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
M
alignant salivary gland epithelial tumors are histologically diverse with at least 24 recognized distinct entities. In general, malignant tumors account for 15% to 30% of parotid tumors, 40% to 45% of submandibular tumors, 70% to 90% of sublingual tumors, and 50% of minor salivary tumors. Common malignancies include mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, salivary duct carcinoma, carcinoma ex pleomorphic adenoma, polymorphous low-grade adenocarcinoma, and myoepithelial carcinoma. Each tumor type has its own unique histologic variants and prognostic pathologic features, and only mucoepidermoid carcinomas have a formalized grading system. The molecular pathogenesis of certain tumors, such as mucoepidermoid carcinoma and adenoid cystic carcinoma, has recently begun to be elucidated.
OVERVIEW Salivary tumors are uncommon, accounting for 2.0% to 6.5% of all neoplasms of the head and neck with a worldwide incidence of about 0.4 to 6.5 cases per 100,000 population.1 According to Ellis and Auclair,2 approximately 60% to 80% of all primary epithelial neoplasms occur in the parotid gland, 5% to 10% in the submandibular gland, less than 1% in the sublingual gland, and 10% to 25% in the minor glands. Depending on the series,
50% to 80% of all salivary neoplasms are benign and 20% to 50% are malignant. The probability of malignancy is inversely proportional to the volume of salivary tissue. In general, malignant tumors account for 15% to 30% of parotid tumors, 40% to 45% of submandibular tumors, 70% to 90% of sublingual tumors, and 50% of minor salivary tumors.2 A comprehensive review of all tumors is not possible but can be found in other sources.1–4 The World Health Organization currently recognizes 13 benign and 24 malignant primary epithelial neoplasms of salivary origin.1 The focus of this article is on the more commonly encountered malignant epithelial neoplasms (Box 1).
MUCOEPIDERMOID CARCINOMA OVERVIEW Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy overall in adults and children, with a peak incidence in the fifth decade. As with most salivary gland tumors, there is a slight female predilection with a male: female ratio of approximately 1.5:1.0 in most series.2,5 It is primarily a tumor of the major salivary glands (50% to 60%), and most frequently involves the parotid gland. Of the minor salivary gland sites, the palate is by far the most common (20% to 25% of MEC overall). Of note, palate tumors tend to occur in a slightly younger age group, whereas other minor salivary sites are rarely seen
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: [email protected]
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.
surgpath.theclinics.com
ABSTRACT
1178
Seethala & Barnes
Box 1 Commonly encountered malignant salivary gland epithelial tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Salivary duct carcinoma Carcinoma ex pleomorphic adenoma Polymorphous low-grade adenocarcinoma Myoepithelial carcinoma
in patients younger than 30 years. Rare case of intraosseous or “central” mucoepidermoid carcinomas have been described and comprise only 1% to 2% of most cohorts.2,5,6 MEC typically presents as a well-circumscribed, painless mass that is present on average for 1.5 years in the Armed Forces Institute of Pathology (AFIP) database.2,7,8 Longer durations of up to 20 years have been reported, suggesting that many of these tumors are quite slow growing. Pain and facial nerve paralysis can be associated with highgrade lesions, but is reported in only about 8% of all MEC.2 Occasionally, cystic tumors may rupture, resulting in an inflammatory response that presents with pain. Superficial palate lesions may ulcerate. MEC is also the most common salivary gland tumor seen in the postirradiation setting, both in the pediatric and adult populations comprising
Key Features MUCOEPIDERMOID CARCINOMA Mucoepidermoid carcinoma is the most common malignant salivary gland tumor in adults and children. Tumors are composed of varying proportions of mucous, intermediate, and epidermoid cell types arranged in solid or cystic growth patterns. Common variant morphologies include clearcell, oncocytic, and sclerosing variants. Histologic grade is one of the most important prognosticators, although there is considerable variation in grading schemes, particularly with respect to intermediate grade. The t(11;19)(q21;p13) CRTC1-MAML2 translocation is frequent in mucoepidermoid carcinomas and may be a favorable prognosticator.
almost half of postirradiation salivary gland tumors. MEC typically arises 1 to 2 decades after irradiation.9,10 MECs are rarely multifocal or bilateral, but they have been described in association with other tumors such as pleomorphic adenoma, Warthin tumor, and oncocytoma.11,12 The relationship between MEC and these other entities, however, is controversial.
GROSS FEATURES 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 MEC tends to have more of a solid tan appearance, although these are still well demarcated. Highgrade MEC, however, may be an infiltrative tanwhite with some degree of surrounding fibrosis.2,5 Oncocytic MEC may mimic the gross appearance of an oncocytoma or a Warthin tumor with a deeper brown cut surface.13 Cyst contents in MECs are typically viscous and mucoid with varying degrees of hemorrhage. Subcentimeter tumors are fairly common in the minor oral salivary glands, although overall, tumors are typically 3 to 4 cm.
