Update of Common Salivary Tumors
Moderators: Dr. John Eveson and Dr. Silloo Kapadia
Section 3 -
Mucoepidermoid carcinoma (MEC) accounts for 2.8% to 15.5% of all salivary gland tumors, 12% to 29% of
malignant salivary gland tumors, and 6.5% to 41% of minor salivary gland tumors, representing the most
common type of malignant minor salivary gland tumor in most series.
Approximately 55% occur
in the major salivary glands, with 85-88% occurring in the parotid gland, 8-13% occurring in the
submandibular gland, and 2-4% involving the sublingual gland.
In the minor salivary glands,
MEC most commonly arises on the palate, but a significant number may also be found in other intraoral
MEC may also rarely occur primarily within the body of the mandible or
maxilla  and may occasionally arise from heterotopic intralymph nodal salivary
gland tissue and in the larynx, lacrimal gland, nose, paranasal sinuses, lung, and trachea. MEC is most
frequently seen in the 35- to 65-year-old age group but may be found at any age. It is the most common
malignant salivary gland tumor to arise in children and adolescents under the age of 20  and
is unusual in the first decade of life. MEC has a slight predilection for women, with approximately 60%
of tumors arising in women. 
The most common etiologic factor that has been implicated in the development of MEC is radiation,
with up to 44% of patients with a history of a radiation-associated adenocarcinoma developing a MEC.
Latency periods in this group ranged from 4 to 64 years.
The mean age between radiation
exposure and tumor diagnosis in a recent study was 21 years. 
Land et al.  reviewed
data on 145 major and minor salivary gland tumors from atomic bomb survivors. They found an increased
relative risk of 9.3 for patients with MEC, with the proportion of MECs increasing with increasing dose
MECs typically present as slowly growing (up to 40 years), firm, unilateral masses clinically
indistinguishable from the more common pleomorphic adenoma.  Bilaterality is rare.
Pain is unusual and more often associated with high-grade tumors. In one large series, high-grade
MEC was the carcinoma most often associated with facial nerve palsy. 
On gross examination, MEC may appear circumscribed, but it is seldom encapsulated. High-grade tumors
have poorly defined margins and may be associated with fixation to the adjacent skin and soft tissues.
The cut surface ranges from gray to tan-yellow to pink, and cystic features are common and may be
prominent.  Tumors usually range in size from 1 to 6 cm in greatest dimension; however,
occasional patients may present with larger tumors with the largest one in a recent series being 16 cm in
greatest dimension. 
Microscopically, MECs are composed of varying proportions of epidermoid cells, mucus-secreting cells,
and "intermediate" cells, which are cells of intermediate differentiation between the other two cell
types. Intermediate cells include the smaller basal cells as well as larger cells that are
differentiating toward squamous and mucin-secreting cells. Clear cells, many of which contain glycogen
or mucin or both, are present in most mucoepidermoid carcinomas and often are a prominent feature.
Tumors, especially low-grade neoplasms, frequently have columnar cells containing intracellular mucin
(goblet-like cells). Epidermoid cells have abundant eosinophilic cytoplasm and are occasionally
associated with keratin production, including pearl formation, which rarely may be prominent. MECs show
great variability in the composition of cell types. Cellular pleomorphism and atypia may be found
ranging from minimal to severe. Necrosis, prominent mitotic activity, neural invasion, and, rarely, a
prominent lymphoid reaction may be seen. Occasional MECs are associated with a prominent oncocytic
component (oncocytic variant)  with dense sclerosis or may arise within a salivary duct cyst,
within cervical lymph nodes or within a benign mixed tumor. Dedifferentiation has also been
These tumors are histologically classified into low-, intermediate-, and high-grade by most observers
although some prefer to use a two-tiered grading system. Suggested grading criteria have included the
relative proportion of cell types, degree of tumor invasiveness, anaplasia, pattern of invasion, degree
of maturation of the various cellular components, mitotic rates, presence or absence of necrosis, neural
or vascular invasion, and proportion of tumor composed of cystic spaces relative to solid growth
Low-grade tumors commonly have a nesting pattern with multiple
well-circumscribed squamous nests containing numerous clear cells, some of which contain intracytoplasmic
mucin. Many low-grade tumors, especially in the minor salivary glands, contain a prominent
mucin-secreting component composed of columnar cells lining prominent cystic spaces. Nuclear atypia,
mitotic activity, and an infiltrative growth pattern are not usually features of low-grade tumors. Intermediate-grade tumors are less cystic and show a greater tendency to form
larger, more irregular nests or sheets of squamous cells and often have a more prominent intermediate
cell population. A minor degree of nuclear atypia and mitotic activity may be present, and a small
infiltrative component is usually noted. High-grade tumors are
predominantly solid with greater atypia and are usually similar to squamous cell carcinoma. These are
infiltrative tumors with scant mucin production that may require careful search and special stains for
identification of intracellular mucin.
Grading MEC is subjective with different criteria used in various series.
Unfortunately, there is no universally accepted grading system. Auclair, Goode, and Ellis established
more uniform and reproducible histologic criteria that correlated with clinical outcome.
The histopathologic features that were most useful in indicating aggressive behavior were a cystic
component of less than 20% of tumor area, 4 or more mitotic figures per 10 hpf, nerve invasion, tumor
necrosis and the presence of cellular anaplasia. Each parameter was assigned a point value and the total
sum of points for the five variables determined the tumor grade. Although reproducible, in the
experience of other authors, this scheme tended to "downgrade" MEC  and did not work as well
for submandibular gland tumors. Brandwein et al  proposed adding several additional grading
parameters (vascular/lymphatic invasion, aggressive pattern of infiltration), in addition to those used
by Auclair et al. Alos et al. compared the AFIP and Brandwein et al grading schemes and found that the
latter classification was the only prognostic-associated feature that retained significance in a
multivariate analysis.  A recent paper from Mayo clinic used their own grading criteria
comparing their grading to the AFIP and Brandwein et al modifications in 5 cases.  Two of the
5 cases with disease progression were graded differently in all 3 systems, supporting the fact that
additional work needs to be done to establish a more universal grading system.
