix: another tumor with the t(11;19)-associated
Ann Oncol. 2017;28:748–753. CRTC1-MAML2 gene fusion. Am J Surg Pathol. 2009;33:835–843.
73. Jee KJ, Persson M, Heikinheimo K, et al. Genomic profiles and 95. Behboudi A, Winnes M, Gorunova L, et al. Clear cell hidradenoma
CRTC1-MAML2 fusion distinguish different subtypes of mucoepi- of the skin-a third tumor type with a t(11;19)—associated TORC1-
dermoid carcinoma. Mod Pathol. 2013;26:213–222. MAML2 gene fusion. Genes Chromosomes Cancer. 2005;43:202–205.
74. Di Palma S, Simpson RHW, Skálová A, et al. Metaplastic (infarcted) 96. Nemoto N, Suzukawa K, Shimizu S, et al. Identification of a novel
Warthin’s tumour of the parotid gland: a possible consequence of fine fusion gene MLL-MAML2 in secondary acute myelogenous
needle aspiration biopsy. Histopathology. 1999;35:432–438. leukemia and myelodysplastic syndrome with inv(11)(q21q23).
75. Tirado Y, Williams MD, Hanna EY, et al. CRTC1/MAML2 fusion Genes Chromosomes Cancer. 2007;46:813–819.
transcript in high grade mucoepidermoid carcinomas of salivary 97. Bishop JA, Yonescu R, Batista D, et al. Glandular odontogenic
and thyroid glands and Warthin’s tumors: implications for histo- cysts (GOCs) lack MAML2 rearrangements: a finding to discredit
genesis and biologic behavior. Genes Chromosomes Cancer. 2007; the putative nature of GOC as a precursor to central mucoepi-
46:708–715. dermoid carcinoma. Head Neck Pathol. 2014;8:287–290.
76. Bell D, Luna MA, Weber RS, et al. CRTC1/MAML2 fusion 98. Behboudi A, Enlund F, Winnes M, et al. Molecular classification of
transcript in Warthin’s tumor and mucoepidermoid carcinoma: mucoepidermoid carcinomas-prognostic significance of the
evidence for a common genetic association. Genes Chromosomes MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer.
Cancer. 2008;47:309–314. 2006;45:470–481.
77. Martins C, Cavaco B, Tonon G, et al. A study of MECT1-MAML2 99. Anzick SL, Chen WD, Park Y, et al. Unfavorable prognosis of
in mucoepidermoid carcinoma and Warthin’s tumor of salivary CRTC1-MAML2 positive mucoepidermoid tumors with CDKN2A
glands. J Mol Diagn. 2004;6:205–210. deletions. Genes Chromosomes Cancer. 2010;49:59–69.
78. Okabe M, Miyabe S, Nagatsuka H, et al. MECT1-MAML2 fusion 100. Coca-Pelaz A, Rodrigo JP, Bradley PJ, et al. Adenoid cystic
transcript defines a favorable subset of mucoepidermoid carcinoma. carcinoma of the head and neck—an update. Oral Oncol. 2015;
Clin Cancer Res. 2006;12:3902–3907. 51:652–661.
79. Fehr A, Roser K, Belge G, et al. A closer look at Warthin tumors 101. Seethala RR. An update on grading of salivary gland carcinomas.
and the t(11;19). Cancer Genet Cytogenet. 2008;180:135–139. Head Neck Pathol. 2009;3:69–77.
80. Seethala RR, Dacic S, Cieply K, et al. A reappraisal of the MECT1/ 102. Seethala RR, Hunt JL, Baloch ZW, et al. Adenoid cystic carcinoma
MAML2 translocation in salivary mucoepidermoid carcinomas. with high grade transformation: a report of 11 cases and review of
Am J Surg Pathol. 2010;34:1106–1121. the literature. Am J Surg Pathol. 2007;31:1683–1694.
103. Hellquist H, Skalova A, Azadeh B. Salivary hybrid tumour 124. Fonseca I, Assaad A, Catabi N, et al. Polymorphous adenocarci-
revisited: could they represent high-grade transformation in a low- noma. In: El-Naggar A, Chan JKC, Grandis JR, Takata T,
grade neoplasm? Virchows Arch. 2016;469:643–650. Slootweg PJ, eds. World Health Organization (WHO) Classifica-
104. Hellquist H, Skálová A, Barnes L, et al. Cervical lymph node tion of Head and Neck Tumours. Lyon, France: IARC Press;
metastasis in high-grade transformation of head and neck adenoid 2017:167–168.
cystic carcinoma: a collective international review. Adv Ther. 2016;33: 125. Weinreb I, Zhang L, Tirunagari LM, et al. Novel PRKD gene
357–368. rearrangements and variant fusions in cribriform adenocarcinoma
