Common Malignant Salivary Gland Epithelial Tumors

COMMON MALIGNANT
S A L I VA RY G L A N D
EPITHELIAL TUMORS
Raja R. Seethala, MDa,*, E. Leon Barnes, MDb
KEYWORDS
Salivary gland Malignant Mucoepidermoid carcinoma Adenoid cystic carcinoma
Adenocarcinoma Salivary duct carcinoma
ABSTRACT 50% to 80% of all salivary neoplasms are benign
M
and 20% to 50% are malignant. The probability of
alignant salivary gland epithelial tumors malignancy is inversely proportional to the volume
are histologically diverse with at least 24 of salivary tissue. In general, malignant tumors
recognized distinct entities. In general, account for 15% to 30% of parotid tumors, 40%
malignant tumors account for 15% to 30% of to 45% of submandibular tumors, 70% to 90% of
parotid tumors, 40% to 45% of submandibular sublingual tumors, and 50% of minor salivary
tumors, 70% to 90% of sublingual tumors, and tumors.2 A comprehensive review of all tumors is
50% of minor salivary tumors. Common malignan- not possible but can be found in other sources.1–4
cies include mucoepidermoid carcinoma, adenoid The World Health Organization currently recog-
cystic carcinoma, acinic cell carcinoma, salivary nizes 13 benign and 24 malignant primary epithelial
duct carcinoma, carcinoma ex pleomorphic neoplasms of salivary origin.1 The focus of this
adenoma, polymorphous low-grade adenocarci- article is on the more commonly encountered
noma, and myoepithelial carcinoma. Each tumor malignant epithelial neoplasms (Box 1).
type has its own unique histologic variants and
prognostic pathologic features, and only mucoepi-
dermoid carcinomas have a formalized grading MUCOEPIDERMOID CARCINOMA
system. The molecular pathogenesis of certain
tumors, such as mucoepidermoid carcinoma and OVERVIEW
adenoid cystic carcinoma, has recently begun to
Mucoepidermoid carcinoma (MEC) is the most
be elucidated.
common salivary gland malignancy overall in
adults and children, with a peak incidence in the
OVERVIEW fifth decade. As with most salivary gland tumors,
there is a slight female predilection with a male:
Salivary tumors are uncommon, accounting for female ratio of approximately 1.5:1.0 in most
2.0% to 6.5% of all neoplasms of the head and series.2,5
neck with a worldwide incidence of about 0.4 to It is primarily a tumor of the major salivary glands
6.5 cases per 100,000 population.1 According to El- (50% to 60%), and most frequently involves the
lis and Auclair,2 approximately 60% to 80% of all parotid gland. Of the minor salivary gland sites,
primary epithelial neoplasms occur in the parotid the palate is by far the most common (20% to
gland, 5% to 10% in the submandibular gland, 25% of MEC overall). Of note, palate tumors
less than 1% in the sublingual gland, and 10% to tend to occur in a slightly younger age group,
25% in the minor glands. Depending on the series, whereas other minor salivary sites are rarely seen
surgpath.theclinics.com
a
Department of Pathology, University of Pittsburgh Medical Center, A614.X PUH, 200 Lothrop Street,
Pittsburgh, PA 15213, USA
b
Department of Pathology, University of Pittsburgh Medical Center, A608 PUH, 200 Lothrop Street,
Pittsburgh, PA 15213, USA
* Corresponding author.
E-mail address: seethalarr@upmc.edu
Surgical Pathology 4 (2011) 1177–1215

doi:10.1016/j.path.2011.07.005
1875-9181/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
1178 Seethala & Barnes
Box 1 almost half of postirradiation salivary gland

Commonly encountered malignant salivary tumors. MEC typically arises 1 to 2 decades after
gland epithelial tumors irradiation.9,10 MECs are rarely multifocal or bilat-
eral, but they have been described in association
Mucoepidermoid carcinoma
with other tumors such as pleomorphic adenoma,
Adenoid cystic carcinoma Warthin tumor, and oncocytoma.11,12 The relation-
Acinic cell carcinoma ship between MEC and these other entities,
Salivary duct carcinoma however, is controversial.
Carcinoma ex pleomorphic adenoma
GROSS FEATURES
Polymorphous low-grade adenocarcinoma
Myoepithelial carcinoma The gross manifestations of MEC depend to some
extent on histologic grade: low-grade MEC is often
grossly cystic and well demarcated. Papillary
excrescences may be noted. Intermediate-grade
in patients younger than 30 years. Rare case of in- MEC tends to have more of a solid tan appearance,
traosseous or “central” mucoepidermoid carci- although these are still well demarcated. High-
nomas have been described and comprise only grade MEC, however, may be an infiltrative tan-
1% to 2% of most cohorts.2,5,6 white with some degree of surrounding fibrosis.2,5
MEC typically presents as a well-circumscribed, Oncocytic MEC may mimic the gross appearance
painless mass that is present on average for 1.5 of an oncocytoma or a Warthin tumor with a deeper
years in the Armed Forces Institute of Pathology brown cut surface.13 Cyst contents in MECs are
(AFIP) database.2,7,8 Longer durations of up to 20 typically viscous and mucoid with varying degrees
years have been reported, suggesting that many of hemorrhage. Subcentimeter tumors are fairly
of these tumors are quite slow growing. Pain and common in the minor oral salivary glands, although
facial nerve paralysis can be associated with high- overall, tumors are typically 3 to 4 cm.
grade lesions, but is reported in only about 8% of
all MEC.2 Occasionally, cystic tumors may rupture, MICROSCOPIC FEATURES
resulting in an inflammatory response that presents
with pain. Superficial palate lesions may ulcerate. MECs are thought to recapitulate the cell types
MEC is also the most common salivary gland seen in large excretory ducts, and are composed
tumor seen in the postirradiation setting, both in of 3 basic cell types: intermediate cells, epider-
the pediatric and adult populations comprising moid cells, and mucous cells (Fig. 1). Additionally,
columnar cells comprise a minor subpopulation of
tumor cells. Intermediate cells represent the most
primitive phenotype: these cells have small, round
Key Features dark nuclei with inconspicuous nuclei surrounded
MUCOEPIDERMOID CARCINOMA by scant pale to clear cytoplasm.2,5 These are
presumed by many to represent the “basal” cell
type, which differentiates toward the other cell
Mucoepidermoid carcinoma is the most
types.14 Intermediate cells are often arranged in
common malignant salivary gland tumor in
adults and children. solid nests, although other elements may be inter-
spersed. Mucous cells represent ductoacinar
Tumors are composed of varying proportions differentiation in MEC. They range from ovoid to
of mucous, intermediate, and epidermoid columnar and characteristically line cystic spaces,
cell types arranged in solid or cystic growth although are occasionally seen singly. Epidermoid
patterns.
cells on the other hand represent squamous
Common variant morphologies include clear- differentiation in MEC. These cells are larger and
cell, oncocytic, and sclerosing variants. more polygonal than intermediate cells and
Histologic grade is one of the most important have more densely eosinophilic cytoplasm. Well-
prognosticators, although there is consider- developed squamous features, such as keratiniza-
able variation in grading schemes, particu- tion and prominent intercellular bridges, are highly
larly with respect to intermediate grade. uncommon.6
Columnar cells are also a form of ductal differen-
The t(11;19)(q21;p13) CRTC1-MAML2 translo-
tiation and are found only lining cysts or luminae.
cation is frequent in mucoepidermoid carci-
nomas and may be a favorable prognosticator. These are typically interspersed between mucous
cells and have eosinophilic cytoplasm. In addition
Common Malignant Salivary Gland Epithelial Tumors 1179
Fig. 1. Cell types in MEC.

MEC consist of a mixture
of mucous cells (short broad
arrow, top right), epider-
moid cells (medium arrow,
bottom left), and interme-
diate cells (double long
slender arrows) (hema-
toxylin-eosin [H&E], orig-
inal magnification 100).
Clear-cell change is fairly
common.
to these basic cell types, there are some fairly (ie, CK 5/6) and p63.2,5,13 Regarding mucin
common modifications that can affect any cell (MUC) proteins, the membrane-bound MUC1
type, namely clear-cell change and oncocytic and MUC4 are expressed in all cell types in
change, leading to the designation of clear-cell MEC, although MUC1 increases with higher-
MEC or oncocytic MEC variants when prominent.13 grade tumors, whereas MUC4 decreases with
The stroma surrounding tumor nests is often higher-grade tumors. Secretory MUC proteins,
sclerotic with varying levels of lymphoplasmacytic such as MUC 2, 5AC, 5B, 6, and 7, are variably ex-
inflammation. Tumors with heavy sclerosis are pressed and tend to favor mucous and interme-
often labeled as “sclerosing MEC.”15 Some diate cells.17
MECs may show a prominent lymphoid stroma
with germinal centers resembling that seen in War- DIFFERENTIAL DIAGNOSIS
thin tumor.
These cytoarchitectural features, along with other Classic low-grade and intermediate-grade MECs
features of oncologic potential, such as perineural are diagnostically straightforward. However, high-
invasion, angiolymphatic invasion, tumor border, grade MEC and tumors with variant morphologies
necrosis, anaplasia, and mitotic activity, are inte- may be diagnostically challenging. The main diag-
grated into a variety of commonly used grading nostic challenges for high-grade MEC include
schemes (Table 1).16 Although the specific grade adenosquamous carcinoma (primary or intra/peri-
of a tumor varies depending on grading system glandular lymph node metastases), and salivary
used, in general, cystic, well-demarcated tumors duct carcinoma with mucin production. In the oral
with a prominent mucous cell component are low cavity, the overlying mucosa should be examined
grade (Fig. 2); solid, intermediate-cell predominant thoroughly to exclude the presence of a mucosal
tumors are intermediate grade (Fig. 3); and infiltra- dysplasia or carcinoma in situ, which would point
tive, anaplastic tumors with a prominent epidermoid to a diagnosis of adenosquamous carcinoma. In
component are high grade (Fig. 4). the parotid, if a prior history of a cutaneous or
Immunohistochemically, mucous and columnar mucosal carcinoma exists, this should be com-
cells show a ductal staining pattern and are posi- pared with the parotid lesion because it would
tive for low molecular weight cytokeratins (CK7, likely represent a metastasis.6 Adenosquamous
CK 18, CK 19) and negative for p63, whereas the carcinomas tend to be more pleomorphic, infiltra-
epidermoid and intermediate cells are typically tive, mitotically active, and heavily keratinizing
positive for high molecular weight cytokeratins (Fig. 5). They lack a monomorphic intermediate
Table 1
Common grading schemes in MEC
Modified Healey22 AFIP21 Brandwein23