MICROSCOPIC FEATURES MECs are thought to recapitulate the cell types seen in large excretory ducts, and are composed of 3 basic cell types: intermediate cells, epidermoid 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 dark nuclei with inconspicuous nuclei surrounded 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 types.14 Intermediate cells are often arranged in solid nests, although other elements may be interspersed. Mucous cells represent ductoacinar differentiation in MEC. They range from ovoid to columnar and characteristically line cystic spaces, although are occasionally seen singly. Epidermoid cells on the other hand represent squamous differentiation in MEC. These cells are larger and more polygonal than intermediate cells and have more densely eosinophilic cytoplasm. Welldeveloped squamous features, such as keratinization and prominent intercellular bridges, are highly uncommon.6 Columnar cells are also a form of ductal differentiation and are found only lining cysts or luminae. These are typically interspersed between mucous cells and have eosinophilic cytoplasm. In addition
Common Malignant Salivary Gland Epithelial Tumors Fig. 1. Cell types in MEC. MEC consist of a mixture of mucous cells (short broad arrow, top right), epidermoid cells (medium arrow, bottom left), and intermediate cells (double long slender arrows) (hematoxylin-eosin [H&E], original magnification 100). Clear-cell change is fairly common.
to these basic cell types, there are some fairly common modifications that can affect any cell type, namely clear-cell change and oncocytic change, leading to the designation of clear-cell MEC or oncocytic MEC variants when prominent.13 The stroma surrounding tumor nests is often sclerotic with varying levels of lymphoplasmacytic inflammation. Tumors with heavy sclerosis are often labeled as “sclerosing MEC.”15 Some MECs may show a prominent lymphoid stroma with germinal centers resembling that seen in Warthin tumor. These cytoarchitectural features, along with other features of oncologic potential, such as perineural invasion, angiolymphatic invasion, tumor border, necrosis, anaplasia, and mitotic activity, are integrated into a variety of commonly used grading schemes (Table 1).16 Although the specific grade of a tumor varies depending on grading system used, in general, cystic, well-demarcated tumors with a prominent mucous cell component are low grade (Fig. 2); solid, intermediate-cell predominant tumors are intermediate grade (Fig. 3); and infiltrative, anaplastic tumors with a prominent epidermoid component are high grade (Fig. 4). Immunohistochemically, mucous and columnar cells show a ductal staining pattern and are positive for low molecular weight cytokeratins (CK7, CK 18, CK 19) and negative for p63, whereas the epidermoid and intermediate cells are typically positive for high molecular weight cytokeratins
(ie, CK 5/6) and p63.2,5,13 Regarding mucin (MUC) proteins, the membrane-bound MUC1 and MUC4 are expressed in all cell types in MEC, although MUC1 increases with highergrade tumors, whereas MUC4 decreases with higher-grade tumors. Secretory MUC proteins, such as MUC 2, 5AC, 5B, 6, and 7, are variably expressed and tend to favor mucous and intermediate cells.17
DIFFERENTIAL DIAGNOSIS Classic low-grade and intermediate-grade MECs are diagnostically straightforward. However, highgrade MEC and tumors with variant morphologies may be diagnostically challenging. The main diagnostic challenges for high-grade MEC include adenosquamous carcinoma (primary or intra/periglandular lymph node metastases), and salivary duct carcinoma with mucin production. In the oral cavity, the overlying mucosa should be examined thoroughly to exclude the presence of a mucosal dysplasia or carcinoma in situ, which would point to a diagnosis of adenosquamous carcinoma. In the parotid, if a prior history of a cutaneous or mucosal carcinoma exists, this should be compared with the parotid lesion because it would likely represent a metastasis.6 Adenosquamous carcinomas tend to be more pleomorphic, infiltrative, mitotically active, and heavily keratinizing (Fig. 5). They lack a monomorphic intermediate
1179
1180
Seethala & Barnes
Table 1 Common grading schemes in MEC Modified Healey22
AFIP21
Brandwein23
Qualitative
Point Based
Point Based
Low Grade Macrocysts, microcysts, transition with excretory ducts Differentiated mucinproducing epidermoid cells, often in a 1:1 ratio; minimal to moderate intermediate cell population Daughter cyst proliferation from large cysts Minimal to absent pleomorphism, rare mitoses Broad-front, often circumscribed invasion Pools of extravasated mucin with stromal reaction Intermediate Grade No macrocysts, few microcysts, solid nests of cells Large duct not conspicuous Slight to moderate pleomorphism, 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 No macrocysts, predominantly solid but may be nearly all glandular Cell constituents range from poorly differentiated to recognizable epidermoid and intermediate 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
Intracystic component
M
alignant salivary gland epithelial tumors are histologically diverse with at least 24 recognized distinct entities. In general, malignant tumors account for 15% to 30% of parotid tumors, 40% to 45% of submandibular tumors, 70% to 90% of sublingual tumors, and 50% of minor salivary tumors. Common malignancies include mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, salivary duct carcinoma, carcinoma ex pleomorphic adenoma, polymorphous low-grade adenocarcinoma, and myoepithelial carcinoma. Each tumor type has its own unique histologic variants and prognostic pathologic features, and only mucoepidermoid carcinomas have a formalized grading system. The molecular pathogenesis of certain tumors, such as mucoepidermoid carcinoma and adenoid cystic carcinoma, has recently begun to be elucidated.