105. Persson M, Andren Y, Mark J, et al. Recurrent fusion of MYB and of salivary gland origin. Genes Chromosomes Cancer. 2014;53:
NFIB transcription factor genes in carcinomas of the breast and 845–856.
head and neck. Proc Natl Acad Sci U S A. 2009;106:18740–18744. 126. Weinreb I, Piscuoglio S, Martelotto LG, et al. Hotspot activating
106. Stenman G, Sandros J, Dahlenfors R, et al. 6q and loss of the Y PRKD1 somatic mutations in polymorphous low-grade adenocar-
chromosome-two common deviations in malignant salivary gland cinomas of the salivary glands. Nat Genet. 2014;46:1166–1169.
tumors. Cancer Genet Cytogenet. 1986;22:283–293. 127. Piscuoglio S, Fusco N, Ng CK, et al. Lack of PRKD2 and PRKD3
107. Ho AS, Kannan K, Roy DM, et al. The mutational landscape of kinase domain somatic mutations in PRKD1 wild-type classic
adenoid cystic carcinoma. Nat Genet. 2013;45:791–798. polymorphous low-grade adenocarcinomas of the salivary gland.
108. Brill LB 2nd, Kanner WA, Fehr A, et al. Analysis of MYB Histopathology. 2015;68:1055–1062.
expression and MYB-NFIB gene fusions in adenoid cystic 128. Laco J, Kamarádová K, Vítková P, et al. Cribriform adenocarci-
carcinoma and other salivary neoplasms. Mod Pathol. 2011;24: noma of minor salivary glands may express galectin-3, cytokeratin
1169–1176. 19, and HBME-1 and contains polymorphisms of RET and H-RAS
109. West RB, Kong C, Clarke N, et al. MYB expression and proto-oncogenes. Virchows Arch. 2012;461:531–540.
translocation in adenoid cystic carcinomas and other salivary gland 129. Pagano A, Dennis K. Cribriform adenocarcinoma of the minor
tumors with clinicopathologic correlation. Am J Surg Pathol. 2011;35: salivary gland arising in the tonsil with metastasis to a cervical
92–99. lymph node: a case report with description of fine needle aspiration
110. Mitani Y, Li J, Rao PH, et al. Comprehensive analysis of the MYB- cytology. Diagn Cytopathol. 2017;45:468–471.
NFIB gene fusion in salivary adenoid cystic carcinoma: incidence, 130. Takhar AS, Simmons A, Ffolkes L, et al. Not just another
variability, and clinicopathologic significance. Clin Cancer Res. paediatric neck lump: metastatic cribriform adenocarcinoma of the
2010;16:4722–4731. palate in an adolescent. J Laryngol Otol. 2015;129:194–197.
111. Mitani Y, Liu B, Rao PH, et al. Novel MYBL1 gene rearrange- 131. Gnepp DR. Salivary gland tumor “wishes” to add to the next WHO
ments with recurrent MYBL1-NFIB fusions in salivary adenoid Tumor Classification: sclerosing polycystic adenosis, mammary
cystic carcinomas lacking t(6;9) translocations. Clin Cancer Res. analogue secretory carcinoma, cribriform adenocarcinoma of the
2016;22:725–733. tongue and other sites, and mucinous variant of myoepithelioma.
112. Brayer KJ, Frerich CA, Kang H, et al. Recurrent fusions in MYB Head Neck Pathol. 2014;8:42–49.
and MYBL1 define a common transcription factor-driven onco- 132. Brierley D, Green D, Spedight PM. Cribriform adenocarcinoma of
genic pathway in salivary gland adenoid cystic carcinoma. Cancer the minor salivary glands arising in the epiglottis-a previously
Discov. 2016;6:176–187. undocumented occurrence. Oral Maxillofac Pathol. 2015;120:
113. Persson M, Andren Y, Moskaluk CA, et al. Clinically significant e174–e176.
copy number alterations and complex rearrangements of MYB and 133. Gailey MP, Bayon R, Robinson RA. Cribriform adenocarcinoma
NFIB in head and neck adenoid cystic carcinoma. Genes of minor salivary gland: a report of two cases with an emphasis on
Chromosomes Cancer. 2012;51:805–817. cytology. Diagn Cytopathol. 2014;42:1085–1090.
114. Stephens PJ, Davies HR, Mitani Y, et al. Whole exome sequencing 134. Majewska H, Skalova A, Weinreb I, et al. Giant cribriform
of adenoid cystic carcinoma. J Clin Invest. 2013;123:2965–2968. adenocarcinoma of the tongue showing PRKD3 rearrangement. Pol
115. Rettig EM, Talbot CC Jr, Sausen M, et al. Whole-genome J Pathol. 2016;67:84–90.