Qualitative Point Based Point Based
Low Grade Intracystic component <20% Intracystic component <25%
Macrocysts, microcysts, transi- 5 2 pts 5 2 pts
tion with excretory ducts Neural invasion present 5 2 pts Tumor invades in small nests
Differentiated mucin- Necrosis present 5 3 pts and islands 5 2 pts
producing epidermoid cells, Pronounced nuclear atypia
often in a 1:1 ratio; minimal to 5 2 pts
moderate intermediate cell
population
Daughter cyst proliferation
from large cysts
Minimal to absent pleomor-
phism, rare mitoses
Broad-front, often circum-
scribed invasion
Pools of extravasated mucin
with stromal reaction
Intermediate Grade Mitosis (4 or more per 10 HPF) Lymphatic and/or vascular
No macrocysts, few microcysts, 5 3 pts invasion 5 3 pts
solid nests of cells Anaplasia 5 4 pts Bony invasion 5 3 pts
Large duct not conspicuous >4 mitoses per 10 HPF 5 3 pts
Slight to moderate pleomor-
phism, few mitoses, prominent
nuclei and nucleoli
Invasive quality, usually well
defined and uncircumscribed
Chronic inflammation at
periphery, fibrosis separates
nests of cells and groups of
nests
High Grade Perineural spread 5 3 pts
No macrocysts, predominantly Necrosis 5 3 pts
solid but may be nearly all
glandular
Cell constituents range from
poorly differentiated to recog-
nizable epidermoid and inter-
mediate to ductal-type
adenocarcinoma
Considerable pleomorphism,
easily found mitoses
Unquestionable soft tissue,
perineural and intravascular
invasion
Chronic inflammation less
prominent, desmoplasia of
stroma may outline invasive
clusters
Low Grade 5 0–4 pts Low Grade 5 0 pts
Intermediate Grade 5 5–6 pts Intermediate Grade 5 2–3 pts
High Grade 5 7–14 pts High Grade 5 4 or more pts
Abbreviations: AFIP, Armed Forced Institute of Pathology; HPF, high-power field; pts, points.
Fig. 2. Low-grade MEC.

This tumor is almost entirely
cystic or even unicystic (H&E,
original magnification 40).
Inset (H&E, original magnifi-
cation 100): Mucous cells
predominate with under-
lying tufts of compressed
intermediate cells.
cell population. Adenosquamous carcinomas can phenotype and are almost definitionally androgen
have mucinous differentiation, but unlike high- receptor and gross cystic disease fluid protein 15
grade MECs, adenosquamous carcinoma may (GCDFP-15) positive.18 Although CK 5/6 may be
have discrete gland formation, often at the base positive, p63 is not. Furthermore, these tumors
of a lesion. With modern criteria and immuno- tend to be far more pleomorphic and mitotically
histochemistry, MEC is fairly easily distinguished active with prominent comedonecrosis, a feature
from even a solid salivary duct carcinoma. Salivary rarely seen in MEC. Oncocytic MEC may mimic on-
duct carcinomas have a ductal and apocrine cocytoma, oncocytic cystadenoma, and Warthin
Fig. 3. Intermediate-grade
MEC. This tumor is more
solid with scattered micro-
cysts only (H&E, original
magnification 40). Inset
(H&E, original magnifica-
tion 200): Although the
bulk of the tumor consists
of intermediate cells, cysts
are still lined by mucocytes.
Fig. 4. High-grade MEC.

This tumor is fairly infil-
trative with epidermoid
and intermediate cell pre-
dominance (H&E, original
magnification 40). Inset
(mucicarmine, original mag-
nification 200): A muci-
carmine stain is required
to highlight the scattered
mucous cells.
Fig. 5. Key distinguishing features in adenosquamous carcinoma. (A) The presence of a surface dysplasia (H&E,
original magnification 100). (B) Abundant keratinization, seen here in juxtaposition to mucous cell differentia-
tion (H&E, original magnification 200). (C) Discrete adenocarcinomatous foci (H&E, original magnification 200).
clear-cell myoepithelioma. Key features in distin-

Differential Diagnosis guishing clear-cell MEC from other clear cell
MUCOEPIDERMOID CARCINOMA tumors is the recognition of a mucous cell pop-
ulation, and establishment of an intermediate/
epidermoid phenotype (p631 CK 5/61, actin–, cal-
Adenosquamous carcinoma
ponin–, and S100–).
Salivary duct carcinoma Occasionally non-neoplastic conditions may be
mistaken for MEC, especially on small biopsy. In
Oncocytoma
the palate, necrotizing sialometaplasia, a self-
Oncocystic cystadenoma limited reactive condition may resemble MEC
Warthin tumor because of the reactive squamous metaplasia of
the ductoacinar units.19 Similarly in the major sali-
Hyalinizing clear-cell carcinoma vary glands, chronic sclerosing sialadenitis may
Clear-cell myoepithelioma also have metaplastic changes in the ducts and
may resemble a sclerosing MEC. However, these
Epithelial-myoepithelial carcinoma reactive conditions will retain the normal ductoaci-
nar architecture and will not have areas of interme-
diate cell proliferation.
For all diagnostically challenging MECs, molec-
tumor, particularly if there is prominent lymphoid ular testing for the MECT(CRTC)1/MAML2 translo-
stroma. However, oncocytoma can show tubules, cation may be useful. This is present in 40% to 80%
and tends to have less sclerosis around tumor of all MECs with a predilection for lower-grade
nests. Mucous cells should not be seen in oncocy- tumors.6 The presence of this translocation is fairly
toma. By immunohistochemistry, oncocytic MEC specific for MECs and can establish the diagnosis
will show more diffuse staining with p63 than onco- in difficult cases (Fig. 6); however, the absence of
cytoma, which is reflective of an intermediate/ this translocation does not exclude MEC.
epidermoid phenotype.13 Cystic oncocytic MECs
are more architecturally complex than oncocytic TREATMENT AND PROGNOSIS
cystadenoma or Warthin tumor and have a more
prominent mucous cell component. Clear-cell Treatment of MEC varies depending on grade
MEC may mimic a variety of tumors with clear- and stage. For low-grade tumors, excision with
cell change, such as epithelial myoepithelial negative margins is sufficient. For high-grade
carcinoma, hyalinizing clear-cell carcinoma, and tumors, patients may also undergo a neck
Fig. 6. Fluorescence in-situ

hybridization using break-
apart probes spanning the
MAML2. Two probes (red
and green) are normally
juxtaposed resulting in 2
yellow signals; however in
this case, there is a translo-
cation involving one copy
resulting in disruption of
the probes, which flank
the breakpoint, resulting
in a split as indicated by
a distinct red and green
signal (arrows). This is re-
flective of the MECT1-
MAML2 translocation that
is commonly noted in MEC.
behave in a similarly aggressive fashion to high-

Pitfalls grade tumors.21 However, under the Brandwein
MUCOEPIDERMOID CARCINOMA system, which requires fewer adverse parameters
to move to the next grade, intermediate-grade
tumors behave in an indolent fashion akin to low-
! Necrotizing sialometaplasia may mimic mu-
grade MEC.20,22 Another obstacle is the interob-
coepidermoid carcinoma on biopsy, because
of the squamous metaplasia of ductoacinar server variability that may be seen when assigning
units in the salivary glands of the palate. a grade. Finally, one underrecognized phenomenon
is the historical lack of accuracy of classification of
! Distinguishing chronic sclerosing sialadenitis high-grade tumors.6 In earlier series, the terms MEC
from sclerosing mucoepidermoid carcinoma and adenosquamous carcinoma were often used
may be difficult on biopsy.
interchangeably, and criteria for the delineation
were not rigorously applied. More recent series
likely have a more pure population of high-grade
dissection and receive postoperative radiotherapy. MEC, as reflected by more favorable outcomes.
The treatment of intermediate-grade tumors is Thus, in certain situations, particularly inter-
controversial in large part because of the variability mediate-grade MEC, more objective prognostic
in grading systems (see the following paragraph). markers are desirable. Immunohistochemical mar-
Generally low-stage intermediate-grade MEC kers of proliferation, such as Ki-67 and ploidy, cor-
may be treated surgically, whereas higher-stage relate with histologic grade and thus outcome in
tumors may be treated with adjuvant radiotherapy a univariate fashion, but not independent of the
and neck dissection. Only recurrent or dissemi- other traditional markers. Similarly, p53 and EGFR
nated disease (usually high-grade MEC) is treated immunoexpression are noted to correlate with
with chemotherapy.3,20 There is no specifically grade, but do not contribute significantly as inde-
tailored regimen for MEC, and the few patients pendent prognosticators.23 The single most impor-
enrolled in prospective trials have shown limited tant molecular advance in MEC has been the
objective response. The best single-agent therapy description and characterization of the t(11;19)
appears to be paclitaxel, with a partial response (q21;p13), which results in the fusion of CREB coac-
rate of 21%. Epidermal growth factor receptor tivator MECT(CRTC)-1 and the notch signaling
(EGFR) is overexpressed by immunohistochem- activator MAML2.6 As mentioned previously, it is
istry in more than two-thirds of MECs; however, frequently found in MEC and can be used dia-
activating mutations are quite rare. The rare case gnostically if positive; however, perhaps an equally
reports of patients treated with targeted anti- important role is its function as a prognosticator.
EGFR therapy show no response.3 Although almost 70% of low-grade and inter-
Clinical parameters that correlate most strongly mediate-grade MECs tested and reported in the
with disease-free and overall survival across the literature are translocation positive, only 30% of
few studies that use multivariate analysis include high-grade MECs are reported to be positive.
age, stage, and margin status.6,20,21 Submandib- Okabe and colleagues24 have demonstrated inde-
ular gland tumors, floor of mouth, and base of pendent prognostic value of translocation status in
tongue tumors may have a more aggressive predicting outcome. In our cohort, we were unable
behavior than parotid tumors, although this has to establish as strong a link with prognosis, although
not been as robustly validated as the other clinical even within the high-grade MEC subgroup,
prognosticators. Unlike other salivary carcinoma translocation-positive tumors had a more favorable
types, with perhaps the exception of adenoid cystic outcome, although not all tumors behaved in an
carcinoma, MEC grade is also an important prog- indolent fashion.6 Thus, translocation status may
nostic factor. Low-grade tumors have a 92% to supplement clinicopathologic parameters but will
100% 5-year survival, whereas intermediate- not replace them. The few translocation-positive
grade tumors have a reported 5-year survival of MECs that have proven lethal in the literature have
62% to 100%, and high-grade tumors have a 5- demonstrated CDKN2A deletions as a possible
year survival of 0% to 52%.16 Whereas all grading mechanism for tumor progression.25
systems correlate significantly with outcome given
a sufficient sample size, the behavior of each indi-
ADENOID CYSTIC CARCINOMA
vidual grade category varies under the different
grading schemes, particularly with respect to inter- CLINICAL FEATURES
mediate grade. Under the AFIP system, which
requires more adverse parameters to move to the Adenoid cystic carcinoma (ACC) is a distinctive
next grade category, intermediate-grade MEC will malignant salivary tumor described in the early
19th century as a “hetradenic tumor” by Robin and

