Common Malignant Salivary Gland Epithelial Tumors
Common Malignant Salivary Gland Epithelial Tumors
Common Malignant Salivary Gland Epithelial Tumors
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
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
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
1180 Seethala & Barnes
Table 1
Common grading schemes in MEC
Abbreviations: AFIP, Armed Forced Institute of Pathology; HPF, high-power field; pts, points.
Common Malignant Salivary Gland Epithelial Tumors 1181
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.
1182 Seethala & Barnes
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).
Common Malignant Salivary Gland Epithelial Tumors 1183
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
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. 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
1190 Seethala & Barnes
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
Common Malignant Salivary Gland Epithelial Tumors 1191
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
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.
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).
Common Malignant Salivary Gland Epithelial Tumors 1199
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.
Common Malignant Salivary Gland Epithelial Tumors 1201
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
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
1204 Seethala & Barnes
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
Common Malignant Salivary Gland Epithelial Tumors 1205
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,
1206 Seethala & Barnes
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
Common Malignant Salivary Gland Epithelial Tumors 1207
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).
1208 Seethala & Barnes
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).
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.
Common Malignant Salivary Gland Epithelial Tumors 1211
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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