The t(11;19)(q21;p12-13) chromosomal translocation is the most frequently detected aberration in MEC
and has been shown to generate a MECT1-MAML2 (Mucoepidermoid carcinoma translocated 1 - Mastermind-like
2) fusion gene and is also associated with fusion of a novel gene designated WAMTP1 (Warthin and
Mucoepidermoid tumor Translocation Partner gene 1) to the Notch coactivator MAML2 (Mastermind-like
The differential diagnosis consists of necrotizing sialometaplasia (NSM), inverted duct papilloma,
cystadenoma and cystadenocarcinoma, metastatic squamous carcinoma (for high-grade tumors), sebaceous
carcinoma and other clear cell tumors, adenosquamous carcinoma, and, rarely, pleomorphic adenoma. NSM
can rarely simulate low-grade MEC; however, NSM retains the lobular architecture of the normal gland and
has smooth-edged cell nests. It lacks the cystic growth typical of low-grade MEC; intermediate-type
cells are not found. Inverted duct papilloma also contains squamous and mucous secreting cells.
However, the physical arrangement of the latter is somewhat characteristic with a smooth edged
invaginating mass with a central cavity. In both cystadenoma and cystadenocarcinoma there is usually
less stroma between the cysts as compared with MEC, there is usually a papillary component, and the
squamous component typical of MEC is not seen. Metastatic squamous carcinoma typically has more keratin
production than MEC and it does not contain any cells with intracellular mucin, whereas high-grade MEC
will always contain at least a few mucin-containing cells. Sebaceous carcinoma and other clear cell
carcinomas do not usually contain intracellular mucin material in the clear cell population and they lack
intermediate-type cells and goblet cells. Adenosquamous carcinoma is in the differential primarily for
minor gland tumors. It can usually be separated from MEC because these tumors have two distinctly
separate components, squamous and glandular, while in MEC the squamous and mucinous components are
usually intimately associated with each other in the same tumor nests. Rarely, a mixed tumor may have
areas of prominent mucoepidermoid metaplasia or have MEC arise as the malignant component of a carcinoma
ex pleomorphic adenoma. Careful histologic sampling will allow separation from the latter, while the
absence of destructive overgrowth of normal tissues and the presence of stromal myoepithelial cells will
allow separation from the former.
Prognosis is a function of the histologic grade, adequacy of excision, and clinical staging. Complete
surgical excision is the treatment of choice for MEC. Adequate excision is important in all grades of
tumor, with higher recurrence rates reported with positive surgical margins (on the order of 50% for low
and intermediate-grade tumors and slightly over 80% for high-grade tumors). Radiation therapy should be
added in high-grade tumors and in patients with residual microscopic disease at the surgical margins. In
patients with low-grade tumors, the survival rate is 90-100%; with the exception of submandibular gland
tumors, these tumors rarely recur or metastasize. Data from the AFIP indicated that 5% of major gland
and 2.5% of minor gland low-grade MECs metastasized to regional lymph nodes or resulted in
death.  The metastatic rate for high-grade tumors was 55% for the major glands and 80% for
those of minor salivary gland origin.  Metastatic, recurrence and death rates for patients
with low-grade submandibular tumors were 13%, 9%, and 13%, respectively.  Several patients in
this latter series with small (low stage) low-grade tumors with adequate treatment inexplicably died of
disease. Spiro et al.  also found more frequent metastases with submandibular gland MEC than
from other major gland sites and Bhattacharyya found similar 5 and 10 year survivals for low and high
grade submandibular gland tumors ranging from just over 20% to just over 30%.  Therefore,
any submandibular tumor, irrespective of grade, should be treated aggressively. Survival is better with
tumors arising in younger patients and among females; survival is adversely affected in patients > 60
years of age.  Intermediate and high-grade tumors have a greater tendency to infiltrate,
recur, and metastasize, with reported cure rates at 5, 10, and 15 years of 49%, 42%, and 33%,
Plambeck et al.  reported 5- and 10-year survival rates of 91.9%
and 89.5%, respectively, regardless of tumor grade. Stage appeared to be a better prognosticator: all
patients who died had stage 3 or 4 disease, and 5- and 10-year survival rates for this group were 63.5%
and 52%, respectively. In a recent study, Pires et al  found that age > 40 years, tumors
with fixation, T and N stage and histologic grade were all independent prognostic variables. Ki67
activity and p53 staining also corresponded to a poor prognosis while expression of carcinoembryonic
antigen and bcl-2 correlated with a better prognosis. Suzuki et al.  found that MECs that
overexpressed HER-2/neu had lower 5-year survival rates than tumors with weak expression (25% vs 89%).
Activation of extracellular signal-regulated kinases ERK-1 and ERK-2 was found in 39% of
MEC ; tumors with this pathway activated were associated with a more aggressive clinical
course and higher proliferative activity. Recently, several series examined the expression of epithelial
mucins in MEC.
They found that strong staining with MUC1 was related to high histologic
grades, high recurrence and metastatic rates and a shorter disease-free interval while staining with MUC4
was predominantly related to low-grade tumors, lower recurrence rates, and a longer disease-free
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