Laboulbene.26 The relative prevalence of this Key Features
tumor varies both temporally and geographically. ADENOID CYSTIC CARCINOMA
In the United States, the incidence of ACC appears
to have decreased slightly over the past decade.2,5
Adenoid cystic carcinoma is a slow-growing
This in part can be attributed to the recognition of
but relentless malignancy that is frequently
polymorphous low-grade adenocarcinoma (see seen at minor salivary gland sites.
later in this article). There is a slight female predi-
lection with a male:female ratio of approximately Adenoid cystic carcinoma is a biphasic tumor
1.5:1.0 in most series. composed of hyperchromatic but bland an-
It is a tumor of minor salivary gland sites in about gulated outer myoepithelial cells and small
slightly eosinophilic inner ductules, arranged
one-half of all cases; however, the parotid gland is
in tubular, cribriform, and solid growth
still the most common single specific site. Of the patterns.
specific minor salivary gland sites, the palate is
the most common. ACC is typically a tumor of Solid growth pattern imparts an aggressive
adults with a peak incidence in the sixth decade.2,5 behavior.
ACC typically presents as a slow but progres- Adenoid cystic carcinomas with high-grade
sively enlarging mass. Signs and symptoms, transformation behave aggressively and
such as pain, and nerve paralysis, are more unlike conventional adenoid cystic carci-
common than in other salivary gland malignancies nomas, these tumors have a high propensity
as a result of this tumor’s notorious propensity for for nodal metastases.
perineural invasion. Because of the infiltrative
nature of these tumors, fixation to skin, mucosa,
and other soft tissue is also fairly common. Palate
lesions may ulcerate.2,5 a homogeneous gray-white.2,27 Despite the name,
ACCs are not typically cystic. Because ACC is
GROSS FEATURES such an infiltrative tumor, the gross impression of
extent of disease is often inaccurate, which neces-
ACCs are typically firm, ill-defined, and grossly sitates in some cases several frozen sections for
adherent to adjacent structures. Tumors may margination, particularly for named nerves. Nerve
occasionally appear well demarcated when they segments that are submitted for intraoperative
are small or assume the contours of the structures diagnosis, if involved, are often thickened and
involved (ie, bone) (Fig. 7). Cut surfaces are usually less pliable.
Fig. 7. Gross appearance

of ACC of the palate.
This tumor appears well
demarcated, but this is
because it has assumed
the rounded contour of
the hard palate, which is
infiltrated (arrow).
Fig. 8. ACC tubular pat-

tern (H&E, original mag-
nification 100). Tubules
are composed of a ductal
and myoepithelial layer,
both of which are com-
posed of cells with scant
cytoplasm and hyperchro-
matic angulated nuclei.
Tubules show prominent
retraction or clefting from
the adjacent hyaline stroma.
MICROSCOPIC FEATURES from myxoid to hyaline. The hyaline stroma is often

arranged in “cylinders” within cribriform spaces
ACC has a very characteristic appearance. Like (hence the archaic term “cylindroma”).28,29 A
many salivary gland tumors, it is a biphasic tumor variant of ACC, the “sclerosing” variant has abun-
composed of ducts and abluminal myoepithelial dant stroma with only scattered nests of tumor
cells arranged in tubular, cribriform, and solid embedded within (Fig. 11).30 Both ductal and my-
growth patterns (Figs. 8–10).2,27 The tumor nests oepithelial components are characterized by
are embedded in an acellular stroma ranging monomorphic hyperchromatic angulated nuclei
Fig. 9. ACC cribriform pat-

nification 100). Tumor
nests show well-demarcated
spaces filled with hyaline
basement membrane type
material, and are also com-
posed of cells with hyper-
chromatic nuclei with scant
cytoplasm. Note similar re-
traction of the tumor nests
from the stroma. True ducts
are noted occasionally as
well (arrows) within these
cribriform nests.
Fig. 10. ACC solid pattern

tion 100). Despite the solid
growth pattern, cells con-
tain monomorphic angu-
lated hyperchromatic nuclei
with indistinct nucleoli.
with inconspicuous nucleoli. At low-power magni- tubular and cribriform tumors have a high propor-
fication, this imparts a dark “blue” appearance to tion of myoepithelial cells. Unlike many other sali-
the tumor. Cytoplasm is typically scant in the my- vary gland tumors, ACC is a morphologically
oepithelial component, although ductal elements “pure” tumor in that metaplasias (ie, squamous
may contain some eosinophilic cytoplasm. The or oncocytic) and heterologous elements (ie, seba-
proportion of these components varies with ceous glands) are not seen, and in fact may raise
growth pattern. Solid tumors tend to have an the possibility of another diagnosis when present.
“overgrowth” of the ductal component, whereas However, for sinonasal tumors, when they involve
Fig. 11. Sclerosing ACC

tion 100). The hyaline
stroma is particularly abun-
dant with scant com-
pressed epithelial tubules;
however, the nuclei are
similarly hyperchromatic as
compared with usual ACC.
the excretory ducts as they open onto the surface component is usually a high-grade adenocarci-
mucosa,31 slight columnar or oncocytic change noma with cribriform, solid, or occasionally micro-
may be noted, and nuclei may be slightly more papillary areas. Squamoid areas are rare but have
vesicular and enlarged. Conventional ACC, regard- been described. Comedonecrosis, calcifications,
less of growth pattern, does not display pleomor- and desmoplasia are also common features.
phism. Perineural invasion is very common in High-grade transformation may occur de novo or
ACC, and essentially all tumors will show evidence on recurrent tumors.32
for this with adequate sampling. Immunohistochemically, the ductal component
The architectural growth pattern is the main is positive for low molecular weight cytokeratins
parameter used for “grading” adenoid cystic carci- (CK7, CK 18, CK 19) and negative for p63, whereas
nomas. Generally, a predominantly tubular ACC is the abluminal myoepithelial cells are positive for
grade I, cribriform ACC is grade II, and solid ACC is high molecular weight cytokeratins (ie, CK 5/6), vi-
grade III.2,27 Other features, such as mitotic count, mentin, actin, calponin, and p63 (Fig. 13A, B).2,27
nuclear atypia, and necrosis, are not incorporated S100 has low fidelity as a myoepithelial marker,
into this scheme, because, with the exception of and in ACC is only variably expressed in either
solid ACC, these are rarely ever seen. Currently, component. Various diagnostic markers have
this scheme is not formalized because it is not as been applied to ACC, among which the most
therapeutically relevant (see later in this article), prominent is the tyrosine receptor c-kit. C-kit
as the grading scheme for MEC for example (see shows strong immunoexpression in all ACCs,
previously). including transformed components, typically in
Apart from the conventional ACC morphology the ductal component (see Fig. 13C). However,
outlined previously, a rare entity known as ACC c-kit activating mutations are very rare.33 Other
with high-grade transformation (also known as de- markers such as cyclin D1, and surprisingly
differentiated ACC) exists. This is a form of tumor CD43, also expressed in ACC.34,35 The former is
progression that is characterized by a departure not sufficiently specific, and the latter is not suffi-
from the usual monomorphic biphasic appearance ciently sensitive as ACC markers, however.
of conventional ACC (Fig. 12). The transformed
areas may be localized or intermingled with any DIFFERENTIAL DIAGNOSIS
pattern of conventional ACC and are characterized
by a very pleomorphic carcinoma that has lost its Each pattern of ACC invokes a unique set of differ-
biphasic appearance. Nuclear size variation is often ential diagnostic considerations. Adding to the
greater than 4:1, nuclei may be more vesicular, diagnostic challenge is that many palatal or minor
often with prominent nucleoli. The transformed salivary ACCs are encountered on biopsy rather
Fig. 12. ACC-HGT showing

a transition from a mono-
morphic cribriform conven-
tional component (left)
to a pleomorphic high-
grade adenocarcinoma
(right) (H&E, original mag-
nification 200).
Fig. 13. Immunophenotype of ACC. (A) A low molecular weight pan cytokeratin cocktail highlights the ductal
elements (DAB chromogen hematoxylin counterstain, original magnification 200). (B) A p63 stain shows an
inverse staining pattern highlighting the abluminal myoepithelial cells (DAB chromogen hematoxylin counter-
stain, original magnification 200). (C) A c-kit immunostain shows a ductal predilection (DAB chromogen hema-
toxylin counterstain, original magnification 200).
than a complete excision. For instance, pleomor- (EMCa). This may be a difficult distinction, and in
phic adenomas may have ACC-like areas some cases both tumors coexist as a hybrid
(Fig. 14). Without adequate sampling or observa- tumor. Both tumors are defined by a biphasic bi-
tion of the circumscription from the surrounding layered appearance of abluminal myoepithelial
normal tissue, such a pleomorphic adenoma can cells and luminal ductal cells. However in ACC,
be mistaken as an ACC. the nuclei are more hyperchromatic and angulated
Perhaps the main diagnostic consideration for than those of EMCa. Additionally, tumor nests and
tubular ACC is epithelial myoepithelial carcinoma tubules in ACC tend to be more dyshesive and will
show “stromal clefting.” If there is dyshesion in
EMCa, it is more commonly between tumor cells
Differential Diagnosis rather than between the tumor and stroma. Addi-
ADENOID CYSTIC CARCINOMA tionally, the tumor border for EMCa tends to be
more rounded, even if permeative. Immunohisto-
chemically, these are similar. C-kit may be useful
Epithelial-myoepithelial carcinoma if negative, as this argues against ACC; however,
Polymorphous low-grade adenocarcinoma up to 75% of EMCa are c-kit positive, making
this marker less useful if positive.36
Basal cell salivary tumors (adenoma/adeno-
For tubular and cribriform ACC, tumors such as
carcinoma)
polymorphous low-grade adenocarcinoma (PLGA)
Basaloid squamous cell carcinoma and basal cell salivary tumors (BCST), both
Small cell neuroendocrine carcinomas adenomas and adenocarcinomas, particularly the
membranous and cribriform types, are major
Fig. 14. ACC-like areas in a cellular pleomorphic adenoma. (A) Tumor nuclei are hyperchromatic and angulated
with vague cribriforming reminiscent of ACC (H&E, original magnification 100). (B) Taking a step back, this
lesion is well demarcated and demonstrates streaming of myoepithelial cells into a myxoid stroma in other areas
(H&E, original magnification 20). This tumor was erroneously diagnosed as an ACC arising as a pleomorphic
adenoma, but the patient had remained disease free at the time of last follow-up 17 years after excision.
differential diagnostic considerations. Although useful.39 BCST are also biphasic and have similar
historically, PLGA was the leading differential diag- myxohyaline stroma to ACC, particularly membra-
nosis for ACC, and in fact, the decreasing preva- nous variants; however, nuclei of BCST are more
lence of ACC may be related to the recognition of vesicular than those of ACC. Additionally, BCST
PLGA,2 given adequate material, the challenges in tend to demonstrate peripheral palisading in tumor
distinguishing these 2 are largely exaggerated. nests. BCST also may often show squamous or
Although PLGA can have similar myxohyaline sebaceous metaplasia, which are rare to absent in
stroma, and similar growth patterns to ACC, funda- ACC. Immunohistochemically, although the outer
mentally this is a monophasic tumor with a ductal layers of BCST are also p63 positive like those of
phenotype. Even when there is focal myoepithelial ACC, these tend to have only a small subpopulation
marker expression by immunostaining, it is focal of myoepithelial cells; the rest of the p63-positive
and not distinctly bilayered, as in a truly biphasic cells are strictly “basal” in phenotype. Again c-kit
tumor.37,38 Furthermore, the nuclei of PLGA are may be expressed in some basal cell adenocarci-
very characteristically ovoid with vesicular, powdery nomas, which may lessen its utility here.40
almost clear chromatin, reminiscent of papillary Solid ACC and ACC with high-grade transfor-
thyroid carcinoma nuclei. By immunostaining, the mation may be confused with a variety of high-
distinction between the monophasic PLGA and grade lesions, ranging from basaloid squamous
biphasic ACC are readily apparent. Furthermore, carcinoma, or small-cell neuroendocrine carci-
PLGA are diffusely, strongly S100 positive, unlike noma. Small-cell neuroendocrine carcinomas
ACC.38 These are usually sufficient to resolve this tend to have more of a diffuse growth pattern
differential. However, c-kit, which is strongly posi- with a high mitotic/karyorrhectic index. These
tive in ACC, but weak to negative in PLGA, is also can be easily excluded with neuroendocrine
markers, such as synaptophysin or chromogranin. progression to high-grade transformation in

