—  SYMPOSIUM #51  —

Update of Common Salivary Tumors
Moderators: Dr. John Eveson and Dr. Silloo Kapadia

Section 3 - Mucoepidermoid Carcinoma

Doug Gnepp
USA


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. [1, 2, 3] 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. [1, 2] In the minor salivary glands, MEC most commonly arises on the palate, but a significant number may also be found in other intraoral sites. [1, 2, 3] MEC may also rarely occur primarily within the body of the mandible or maxilla [4] and may occasionally arise from heterotopic intra–lymph 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 [5] and is unusual in the first decade of life. MEC has a slight predilection for women, with approximately 60% of tumors arising in women. [1]

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. [6, 7] The mean age between radiation exposure and tumor diagnosis in a recent study was 21 years. [6] Land et al. [8] 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 of radiation.

MECs typically present as slowly growing (up to 40 years), firm, unilateral masses clinically indistinguishable from the more common pleomorphic adenoma. [7] 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. [9]

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. [1] 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. [10]

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) [11] 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 reported. [12]

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 [9, 13, 14, 15, 16].

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. [9, 13, 14, 15, 16, 17, 18, 19] Unfortunately, there is no universally accepted grading system. Auclair, Goode, and Ellis established more uniform and reproducible histologic criteria that correlated with clinical outcome. [13, 16] 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 [18] and did not work as well for submandibular gland tumors. Brandwein et al [18] 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. [19] 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. [17] 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 2). [20, 21]

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. [1] The metastatic rate for high-grade tumors was 55% for the major glands and 80% for those of minor salivary gland origin. [1] Metastatic, recurrence and death rates for patients with low-grade submandibular tumors were 13%, 9%, and 13%, respectively. [1] Several patients in this latter series with small (low stage) low-grade tumors with adequate treatment inexplicably died of disease. Spiro et al. [9] 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%. [22] 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. [23] 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%, respectively. [9] Plambeck et al. [24] 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 [10] 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. [25] 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 [26]; 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. [19, 27] 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 survival.

References
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  15. Hicks JM, El-Naggar AK, Flaitz CM, et al. Histologic grading of mucoepidermoid carcinoma of major salivary glands in prognosis and survival: A clinicopathologic and flow cytometric investigation. Head Neck 1995;17:89–95.

  16. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carcinoma of the major salivary glands: Clinical and histologic analysis of 234 cases with evaluation of grading criteria. Cancer 1998;82:1217–24.

  17. Boahene DKO, Olsen KD, Lewis JE, et al. Mucoepidermoid carcinoma of the parotid gland. Arch Otolaryngol Head Neck Surg 2004;130:849-856.

  18. Brandwein MS, Ivanov K, Wallace DI, et al. Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 2001;25:835-45.

  19. Alos L, Lujan B, Castillo M, et al: Expression of membrane-bound mucins (MUC1 and MUC4) and secreted mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in mucoepidermoid carcinomas of salivary glands. Am J Surg Pathol 2005;29:806-13.

  20. Enlund F, Behboudi A, Andren Y, et al. Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Exp Cell Res 2004;292:21-8.

  21. Martins C, Cavaco B, Tonon G, et al. A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's Tumor of salivary gland. J Mol Diag 2004;6:205-10.

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  23. O'Brien CJ, Soong SJ, Herrera GA, et al. Malignant salivary tumors: Analysis of prognostic factors and survival. Head Neck Surg 1986;9:82–92.

  24. Plambeck K, Friedrich RE, Heller D, et al. Mucoepidermoid carcinoma of the salivary glands: Clinical data and follow-up of 52 cases. J Cancer Res Clin Oncol 1996;122:177–80.

  25. Suzuki M, Ichimiya I, Matsushita F, et al. Histologic features and prognosis of patients with mucoepidermoid carcinoma of the parotid gland. J Laryngol Otol 1998;112:944–7.

  26. Handra-Luca A, Bilal H, Bertrand JC, et al. Extra-cellular signal-regulated ERK-1/ERK-2 pathway activation in human salivary gland mucoepidermoid carcinoma. Am J Pathol 2003;163:957-67.

  27. Handra-Luca A, Lamas G, Bertrand JC, et al. MUC1, MUC2, MUC4 and MUC5AC expression in salivary gland mucoepidermoid carcinoma. Am J Surg Pathol 2005;29:881-9.