sequencing of salivary gland adenoid cystic carcinoma. Cancer 135. Cocek A, Hronkova K, Voldanova J, et al. Cribriform adenocarci-
Prev Res (Phila). 2016;9:265–274. noma of the base of the tongue and low-grade, polymorphic
116. Skálová A, Simpson RHW, Lehtonen H, et al. Assessment of adenocarcinomas of the salivary glands. Oncol Lett. 2011;2:
proliferative activity using the MIB1 antibody helps to distinguish 135–138.
polymorphous low grade adenocarcinoma from adenoid cystic 136. Michal M, Kacerovska D, Kazakov DV. Cribriform adenocarci-
carcinoma of salivary glands. Pathol Res Pract. 1997;193:695–703. noma of the tongue and minor salivary glands: a review. Head Neck
117. Ferlito A, Shaha AR, Rinaldo A, et al. Management of clinically Pathol. 2013;7:S3–S11.
negative cervical lymph nodes in patients with malignant neoplasms of 137. Xu B, Aneja A, Ghossein R, et al. Predictors of outcome in the
the parotid gland. J Otorhinolaryngol Relat Spec. 2001;63:123–126. phenotypic spectrum of polymorphous low-grade adenocarcinoma
118. Min R, Siyi L, Wenjun Y, et al. Salivary gland adenoid cystic (PLGA) and cribriform adenocarcinoma of salivary gland (CASG).
carcinoma with cervical lymph node metastasis: a preliminary study A retrospective study of 69 patients. Am J Surg Pathol. 2016;
of 62 cases. Int J Oral Maxillofac Surg. 2012;41:952–957. 40:1526–1537.
119. Silver CE, Bradley PJ, Barnes L, et al. Cervical lymph node 138. Bahrami A, Perez-Ordoñez B, Dalton JD, et al. An analysis of
metastasis in adenoid cystic carcinoma of the major salivary glands. PLAG1 and HMGA2 rearrangement in salivary duct carcinoma
J Laryngol Otol. 2017;131:96–105. and examination of the role of precursor lesions. Histopathology.
120. Suarez C, Barnes L, Silver CE, et al. Cervical lymph node 2013;63:250–262.
metastasis in adenoid cystic carcinoma of oral cavity and 139. Simpson RHW. Salivary duct carcinoma: new developments-
oropharynx: a collective international review. Auris Nasus Larynx. morphological variants including pure in situ high grade lesions;
2016;43:477–484. proposed molecular classification. Head Neck Pathology. 2013;7:
121. Carlson J, Licitra L, Locati L, et al. Salivary gland cancer: an S48–S58.
update on present and emerging therapies. Am Soc Clin Oncol Educ 140. Chiosea SI, Williams L, Griffith CC, et al. Molecular characterization
Book. 2013:257–263. of apocrine salivary duct carcinoma. Am J Surg Pathol. 2015;39:
122. Michal M, Skálová A, Simpson RHW, et al. Cribriform 744–752.
adenocarcinoma of the tongue: a hitherto unrecognized type of 141. Masubuchi T, Tada Y, Maruya S, et al. Clinicopathological
adenocarcinoma characteristically occurring in the tongue. Histo- significance of androgen receptor, HER2, Ki-67 and EGFR
pathology. 1999;35:495–501. expressions in salivary duct carcinoma. Int J Clin Oncol. 2015;20:
123. Skálová A, Sima R, Kaspirkova-Nemcova J, et al. Cribriform 35–44.
adenocarcinoma of the tongue and other minor salivary glands: 142. Williams MD, Roberts D, Blumenschein GR Jr, et al. Differential
characterization of new entity. Am J Surg Pathol. 2011;35:1168–1176. expression of hormonal and growth factor receptors in salivary duct
carcinomas: biologic significance and potential role in therapeutic pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat
stratification of patients. Am J Surg Pathol. 2007;31:1645–1652. Genet. 1997;15:170–174.
143. Di Palma S, Simpson RHW, Marchiò C, et al. Salivary duct 153. Foo WC, Jo VY, Krane JF. Usefulness of translocation-associated
carcinomas can be classified into luminal androgen receptor- immunohistochemical stains in the fine-needle aspiration diagnosis
positive, HER2 and basal-like phenotypes. Histopathology. 2012;61: of salivary gland neoplasms. Cancer Cytopathol. 2016;124:397–405.
629–643. 154. Bahrami A, Dalton JD, Shivakumar B, et al. PLAG1 alteration in