Basaloid squamous cell carcinoma can easily ACC.47 Gains on chromosome 8, particularly in
mimic ACC, particularly of the solid type; however, the region of c-myc, suggest that this may also
these tumors are surface mucosa derived, and be another mechanism of tumor progression.32
may thus show evidence of squamous dysplasia Earlier literature points to some utility in using
or carcinoma in situ or evidence of keratinization. DNA ploidy and S-phase analysis in predicting
Furthermore, basaloid squamous cell carcinomas aggressiveness, but it is unclear whether these
are more pleomorphic, and mitotically active than contribute beyond traditional clinicopathologic
solid ACC, although ACC with high-grade transfor- parameters. More recently, comparative genomic
mation may be equally pleomorphic and mitoti- hybridization studies have pointed to several
cally active. Perhaps the most useful ancillary important regions of loss including 1p32-36,
stain to add in the distinction of solid ACC, and 6q23-27, and 12q12-14.48,49 The 1p32-36 is re-
ACC with high-grade transformation from basaloid ported to be a significant prognosticator as
squamous cell carcinoma is p63. Basaloid squa- well.49 Candidate tumor suppressor genes in
mous cell carcinomas are diffusely p63 positive. these regions have yet to be identified. Recently,
Solid ACCs are positive only in the outermost layer a reproducible translocation, (6;9)(q22-23;p23-24)
in tumor nests, whereas ACCs with high-grade resulting in a fusion of MYB-NFIB has been
transformation are p63 negative altogether.32,41 described in up to 25% of head and neck ACC,
although its prognostic value remains to be
TREATMENT AND PROGNOSIS seen.50
Despite the emergence of molecular prognosti-
ACC follows a slow but relentless course, with a 5- cators, and regardless of the debate surrounding
year survival of 75% to 80%, but a 15-year survival the utility of grading of ACC, the therapeutic
of only 35%.42–46 ACC with high-grade transfor- approach to an ACC is mainly dependent on
mation is a very aggressive tumor with a median stage. ACC, regardless of pattern and phenotype,
survival of only 12 to 36 months, although long- is considered a locally aggressive tumor that
term survivors have been described.32 requires wide resection, and radiotherapy for local
Stage is perhaps the most important prognostic control. Despite the locally aggressive nature,
factor in ACC.43 Growth pattern–based grade in ACC has a fairly low propensity to metastasize to
most series is also important as a prognosticator, lymph nodes (5%–20%); thus, neck dissection is
although there is some degree of controversy not routinely done at many institutions. ACC with
surrounding this parameter. Generally, any solid high-grade transformation, in contrast, has
component suggests the possibility of an aggres- a much higher propensity for lymph node metas-
sive behavior, although the typical cutoff for tases, which present in more than 50% of reported
“grade 3” tumors is a solid component of 30% or cases to date, suggesting a potential role for
more. Using this cutoff, several studies have lymph node dissection for this variant of ACC.16
shown that tumors with a high solid component On the other hand, ACC spreads hematogenously
behave more aggressively42,44,46; however, Spiro with considerable frequency. As many as one-half
and Huvos43 suggested that pattern-based of patients develop metastatic disease, most
grading is not useful. The major flaw in this asser- commonly to lung, but other sites, such as bone,
tion is the use of an arbitrary grading scheme in liver, and brain are also fairly common.44 Thus,
which tumors with up to 50% of a solid component patients should have routine aggressive surveil-
could still be considered “grade 1.” lance throughout their life. Isolated small metas-
Regarding biomarkers, p53 overexpression tases are amenable to resection in the lung and
appears to be a useful prognosticator even on liver; however with disseminated disease, patients
multivariate analysis in one large series.45 In fact, are typically treated with a chemotherapeutic
p53 alterations appear to be one mechanism for regimen. Standard cytotoxic regimens, either
single agent or in combination have been used,
but typically show only partial response at best
to varying degrees (0%–70%). Empiric treatment
Pitfalls with monoclonals or inhibitors targeting EGFR
ADENOID CYSTIC CARCINOMA and human epidermal growth factor receptor 2
(HER-2) have shown no response and may not
be relevant targets. Although c-kit is overex-
! Pleomorphic adenomas may have adenoid
pressed in ACC, treatment with the inhibitor imati-
cystic carcinoma–like areas that can be
mistaken on biopsies. nib mesylate has shown only partial response in
a few isolated case reports.3
ACINIC CELL CARCINOMA

Key Features
OVERVIEW ACINIC CELL CARCINOMA
Acinic cell carcinoma (AciCC) is a low-grade sali-
vary neoplasm that shows evidence, either focally Acinic cell carcinomas most frequently occur
or diffusely, of serous acinar differentiation.51–55 It in the parotid.
comprises about 10% of all malignant salivary Tumors are defined by the presence of serous
neoplasms, occurs in all age groups, and is the acinar differentiation, but can consist of up
second-most frequent malignant salivary tumor to 5 different cell types (acinar, intercalated
in children, exceeded only by mucoepidermoid duct, vacuolated, clear, nonspecific glan-
carcinoma. Most large series indicate a female dular) arranged in up to 4 different growth
preference of about 60%.52,54 patterns (solid, microcystic, papillary-cystic,
follicular).
The parotid gland is, by far, the most common
site of origin (85%–90% of all cases), followed by Acinic cell carcinomas are generally indolent,
the minor salivary glands (5%–10% of all cases) but some adverse prognosticators include
and the submandibular gland (3% of all positive margins, elevated mitotic count,
cases).52,54 Among the minor salivary glands, the necrosis, perineural and angiolymphatic
buccal mucosa and upper lip are the more invasion, and high-grade transformation.
common sites, whereas the sinonasal tract is A subset of zymogen granule–poor and S100-
rarely involved.56 positive tumors historically categorized as
Most tumors present as a slowly enlarging, acinic cell carcinoma are now classified as
sometimes painful mass of less than a year’s dura- mammary analog secretory carcinomas and
tion. Facial nerve paresis or paralysis is apparent in are characterized by (12;15) (p13;q25) ETV6-
2% to 8% of patients.53,55 Fixation to skin and NTRK3 translocation.
muscle and lymph node metastasis at presenta-
tion are uncommon.
Although an infrequent occurrence, the AciCC is
the third-most frequent salivary neoplasm to abundant blue-purple zymogen granules (the
present with bilateral parotid involvement, ex- “blue dot tumor”). Intercalated duct cells are
ceeded in frequency by Warthin tumor and pleo- cuboidal with eosinophilic to basophilic cyto-
morphic adenoma.57,58 Such tumors may be plasm, round nuclei, and may or may not contain
either synchronous or asynchronous. zymogen granules (see Fig. 17). Vacuolated cells,
as the name implies, contain cytoplasmic vacuoles
GROSS FEATURES that are negative for glycogen and mucin (see
Most AciCCs rarely exceed 3 to 4 cm in greatest Fig. 17). Clear cells have an optically clear cyto-
dimension. On cut surface, they are firm, tan to plasm devoid of zymogen granules, glycogen,
reddish-gray, solid to cystic, and have margins and mucin. Nonspecific glandular cells possess
that vary from circumscribed to poorly defined eosinophilic to amphophilic cytoplasm, round
(Fig. 15). nuclei, and poorly defined cell borders and are ar-
ranged in syncytial aggregates (see Fig. 18).
MICROSCOPIC FEATURES The stroma ranges from sparse to dense and
sclerotic. Some tumors appear circumscribed,
AciCCs, histologically, are rather heterogeneous whereas others are infiltrative. Prominent mitotic
neoplasms. Five different cell types (acinar, inter- activity, focal necrosis, and perineural invasion
calated duct, vacuolated, clear, nonspecific glan- are variable, but, when seen, often signify a tumor
dular) and 4 patterns of growth have been with more aggressive behavior. A prominent
recognized (solid, microcystic, papillary-cystic, stromal lymphoid infiltrate is a component of
follicular) (Figs. 16–20).51 Although the prototypic many tumors (Fig. 21).59 A few may also contain
tumor is composed of acinar cells arranged in psammoma bodies.
a solid pattern, tumors composed of more than AciCCs can undergo high grade transformation,
one cell type and pattern of growth are almost previously referred to as dedifferentiation and
the rule rather than the exception (see Fig. 16). underscores the need for thorough histologic eval-
Acinar cells are round to polygonal with central uation to rule out this possibility.60 The transforma-
to eccentric nuclei that vary from small, hyperchro- tion may be apparent at the time of original
matic to vesicular. Nucleoli are usually absent or diagnosis or in a recurrent lesion. Such tumors
barely discernible. The cytoplasm contains are characterized by a “typical” low-grade AciCC
Fig. 15. Acinic cell carci-

noma, cut surface. Tumor
is reddish-tan and decep-
tively well circumscribed.
juxtaposed to a high-grade adenocarcinoma or an positive for S-100 protein. Antiamylase, which

undifferentiated carcinoma (Fig. 22). is reactive in normal serous acinar cells, has
The zymogen granules, the histologic hallmark been found to be an unreliable indicator of ac-
of an AciCC, are periodic acid-Schiff-positive inar differentiation and is often negative in
and diastase resistant. Most tumors are either AciCC.
negative or weakly reactive for mucin. AciCCs AciCCs with high-grade transformation show
are immunoreactive for cytokeratin (AE 1/3, CK5/6, a markedly elevated Ki-67, and are positive for
CK7, CK18, CK19) and negative for P63 and other p53 and cyclin D1 and exhibit strong membrane
“myoepithelial markers.” A few may be focally staining for beta-catenin.60

noma composed of acinar
cells arranged in a solid
pattern (H&E, original mag-
nification x100).

noma. Left image shows
intercalated duct cells for-
ming glands (H&E, orig-
inal magnification x200).
Right image shows vacuo-
lated cells (H&E, original
magnification x200).
DIFFERENTIAL DIAGNOSIS sampling, where it is sometimes mistaken for

normal parotid tissue. In normal parotid tissue,
Although the diagnosis of AciCC is usually the acini are arranged in lobules and are associ-
straightforward, 6 classic potentially problematic ated with ducts, whereas in AciCC a lobular
areas exist: architecture and ducts are not conspicuous.
1. The solid acinar variant may be difficult to recog- 2. Because the tumor is often histologically bland
nize, especially on frozen section or limited and well demarcated, it is often mistaken for
an “adenoma.” A thorough examination for the

noma. Nonspecific glan-
dular cells arranged in a
syncytial pattern (H&E, orig-

noma. Left image shows
microcystic pattern (H&E,
original magnification x100).
Right image shows follic-
ular pattern. Note the
colloidlike material with
peripheral scalloping, simu-
lating thyroid follicles (H&E,
original magnification x100).
diagnostic zymogen-containing cells will con- medullary sinuses, which are characteristic of
firm the diagnosis. a lymph node. In their absence, a tumor-
3. AciCC associated with a prominent lymphoid associated lymphoid response is more likely.
response is occasionally mistaken for lymph 4. Some pathologists are not familiar with the
node metastasis. In this instance, it is important papillary-cystic variant of AciCC and mistake it
to look for a capsule around the lymphoid for a benign salivary cyst or cystadenoma. The
stroma and the presence of subcapsular and presence of zymogen-containing acinar cells

noma, papillary-cystic pattern
tion x40).

noma, microcystic pattern
with tumor-associated lym-
phoid response. Note
germinal center (H&E, orig-
lining the cyst, either focally or diffusely, should should not be confused with other clear cell–
suggest the proper diagnosis. Additionally, dominant tumors.
papillary cystic AciCC often show hobnailed 6. The high-grade transformed component of an
epithelium in the cyst lining. AciCC can be very focal, representing in some
5. Although AciCC may contain clear cells, such cases only 5% of the total tumor volume.60
cells are very focal and never dominate the Thorough sampling of all AciCCs, therefore, is
tumor. As such, a clear cell variant of AciCC essential to avoid missing these more aggres-
for all practical purposes does not exist and sive variants.

noma with high-grade
transformation. Left image
shows typical low-grade
acinic cell component.
Right image shows undif-
ferentiated component.
Note nuclear pleomor-
phism and mitoses (H&E,
original magnification
x400).
Ki-67 greater than 10%, necrosis, perineural and

Differential Diagnosis angiolymphatic invasion, recurrent tumors, and
ACINIC CELL CARCINOMA high-grade transformation.55,60,62
The 5-year, 10-year, and 20-year determinant
survival rates for the “usual” AciCC are 90%,
Metastatic adenocarcinoma
83%, and 67%, respectively.53 Approximately
Cystadenoma 35% to 45% of patients will develop local recur-
rences, with the median time from diagnosis to
Clear-cell salivary gland tumors
first recurrence being 3 years53,63; 15% to 20%
Mammary analog secretory carcinoma will also develop cervical lymph node or more
distant metastases (lungs, bones). High-grade
transformed tumors are much more aggressive.
Molecular advances have resulted in yet another In a report of 9 transformed tumors, Skalova and
differential diagnostic consideration. A subset of colleagues60 observed that 56% developed lymph
AciCC, composed of intercalated and nonspecific node metastases and 66% developed distant
ductal cells often arranged in a microcystic pattern dissemination to various sites, especially lungs
showing strong S100 positivity, are now known and brain. Six of the 9 patients died of their tumor,
to be characterized by a (12;15) (p13;q25) ETV6- all within an overall median survival of 4.3 years.60
NTRK3 translocation identical to that seen in The propensity for lymph node metastases for this
juvenile secretory carcinoma of breast.61 It is not variant of tumor indicates the need for a neck
clear whether clinical behavior of this newly re- dissection at the time of diagnosis.
cognized entity, dubbed mammary analog secre- Although grading systems for AciCC have been
tory carcinoma, is different from AciCC, but it proposed, all are controversial and rarely used.64
appears biologically distinct. Thus, any zymogen- All agree that cell type and pattern of growth
poor, strongly S100-positive acinar microcystic- have no prognostic significance.53,55 It has been
patterned tumor should raise this entity as a suggested that those AciCCs that are well circum-
potential diagnostic consideration. scribed, arranged in a microcystic pattern with
a low Ki-67 proliferative index, and completely sur-
TREATMENT AND PROGNOSIS rounded by a heavy lymphoid infiltrate with
germinal centers tend to be less aggressive than
The standard treatment of AciCC is local resection other tumors.65
with tumor free margins without a neck dissection. Whether DNA ploidy analysis of AciCCs has any
In the parotid gland, a superficial lobectomy is clinical relevance is debatable.66 Some of the aneu-
sufficient, rarely a total parotidectomy. Postopera- ploid tumors, alleged to be more aggressive than
tive radiation and/or a neck dissection should be diploid tumors, have had areas that are probably
considered only for those patients with positive best classified as foci of high-grade transformation.
margins or other adverse indicators, such as In general, AciCCs arising in minor salivary
greater than 2 mitoses per 10 high-power fields, glands are less aggressive than those occurring
in the major glands. Tumors of the submandibular
gland, although rare, also tend to be more aggres-
sive than those of the parotid gland.63
Pitfalls
ACINIC CELL CARCINOMA
SALIVARY DUCT CARCINOMA
! Distinguishing normal acini from acinic cell OVERVIEW

carcinoma by the presence of lobular archi-
tecture and presence of central ducts Salivary duct carcinoma (SDC) is a relatively
uncommon, clinically aggressive adenocarcinoma
! Acinic cell carcinomas may be well demar-
of salivary origin that is histologically similar to
cated and mimic a benign neoplasm or
“adenoma”; however, examination for serous carcinoma of the breast.67–72 It was first recognized
acinar differentiation (ie, zymogen granules) by Kleinsasser and colleagues in 1968.73 In a review
will exclude benign lesions. of 104 cases, Barnes and colleagues68 noted that
the tumor was 3 times more common in men and
! Acinic cell carcinoma with high-grade trans- occurred primarily in patients older than 50 years
formation may not be recognizable as acinic
(range 22–91 years). The tumor occurs mainly in
cell carcinoma unless carefully examined for
a “differentiated” component. the parotid gland, infrequently in the submandib-
ular gland, and rarely in the minor salivary glands.
Most patients present with a progressively, some- cells with a desmoplastic stromal resection, such
times rapidly, enlarging mass, with or without as seen in scirrhous carcinoma of the breast. The
evidence of positive cervical lymph nodes. Pain tumor cells have amphophilic to pink cytoplasm
and facial nerve paralysis are additional features. and large, pleomorphic, vesicular nuclei with
prominent nucleoli. Some have an apocrine
GROSS FEATURES appearance, replete with apical snouts. Occasion-
ally the tumor cells are more uniform and com-
The tumor may arise de novo or in a pleomorphic posed of small, hyperchromatic nuclei. Mitoses,
adenoma (salivary duct carcinoma ex pleomorphic lymph node metastases (59%), and vascular
adenoma). Most vary from a few millimeters up (31%) and peri-intraneural invasion (60%) are
to 7 cm and on cross section are gray-white to common.74 Dystrophic calcification may also be
yellow-tan with borders that range from well to seen, sometimes even on imaging, which mas-
poorly defined. Some have a uniform, firm solid querades as calculi. Rare sarcomatoid, mucin-
appearance, and others have both solid and cystic rich, micropapillary, and intraductal variants have
components. The cysts range up to 1.5 cm and are also been described.74–77
filled with either serous fluid or necrotic tumor. The presence of a uniform layer of cells around
tumor islands that are positive for cytokeratin 14
MICROSCOPIC FEATURES and/or p63 is useful in identifying an in-situ (intra-
ductal) component of the tumor (Fig. 24). Immuno-
SDCs are characterized by both intraductal and histochemical evaluation of SDC shows that it
infiltrating ductal carcinoma (Fig. 23). The tumor shares many features in common with breast carci-
grows in papillary, cribriform, and/or solid patterns, noma, especially with regard to carcinoembryonic
with central (comedo) necrosis. In other instances, antigen and gross cystic disease fluid protein;
the infiltrating tumor forms small ducts or cords of however, with regard to hormonal receptors, there
Fig. 23. Salivary duct carcinoma. (A) Intraductal component. Note prominent layer of peripheral myoepithelial
cells (H&E, original magnification x400). (B) Tumor is positive for androgen receptor (DAB chromogen hematox-
ylin counterstain, original magnification x400).
showed strong distinct membrane staining for

Key Features this marker (score 31) with immunohistochemistry,
SALIVARY DUCT CARCINOMA whereas the remaining 3 cases were inconclusive
with scores of 11 to 21. Using fluorescence in
situ hybridization, they observed that 4 of the 10
Salivary duct carcinomas are highly aggres-
cases that were analyzed showed HER-2/neu
sive malignancies that resemble ductal carci-
noma of the breast. gene amplification. They, however, observed no
differences in prognosis between amplified and
Salivary duct carcinoma shows frequent calci- nonamplified tumors.
fications and comedonecrosis. P53 positivity was found in 58% of SDCs
Variants include micropapillary, sarcomatoid, studied by Felix and colleagues,83 but did not
and mucin-rich tumors. correlate with the clinical course. Reviews indicate
that 21% to 42% of SDCs are diploid and 58% to
Essentially all tumors have an apocrine
79% are aneuploid. All conclude that tumor ploidy
morphology and are positive for androgen
receptor and GCDFP-15. has no predictive value.
Unlike ductal carcinoma of the breast, HER-2/ DIFFERENTIAL DIAGNOSIS

neu amplification is not prognostically or
therapeutically relevant, although not Although one should consider metastatic breast
uncommonly seen. carcinoma in a woman and, possibly, even meta-
static prostatic carcinoma in a man, these possi-
bilities are distinctly uncommon. According to
are distinct differences. In contrast to breast carci- Gnepp,84 only 2% to 3% of all metastatic tumors
nomas, which are frequently positive for estrogen to the parotid gland are from the breast and only
(ER) and progesterone (PR) receptors, only 2% 0.5% from the prostate. These events would be
and 14% of SDCs are respectively positive for even more unlikely if the parotid mass is also asso-
these markers.18,67,78–81 Interestingly, 80% to ciated with enlarged cervical lymph nodes. The
90% are positive for androgen receptors.18 absence of a breast mass on physical or mammo-
HER-2/neu overexpression has been found in graphic examination, coupled with a tumor that is
25% to 88% of SDCs. Whether it has prognostic negative for estrogen receptor, would also favor
significance, however, is controversial. In one of an SDC rather than a metastasis from the breast.
the best studies of HER-2/neu and SDC, Skalova The finding of unequivocal in situ ductal carcinoma
and colleagues82 observed that 8 of 11 cases would also indicate a primary parotid tumor.
Fig. 24. Salivary duct carci-

noma showing both in-
traductal and infiltrating
carcinoma. Note the come-
donecrosis with dystrophic
calcification and the des-
moplastic stromal response
tion x40).
Differential Diagnosis Pitfalls