144. Mitani Y, Rao PH, Maity SN, et al. Alterations associated with carcinoma ex pleomorphic adenoma: immunohistochemical and
androgen receptor gene activation in salivary duct carcinoma of fluorescence in situ hybridization studies of 22 cases. Head Neck
both sexes: potential therapeutic ramifications. Clin Cancer Res. Pathol. 2012;6:328–335.
2014;20:6570–6581. 155. Katabi N, Ghossein R, Ho A, et al. Consistent PLAG1 and HMGA2
145. Skálová A, Stárek I, Vaněček T, et al. Expression of HER-2/neu abnormalities distinguish carcinoma ex-pleomorphic adenoma from
gene and protein in salivary duct carcinoma of parotid gland as its de novo counterparts. Hum Pathol. 2015;46:26–33.
revealed by fluorescence in-situ hybridization and immunohisto- 156. Chiosea SI, Thompson LD, Weinreb I, et al. Subsets of salivary
chemistry. Histopathology. 2003;42:348–356. duct carcinoma defined by morphologic evidence of pleomorphic
146. Griffith CC, Seethala RR, Luvison A, et al. PIK3CA mutations and adenoma, PLAG1 or HMGA2 rearrangements, and common
PTEN loss in salivary duct carcinomas. Am J Surg Pathol. 2013;37: genetic alterations. Cancer. 2016;122:3136–3144.
1201–1207. 157. Rotellini M, Palomba A, Baroni G, et al. Diagnostic utility of
147. Nardi V, Sadow PM, Juric D, et al. Detection of novel actionable PLAG1 immunohistochemical determination in salivary gland
genetic changes in salivary duct carcinoma helps direct patient tumors. Appl Immunohistochem Mol Morphol. 2014;22:390–394.
treatment. Clin Cancer Res. 2013;19:480–490. 158. Salovaara E, Hakala O, Bäck L, et al. Management and outcome of
148. Qui W, Tong GX, Turk AT, et al. Oncogenic PIK3CA mutation salivary duct carcinoma in major salivary glands. Eur Arch
and dysregulation in human salivary duct carcinoma. Biomed Res Otorhinolaryngol. 2013;270:281–285.
Int. 2014;810487. Doi:10.1155/2014/810487 [Epub January 8, 2014]. 159. Soper MS, Iganej S, Thompson LD. Definitive treatment of
149. Dalin MG, Desrichard A, Katabi N, et al. Comprehensive androgen receptor-positive salivary duct carcinoma with androgen
molecular characterization of salivary duct carcinoma reveals deprivation therapy and external beam radiotherapy. Head Neck.
actionable targets and similarity to apocrine breast cancer. Clin 2014;36:E4–E7.
Cancer Res. 2016;22:4623–4633. 160. Yamamoto N, Minami S, Fujii M. Clinicopathologic study of
150. Wang K, Russell JS, McDermott JD, et al. Profiling of 149 salivary salivary duct carcinoma and the efficacy of androgen deprivation
duct carcinomas, carcinoma ex pleomorphic adenomas, and therapy. Am J Otolaryngol. 2014;35:731–735.
adenocarcinomas, not otherwise specified reveals actionable ge- 161. Falchook GS, Lippman SM, Bastida CC, et al. Human epidermal
nomic alterations. Clin Cancer Res. 2016;22:6061–6068. receptor 2-amplified salivary duct carcinoma: regression with dual
151. Khoo TK, Yu B, Smith JA, et al. Somatic mutations in salivary human epidermal receptor 2 inhibition and anti-vascular endothe-
duct carcinoma and potential therapeutic targets. Oncotarget. 2017. lial growth factor combination treatment. Head Neck. 2014;36:
[Epub ahead of print]. E25–E27.
152. Kas K, Voz ML, Roijer E, et al. Promoter swapping between the 162. Limaye SA, Posner MR, Krane JF, et al. Trastuzumab for the
genes for a novel zinc finger protein and beta-catenin in treatment of salivary duct carcinoma. Oncologist. 2013;18:294–300.

The Role of Molecular Testing in The Differential Diagnosis of Salivary Gland Carcinomas

Uploaded by

Copyright:

Available Formats

The Role of Molecular Testing in The Differential Diagnosis of Salivary Gland Carcinomas

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Role of Molecular Testing in The Differential Diagnosis of Salivary Gland Carcinomas

Uploaded by

Copyright:

Available Formats

SPECIAL ARTICLE