SALIVARY DUCT CARCINOMA SALIVARY DUCT CARCINOMA
Metastatic ductal carcinoma of breast ! Salivary duct carcinoma may express PSA,
which may raise confusion with metastatic
Metastatic prostatic adenocarcinoma prostatic adenocarcinoma.
Oncocytic carcinoma
Mucoepidermoid carcinoma
unfortunately, are common and are directed
Adenocarcinoma, not otherwise specified primarily to the lungs and bones. Chemotherapy
Low-grade salivary duct carcinoma (low- is largely ineffective.
grade cribriform cystadenocarcinoma) Because SDCs are rarely positive for estrogen
receptor and progesterone receptor, one would
expect antiestrogen therapy, as used in breast
Caution must be exercised in distinguishing an cancer, would have little if any, therapeutic value
SDC from metastatic prostatic carcinoma based in the management of the vast majority of patients.
on the results of an immunoperoxidase stain for The observation that 80% to 90% of SDCs are
prostatic-specific antigen (PSA).85 James and positive for androgen receptor raises the question
colleagues86 reported an SDC that was not only of whether antiandrogen therapy, such as fluta-
immunopositive for PSA but was also associated mide, might have merit. Because 25% to 88% of
with an elevated serum PSA level. The absence SDCs are positive for HER-2/neu, one might also
of a palpable lesion of the prostate on physical speculate on whether or not trastuzumab (Hercep-
examination and the simultaneous presence of tin) might be beneficial.
a parotid mass and enlarged cervical lymph nodes SDC is very aggressive. Most patients die of
would, of course, favor the diagnosis of an SDC. their disease within 4 years of diagnosis. The inci-
Other entities that have been mentioned in the dence of local recurrence, cervical lymph node
differential diagnosis include oncocytic carcinoma metastases, and distant metastases are, respec-
(OCa), mucoepidermoid carcinoma (MEC), and ad- tively 33%, 59%, and 46%.68
enocarcinoma not otherwise specified type (ANOS).
Because of the eosinophilic or apocrinelike CARCINOMA EX PLEOMORPHIC ADENOMA
appearance of tumor cells, SDC may be mistaken
for an OCa. OCa, however, does not exhibit prom- OVERVIEW
inent comedonecrosis or papillary intraductal The risk of malignant transformation in a pleomor-
projections of tumor cells. OCa, furthermore, are phic adenoma increases with the longevity of the
packed with mitochondria, whereas in SDC they tumor. According to Eneroth and colleagues,87
are less conspicuous. Stains for mitochondria, the incidence of malignancy in a pleomorphic
such as the phosphotungstic acid hematoxylin or adenoma of 5 years or less duration is 1.6% but
an immunoperoxidase stain for cytochrome-c- increases to 9.6% for those present for more
oxidase, may be helpful in distinguishing the 2. than 15 years.
The absence of epidermoid cells and the overall Auclair and Ellis88 indicate that pleomorphic
resemblance to a breast carcinoma respectively adenomas that show prominent zones of hyalini-
exclude an MEC and an ANOS from consideration. zation and moderate mitotic activity (mean 1.5
Delgado and colleagues81 reported 10 cases mitoses/10 high-power fields [HPFs]) have
of “low-grade salivary duct carcinoma,” which, a 13.8% chance of malignant transformation. Clin-
according to them, represented the low-grade ical findings at diagnosis that point toward
end of a spectrum of salivary duct carcinoma. a greater tendency of malignant change include
The World Health Organization has recently re- an origin in the submandibular gland, older age
named this tumor as “low-grade cribriform (mean 62 years), and large tumor size (mean 4 cm).
cystadenocarcinoma.” Malignant neoplasms arising in pleomorphic
adenomas are collectively referred to as malignant
TREATMENT AND PROGNOSIS mixed tumors and can be divided into 3 categories:
Complete surgical excision with removal of re- 1. carcinoma ex pleomorphic adenoma (CXPA)
gional lymph nodes and postoperative irradiation 2. carcinosarcoma (true malignant mixed tumor)
is the preferred treatment. Systemic metastases, 3. metastasizing pleomorphic adenoma.
Organization has recently proposed that CXPAs

Key Features be divided into 3 categories89 (Fig. 25):
CARCINOMA EX PLEOMORPHIC ADENOMA
1. noninvasive
2. minimally invasive
Carcinoma ex pleomorphic adenoma is 3. invasive.
a term that categorizes all malignancy types
that show evidence of an antecedent pleo- NONINVASIVE CXPA
morphic adenoma.
Noninvasive CXPA, also known as in situ or intra-
Carcinoma ex pleomorphic adenoma can be
subtyped based on growth pattern into capsular CXPA, is a pleomorphic adenoma that
noninvasive (intracapsular), minimally inva- shows either focal or diffuse cellular pleomor-
sive, and invasive, with the former 2 groups phism, increased mitotic activity, prominent
showing an indolent behavior. stromal hyalinization, and/or necrosis, but no
capsular, vascular, or lymphatic invasion.88–90
Adenocarcinoma, not otherwise specified,
The earliest changes are usually observed in the
and salivary duct carcinoma are the most
common histologic subtypes. luminal duct cells, which may or may not be sur-
rounded by myoepithelial cells. Needless to say,
Growth pattern and histologic subtype are the tumor must be thoroughly sampled, preferably
important prognosticators. totally submitted for microscopic evaluation, to
make this diagnosis.
Assessment of androgen receptor, HER-2/neu,
CXPA accounts for more than 90% of these and P53 in evaluating the malignant potential of
tumors and is defined as a carcinoma arising in pleomorphic adenomas must be interpreted with
a primary or recurrent pleomorphic adenoma. As caution, as these markers can be seen focally in
such, only the epithelial component can metasta- 5% to 10% of otherwise benign pleomorphic
size, as opposed to the carcinosarcoma in which adenomas.91
both epithelial and mesenchymal components can If the margins of resection are free of tumor, no
disseminate, either simultaneously or independently. further treatment is warranted and the prognosis is
The term “CXPA” includes a heterogeneous similar to an ordinary pleomorphic adenoma;
group of carcinomas that vary from in situ to widely however, rare recurrences and metastases have
invasive and from low to high grade. Accordingly, been reported.92,93 Perhaps the only thoroughly
“CXPA” cannot be used as a histologic diagnosis documented case, however, is that of Felix and
without further qualification. The World Health colleagues92 in which “missed capsule infiltration
Fig. 25. Diagram showing

progression of pleomor-
phic adenoma (PA) from in-
tracapsular (white area) to
minimally invasive (MIC)
to invasive carcinoma (IC)
based on presence or ab-
sence of capsular invasion
(yellow border) and extent
of invasion beyond the
capsule.
and lymphatic permeation were excluded since “occasional perineural or perivascular tumor
the neoplasm was totally submitted and serial outside nearby the capsule.” No recurrences or
recuts done.” metastases were seen in 11 patients available for
follow-up (mean 4.2 years; range 15 months to
MINIMALLY INVASIVE CXPA 13 years).
Based on the aforementioned, the World Health
There are many histologic indices of CXPA that Organization has recently endorsed 1.5 mm as the
affect survival. Among these include the propor- cutoff between “minimally invasive” and “invasive”
tion of carcinoma, histologic type, surgical CXPA (see Fig. 25; Fig. 26).89 Using the 1.5-mm
margins, perineural and angiolymphatic invasion, definition, Katabi and colleagues93 described 12
and the extent of invasion.4,7–9,90,94–96 Tortoledo cases of noninvasive and minimally invasive
and colleagues95 observed that when CXPAs did CXPA. With a median follow-up of 30 months, 3
not exceed 8 mm of invasion from the capsule of of the 12 (2 noninvasive and 1 minimally invasive)
a pleomorphic adenoma, no patients died of their recurred. Distant metastasis occurred in 3 of 12
tumor. When the microscopic invasion exceeded tumors (not indicated if these were noninvasive
6 mm, the local recurrence was 70.5%, whereas or minimally invasive). One minimally invasive
when it was less than 6 mm, the recurrence rate tumor resulted in death.
was only 16.5%. How then should minimally invasive (1.5 mm or
Lewis and colleagues96 described 4 patients less) CXPA be treated? If the margins are free
with CXPA in which the extent of invasion was and no perineural and/or angiolymphatic invasion
only 5 mm from the capsule of the pleomorphic is seen, we believe that no additional therapy is
adenoma. Of these 4 patients, 2 had no progres- warranted other than periodic follow-up. If, on
sion of disease and 2 died of disease. The investi- the other hand, the margins are positive and/or
gators stated that they would cautiously predict perineural neural or angiolymphatic invasion is
a favorable prognosis in cases of less than 5 mm apparent, then additional surgery and/or radiation
invasion. must be considered. There are several problem-
Brandwein and colleagues90 studied 12 CXPAs atic issues in the diagnosis of minimally invasive
that were either noninvasive or exhibited capsular CXPA:
invasion of no more than 1.5 mm. DNA ploidy was
performed on 7 of these and 5 were found to be First, pathologists must be aware that the
aneuploid and 2 diploid. Ploidy had no predictive capsule around a pleomorphic adenoma is
value. The tumors in their series ranged from 0.8 often focally absent, even in tumors of the major
to 3.5 cm (mean 1.8 cm). Some cases showed salivary glands. Just because a pleomorphic
Fig. 26. Minimally inva-

sive carcinoma arising in
a pleomorphic adenoma.
The tumor has completely
breached the capsule
(C) of the adenoma and
extents laterally on the
surface (H&E, original mag-
nification x40).
equally divided between the submandibular and

Differential Diagnosis minor salivary glands.98 The typical history is that
CARCINOMA EX PLEOMORPHIC of a patient with a long-standing salivary neoplasm
ADENOMA that starts to rapidly increase in size and is associ-
ated with pain and occasionally facial palsy.
Pleomorphic adenoma with pseudopodia
Although any of the salivary carcinomas may
De novo salivary carcinomas of all types arise in a pleomorphic adenoma, in our experience
most are high grade and are usually an adenocar-
cinoma not otherwise specified, salivary duct
carcinoma, or a myoepithelial carcinoma. In most
adenoma abuts normal salivary parenchyma
cases, the carcinoma comprises more than half
without a capsular interface does not always
of the tumor volume. In some instances, the only
indicate invasion.
histologic evidence of an underlying pleomorphic
Second, capsular invasion like in the thyroid
adenoma may be a residual sclerotic, hyalinized
can be very subjective. Not infrequently, small
nodule.
foci of tumor cells can be seen in the capsule
Treatment and prognosis depend on stage and
of an otherwise benign pleomorphic ade-
histologic type, but treatment usually necessitates
noma and should not be mistaken for inva-
wide excision with removal of regional lymph
sion. To qualify for invasion, tumor should
nodes often supplemented by postoperative radi-
completely penetrate the capsule and, ideally,
ation. In a review of 66 cases with a mean follow-
extend laterally over the capsular surface in
up of 3.2 years, Lewis and colleagues96 observed
a “mushroom” fashion.
that 23% developed local recurrences, 56%
Third, distinguishing pseudopods of a pleo-
developed regional metastasis, 44% developed
morphic adenoma from microinvasion can be
distant metastasis, and 53% died of disease with
difficult. Recuts may be helpful. In addition,
an overall 5-year survival rate of 30%. Based on
look for a desmoplastic reaction and/or
the types of carcinoma arising in a pleomorphic
a condensation of myofibroblasts (supple-
adenoma, Tortoledo and colleagues95 observed
mented with an alpha smooth muscle actin
the 5-year survival rate to be 30% for undifferenti-
stain), which is more compatible with invasion
ated carcinomas, 50% for myoepithelial carci-
than a pseudopod.97
nomas, 62% for ductal carcinomas, and 96% for
Fourth, the carcinomas, by definition, are
terminal duct carcinoma.
small and often difficult to subclassify. In
these instances, a diagnosis of carcinoma,
not otherwise specified type, either low or POLYMORPHOUS LOW-GRADE
high grade, may have to suffice. ADENOCARCINOMA
OVERVIEW
INVASIVE CXPA
Polymorphous low-grade adenocarcinoma (PLGA)
Invasive CXPA is defined as a carcinoma that was the term given by Evans and Batsakis in
extends more than 1.5 mm from the capsule of 198499 to describe this distinct salivary gland
a pleomorphic adenoma.89 They represent 5% to tumor, although it was described earlier as
10% of all pleomorphic adenomas and, on the “terminal duct carcinoma” and “lobular carci-
average, occur in individuals who are 10 to 15 years noma,” and may have even composed a subset
older than those with benign pleomorphic ade- of earlier papillary adenocarcinomas.100–102 The
nomas. Most studies indicate a female predilection. increasing recognition of this tumor has led to its
Approximately two-thirds of all invasive CXPAs increasing prevalence in series, and comprises
occur in the parotid gland, with the rest about approximately 20% of all malignant tumors. There
is a female predilection with a female:male ratio of
approximately 2:1 in most series.38,103–105
PLGA is a tumor that occurs almost exclusively
Pitfalls in the minor salivary glands, and of these, 60%
CARCINOMA EX PLEOMORPHIC to 80% arise in the palate. Other common sites
ADENOMA include the lip and buccal mucosa. PLGA is
a tumor of adults, with a wide age range, although
! An acellular sclerotic calcific nodule within
the peak incidence in the sixth decade.2
a carcinoma may be the only residual evidence
of a preexisting pleomorphic adenoma. PLGA typically presents as a nontender swelling
at the hard-soft palate junction. Erythema and
even ulceration of the mucosa may occur. Palate crystals can be seen in 3% to 5% of PLGAs. Papil-
tumors are typically smaller than extrapalatal lary patterned tumors may show psammoma
tumors. Pain and nerve paralysis are not common bodies as well. Angiolymphatic invasion is not
findings with PLGA. Bone erosion/involvement common, and it tends to occur more frequently in
may be seen in approximately one-quarter of papillary predominant PLGA. Mitotic rates are
palate tumors, and virtually all nasopharyngeal low, and tend to be less than 3 per 10 high power
PLGAs will show bone involvement.37 fields.2,37,38,105
Immunohistochemically, this is a “monophasic”
GROSS FEATURES tumor, composed of a ductal phenotype. As
such, PLGA will be positive for low molecular
PLGA are usually firm, ovoid, white masses.
weight cytokeratins (CK7, CK 18, CK 19). Very
Although they are not encapsulated, they often
focally, there may be some phenotypic divergence
appear well delineated. Gross cystic change is
with a few cells, particularly those embedded in
not common.
myxohyaline stroma, showing focal myoepithelial
marker expression, namely for p63, actin, or calpo-
MICROSCOPIC FEATURES
nin. One useful marker for PLGA is S100, which
PLGA, as its name would suggest, has a great shows a diffuse, strong reactivity in tumor cells
variety of growth patterns: solid, tubular, cribri- (Fig. 28A).38,105 C-kit is usually negative and,
form, and papillary. Although grossly not extremely when present, only focally positive (see Fig. 28B).39
infiltrative, microscopically, a highly permeative
border is typical of PLGA. PLGA often replaces DIFFERENTIAL DIAGNOSIS
and permeates adjacent seromucinous acini.
Tubules may stream, giving the appearance of Historically, PLGA has been vastly underrecognized
a single-file growth pattern similar to lobular carci- as a diagnostic category, although recognition of
noma of the breast (hence the earlier name for this diagnostic category has improved2,5,105; how-
PLGA). Often within a tumor, targetoid whorls of ever, in one recent series, overdiagnosis has now
infiltrating cells can be seen. Despite the variety emerged as the more frequent problem.37 It is also
of growth patterns this tumor displays (Fig. 27), important to note that this danger of overdiagnosis
the cytomorphologic features of the tumor cells of PLGA is more prominent in uncommon sites
are, in contrast, monomorphic. Tumor cells have (ie, parotid). The main diagnostic considerations
varying degrees of eosinophilic cytoplasm. Nuclei include ACC, pleomorphic adenoma (PA), and
are ovoid, with delicate powdery, often cleared epithelial-myoepithelial carcinoma (EMCa). The
chromatin reminiscent of papillary thyroid carci- specific distinction from each of these tumors is out-
noma nuclei. Although it is an adenocarcinoma, lined in the following paragraphs, but briefly, PLGA
PLGA can deposit myxohyaline matrix in a similar is separated based on: (1) the recognition of the
fashion to tumors with myoepithelial cells such as PLGA characteristic nuclear features, and (2) recog-
adenoid cystic carcinoma (ACC). Tyrosinelike nition of the monophasic ductal phenotype in PLGA
(in contrast to the biphasic nature of these other
diagnostic considerations).
When PLGA was described, the classic “misdi-
Key Features agnosis” for this tumor was ACC. This distinction
POLYMORPHOUS LOW GRADE can indeed be a troublesome one on biopsy, but
ADENOCARCINOMA with adequate material, this differential diagnosis
Polymorphous low-grade adenocarcinoma is fairly simple. PLGA is a composed of cells with
arises mainly in the minor salivary glands ovoid vesicular nuclei, whereas ACC is composed
and is historically confused with adenoid of angulated hyperchromatic nuclei (Fig. 29). As
cystic carcinoma because of similarities in
growth pattern and propensity for perineu-
ral invasion.
Differential Diagnosis
Polymorphous low-grade adenocarcinomas
POLYMORPHOUS LOW-GRADE
show a variety of growth patterns (solid,
tubular, cribriform, and papillary), but consist ADENOCARCINOMA
of one basic cell type with ovoid nuclei and Adenoid cystic carcinoma
vesicular chromatin.
Pleomorphic adenoma
Papillary predominant tumors are generally
more aggressive, as are extrapalatal tumors. Epithelial-myoepithelial carcinoma
Fig. 27. Different patterns

in PLGA. (A) Tubular pat-
tern percolating through
normal salivary acini (ar-
row) (H&E, original magni-
fication 200). (B) Cribriform
pattern (H&E, original mag-
nification 200).
mentioned, PLGA is a monophasic tumor com- negative.39 Thus, with adequate sampling, this
posed of cells with a ductal phenotype, whereas distinction can be readily resolved.
ACC is a clearly biphasic tumor with a dual popu- The distinction of PLGA from PA can also be
lation of ducts and myoepithelial cells. When this is troublesome, as both can produce myxohyaline
not readily apparent on light microscopy, immu- stroma and can even demonstrate tyrosinelike
nostains can highlight the presence of abluminal crystals. Furthermore, PAs in the palate, although
myoepithelial cells (p63 and actin) in ACC. Further- well demarcated, are not always encapsulated.
more, PLGAs are strongly S100 positive, whereas However, PLGA is a carcinoma; thus, any evi-
ACCs are variably positive to negative.37,38 dence of perineural or angiolymphatic invasion is
Conversely, ACC is diffusely strongly positive for useful in the distinction from PA. More specifically,
c-kit, whereas PLGA is variably positive to however, despite the morphologic diversity in PA,
Fig. 27. (C) Papillary pat-

nification 200). (D) Solid
pattern (H&E, original
magnification 200) with
perineural invasion (right).
Regardless of pattern, all
tumor cells are monomor-
phic, bland, and composed
of ovoid nuclei with vesic-
ular to cleared chromatin
reminiscent of papillary
thyroid carcinoma nuclei.
it is still a biphasic tumor with ducts and myoepi- can lead to confusion with PLGA. The key to
thelial cells, unlike PLGA.105 distinction is the recognition of a biphasic appear-
In one recent series, EMCa was the most ance on light microscopy or immunohistochem-
common named tumor type misdiagnosed as istry in EMCa.
PLGA.37 Both share several similarities in that
they are low-grade carcinomas that can be arrayed TREATMENT AND PROGNOSIS
in a variety of patterns and contain myxohyaline
stroma. Although the prototypical EMCa has large PLGAs tend to behave quite favorably, with deaths
polygonal clear myoepithelial cells, many EMCa from disease rare. However, PLGA can recur
may show less of a clear-cell component, which locoregionally in about one-third of cases.37,104
Fig. 28. (A) S100 showing strong positivity in PLGA (FAST RED chromogen hematoxylin counterstain, original
magnification 200). (B) C-kit when present is only focal (DAB chromogen hematoxylin counterstain, original
magnification 200).
Lymph node metastases are uncommon, ranging The presence of a papillary component in some
from 0% to 17%, and distant metastases are rare. PLGAs raises an important controversy. Some
Recurrences may be late, with a median disease believe that tumors are different entities than
survival ranging from 7 to 12 years. Factors re- PLGA with tubular or solid growth; however, given
ported to predict an aggressive behavior include the large degree of morphologic overlap and
margin status, vascular invasion, extrapalatal site, absence of additional biologic understanding,
and papillary growth.37,104 Although perineural papillary predominant tumors are kept as variants
invasion is a frequent finding in PLGA, it may not of PLGA.105 Similarly, cribriform adenocarcinoma
be a significant predictor of recurrence, although of the tongue has been proposed as an entity
large-nerve perineural invasion may be important. distinct from PLGA, because of its prominent crib-
riform growth, and high propensity for lymph node
metastases. Again, there is too much morphologic
Pitfalls overlap between this entity and standard PLGA to
POLYMORPHOUS LOW-GRADE currently warrant classification as a distinct
ADENOCARCINOMA tumor.106 Additionally, it must be noted that 3 addi-
tional noncribriform PLGAs of the tongue have
! Small biopsies may not show adequate distin-
been reported, all with lymph node metastases,
guishing features between adenoid cystic
carcinoma and polymorphous low-grade suggesting that it is the location rather than tumor
adenocarcinoma. type that is responsible for this “unique” behavior.37
Very rarely, PLGA may progress or transform to
! Major salivary gland polymorphous low- a high-grade carcinoma, which can be potentially
grade adenocarcinomas are rare, and other lethal.107 It is also noted that almost one-half of
diagnoses should be considered before enter-
PLGA recurrences show an “intermediate-grade”
taining this possibility in the parotid or
submandibular gland. morphology, with increased mitotic activity and
nuclear pleomorphism (Fig. 30).
Fig. 29. Distinction of PLGA from ACC. (A) This PLGA shows ovoid vesicular nuclei, including some with clearing
(H&E, original magnification 200). (B) ACC, on the other hand, is composed of dark, angulated, hyperchromatic
nuclei (H&E, original magnification 200).
Fig. 30. Recurrent PLGA

may show “intermediate-
grade” features, such as
nuclear atypia and in-
creased mitotic activity
(arrow, H&E, original mag-
nification 400).
Treatment of PLGA is mainly surgical with nega-

tive margins. Although this is readily feasible in Key Features
palatal and oral tumors, it may be more difficult MYOEPITHELIAL CARCINOMA
in the oropharynx and nasopharyx. Given the pres-
ence of bone invasion in one-quarter of tumors,
Myoepithelial carcinomas may arise de novo
the resection of sizeable palate tumors may
or from pleomorphic adenoma.
include a portion of bone. Although radiotherapy
is given for nasopharyngeal PLGA, these tumors Cell types (spindled, epithelioid, clear cell,
recur despite this treatment suggesting that this plasmacytoid) are identical to their benign
is not particularly useful. Most tumors do not counterparts in myoepitheliomas.
require a neck dissection37,108; however, some Myoepithelial carcinoma is immunopheno-
advocate that base of tongue tumors receive typically confirmed by the expression of kera-
a neck dissection because of the high propensity tins, and one or more smooth muscle–type
for nodal metastases. Recurrent tumors can also markers, such as actin or calponin.
be managed successfully by surgical excision. S100, p63, and vimentin can also be used to
Adjuvant therapy may be warranted in rare cases confirm a myoepithelial carcinoma diagnosis
with transformation to high-grade carcinoma. in the appropriate morphologic context.
Fifty percent to 60% of myoepithelial carci-
MYOEPITHELIAL CARCINOMA
nomas will develop local recurrences, 30%
to 50% will metastasize, and 30% to 45% of
OVERVIEW patients will die of their disease.
Myoepithelial carcinoma (MyoCA) is the term
preferred by the World Health Organization to
describe the malignant counterpart of myoepithe- angiolymphatic invasion, necrosis and/or local
lioma.109 Malignant myoepithelioma is another invasion (Figs. 31 and 32). Occasionally, a tumor
popular synonym. will be invasive yet show little evidence of pleo-
Although uncommon, MyoCAs are being recog- morphism or mitotic activity. Tumors with more
nized more frequently, and currently comprise than 7 mitoses/10 HPFs and a Ki-67 index greater
about 10% to 30% of all myoepithelial neoplasms. than 10% are generally malignant, according to
They may arise de novo or in a pleomorphic Nagao and colleagues.111
adenoma (MyoCA ex pleomorphic adenoma). The range of cell types and growth patterns
The mean age at diagnosis is about 50 to 60 years reflect those seen in their benign counterparts
(range 16–85 years) with a male:female ratio of (see next section on “myoepithelioma”). Clear-
1.0:1.0 to 1.3:1.0.2–6,110–114 Approximately 55% cell myoepithelial neoplasms should always be
arise in the parotid gland, 15% in the submandib- viewed with skepticism. In our experience, this
ular gland, and 30% in minor salivary glands variant often appears deceptively benign but clin-
(especially the palate). ically over a period of time often recurs and may be
Although most patients present with a relatively locally aggressive. A “dedifferentiated” MyoCA
asymptomatic mass, pain and rapid enlargement has also been described.115
may be seen. As with all myoepithelial neoplasms, there is no
one immunohistochemical marker that is specific
GROSS FEATURES for myoepithelial lineage. As such, multiple stains
may be necessary to establish a specific diag-
Although tumors as large as 20 cm have been nosis. In a review of 18 MyoCAs, Savera and
described, most are in the 3 to 5 cm range. On colleagues112 observed that 89% expressed
cut surface, the tumors are tan, yellow, white, or CAM 5.2, 100% AE 1/3, 92% 34BE12, 21% CK7,
gray, often with areas of necrosis and margins 53% CK14, 100% vimentin, 100% S-100 protein,
that vary from well to poorly defined. More than 50% smooth muscle actin, 75% calponin, 31%
50% of MyoCAs are stated to arise from pleomor- muscle-specific actin, 31% glial fibrillary acidic
phic adenomas or preexisting myoepitheliomas protein, 0% carcinoembryonic antigen, and 21%
and, accordingly, areas of blue-white opalescent epithelial membrane antigen.
cartilage may also be apparent.
MICROSCOPIC FEATURES DIFFERENTIAL DIAGNOSIS

MyoCAs exhibit varying degrees of cellular pleo- The first order of business is distinguishing a myoe-
morphism, increased mitotic activity, perineural- pithelioma from a MyoCA. Features that are useful
Fig. 31. Myoepithelial car-

cinoma, plasmacytoid var-
iant, of palate invading
bone (H&E, original magni-
fication x100).
are listed previously. It must be emphasized again MyoCA, especially on small biopsies, may be
that some MyoCAs are low grade and may not confused with an extramedullary plasmacytoma,
exhibit all of the findings described. In this case, whereas the epithelioid MyoCA can be mistaken
look for unequivocal evidence of invasion (angio- for a variety of metastatic carcinomas.
lymphatic, perineural and/or parenchyma, soft Once the differential diagnosis is considered,
tissue, bone), which is the sine qua non for distin- a battery of appropriate immunostains, coupled
guishing benign from malignant tumors. with the clinical history, can usually point toward
The differential diagnosis varies according to the the correct diagnosis.
cellular composition of the MyoCA. For spindle-
cell MyoCAs, amelanotic melanoma, monophasic TREATMENT AND PROGNOSIS
synovial carcinoma, malignant peripheral nerve
sheath tumor, and leiomyosarcoma must be consid- MyoCAs should be widely excised with ample
ered. For the clear-cell MyoCA, clear-cell carcinoma margins.110–112 Because data indicate that
of salivary origin, epithelial-myoepithelial carci- cervical lymph node metastasis is uncommon,
noma, and possibly even metastatic renal cell carci- a neck dissection may not be warranted. Chemo-
noma should be excluded. The plasmacytoid therapy and radiation are largely untested.
Current experience indicates that about 50% to
60% of MyoCAs will develop local recurrences,
30% to 50% will metastasize, and 30% to 45%
Differential Diagnosis of patients will die of their disease.110–112 Most
MYOEPITHELIAL CARCINOMA metastases are directed to the lungs, liver, bones,
kidneys, and occasionally regional lymph nodes.
Most deaths occur within 5 years. There is no
Myoepithelioma
True sarcomas (synovial sarcoma, malignant
peripheral nerve sheath tumor) Pitfalls
Spindle-cell melanoma MYOEPITHELIAL CARCINOMA
Epithelial-myoepithelial carcinoma
Extramedullary plasmacytoma ! The biologic behavior of clear-cell myoepi-
thelial tumors may not be predictable on
Metastatic carcinomas histologic features alone.
Fig. 32. Myoepithelial car-

cinoma, plasmacytoid var-
iant. Higher magnification
of Fig. 31 showing cellular
pleomorphism and 3 mitoses
tion x400).
correlation with cell type and biologic behavior and and application of grading criteria in 143 cases.
no difference in clinical outcome of “de novo” Cancer 1992;69(8):2021–30.
MyoCAs versus those that arise in pleomorphic 8. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid
adenomas and/or myoepitheliomas.109 carcinoma of the major salivary glands: clinical
and histopathologic analysis of 234 cases with
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Common Malignant Salivary Gland Epithelial Tumors

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Common Malignant Salivary Gland Epithelial Tumors

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COMMON MALIGNANT

ABSTRACT 50% to 80% of all salivary neoplasms are benign

Surgical Pathology 4 (2011) 1177–1215

Box 1 almost half of postirradiation salivary gland

Fig. 1. Cell types in MEC.

Modified Healey22 AFIP21 Brandwein23

Fig. 2. Low-grade MEC.

Fig. 4. High-grade MEC.

clear-cell myoepithelioma. Key features in distin-

Fig. 6. Fluorescence in-situ

behave in a similarly aggressive fashion to high-

19th century as a “hetradenic tumor” by Robin and

Fig. 7. Gross appearance

Fig. 8. ACC tubular pat-

MICROSCOPIC FEATURES from myxoid to hyaline. The hyaline stroma is often

Fig. 9. ACC cribriform pat-

Fig. 10. ACC solid pattern

Fig. 11. Sclerosing ACC

Fig. 12. ACC-HGT showing

markers, such as synaptophysin or chromogranin. progression to high-grade transformation in

ACINIC CELL CARCINOMA

Fig. 15. Acinic cell carci-

juxtaposed to a high-grade adenocarcinoma or an positive for S-100 protein. Antiamylase, which

Fig. 16. Acinic cell carci-

Fig. 17. Acinic cell carci-

DIFFERENTIAL DIAGNOSIS sampling, where it is sometimes mistaken for

Fig. 18. Acinic cell carci-

Fig. 19. Acinic cell carci-

Fig. 20. Acinic cell carci-

Fig. 21. Acinic cell carci-

Fig. 22. Acinic cell carci-

Ki-67 greater than 10%, necrosis, perineural and

! Distinguishing normal acini from acinic cell OVERVIEW

showed strong distinct membrane staining for

 Unlike ductal carcinoma of the breast, HER-2/ DIFFERENTIAL DIAGNOSIS

Fig. 24. Salivary duct carci-

Differential Diagnosis Pitfalls

Organization has recently proposed that CXPAs

Fig. 25. Diagram showing

Fig. 26. Minimally inva-

equally divided between the submandibular and

Fig. 27. Different patterns

Fig. 27. (C) Papillary pat-

Fig. 30. Recurrent PLGA

Treatment of PLGA is mainly surgical with nega-

MICROSCOPIC FEATURES DIFFERENTIAL DIAGNOSIS

Fig. 31. Myoepithelial car-

Fig. 32. Myoepithelial car-

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Unlike ductal carcinoma of the breast, HER-2/ DIFFERENTIAL DIAGNOSIS