OVERVIEW Salivary tumors are uncommon, accounting for 2.0% to 6.5% of all neoplasms of the head and neck with a worldwide incidence of about 0.4 to 6.5 cases per 100,000 population.1 According to Ellis and Auclair,2 approximately 60% to 80% of all primary epithelial neoplasms occur in the parotid gland, 5% to 10% in the submandibular gland, less than 1% in the sublingual gland, and 10% to 25% in the minor glands. Depending on the series,
50% to 80% of all salivary neoplasms are benign and 20% to 50% are malignant. The probability of malignancy is inversely proportional to the volume of salivary tissue. In general, malignant tumors account for 15% to 30% of parotid tumors, 40% to 45% of submandibular tumors, 70% to 90% of sublingual tumors, and 50% of minor salivary tumors.2 A comprehensive review of all tumors is not possible but can be found in other sources.1–4 The World Health Organization currently recognizes 13 benign and 24 malignant primary epithelial neoplasms of salivary origin.1 The focus of this article is on the more commonly encountered malignant epithelial neoplasms (Box 1).
MUCOEPIDERMOID CARCINOMA OVERVIEW Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy overall in adults and children, with a peak incidence in the fifth decade. As with most salivary gland tumors, there is a slight female predilection with a male: female ratio of approximately 1.5:1.0 in most series.2,5 It is primarily a tumor of the major salivary glands (50% to 60%), and most frequently involves the parotid gland. Of the minor salivary gland sites, the palate is by far the most common (20% to 25% of MEC overall). Of note, palate tumors tend to occur in a slightly younger age group, whereas other minor salivary sites are rarely seen
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: [email protected]
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.
surgpath.theclinics.com
ABSTRACT
1178
Seethala & Barnes
Box 1 Commonly encountered malignant salivary gland epithelial tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Salivary duct carcinoma Carcinoma ex pleomorphic adenoma Polymorphous low-grade adenocarcinoma Myoepithelial carcinoma
in patients younger than 30 years. Rare case of intraosseous or “central” mucoepidermoid carcinomas have been described and comprise only 1% to 2% of most cohorts.2,5,6 MEC typically presents as a well-circumscribed, painless mass that is present on average for 1.5 years in the Armed Forces Institute of Pathology (AFIP) database.2,7,8 Longer durations of up to 20 years have been reported, suggesting that many of these tumors are quite slow growing. Pain and facial nerve paralysis can be associated with highgrade lesions, but is reported in only about 8% of all MEC.2 Occasionally, cystic tumors may rupture, resulting in an inflammatory response that presents with pain. Superficial palate lesions may ulcerate. MEC is also the most common salivary gland tumor seen in the postirradiation setting, both in the pediatric and adult populations comprising
Key Features MUCOEPIDERMOID CARCINOMA Mucoepidermoid carcinoma is the most common malignant salivary gland tumor in adults and children. Tumors are composed of varying proportions of mucous, intermediate, and epidermoid cell types arranged in solid or cystic growth patterns. Common variant morphologies include clearcell, oncocytic, and sclerosing variants. Histologic grade is one of the most important prognosticators, although there is considerable variation in grading schemes, particularly with respect to intermediate grade. The t(11;19)(q21;p13) CRTC1-MAML2 translocation is frequent in mucoepidermoid carcinomas and may be a favorable prognosticator.
almost half of postirradiation salivary gland tumors. MEC typically arises 1 to 2 decades after irradiation.9,10 MECs are rarely multifocal or bilateral, but they have been described in association with other tumors such as pleomorphic adenoma, Warthin tumor, and oncocytoma.11,12 The relationship between MEC and these other entities, however, is controversial.
GROSS FEATURES 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 MEC tends to have more of a solid tan appearance, although these are still well demarcated. Highgrade MEC, however, may be an infiltrative tanwhite with some degree of surrounding fibrosis.2,5 Oncocytic MEC may mimic the gross appearance of an oncocytoma or a Warthin tumor with a deeper brown cut surface.13 Cyst contents in MECs are typically viscous and mucoid with varying degrees of hemorrhage. Subcentimeter tumors are fairly common in the minor oral salivary glands, although overall, tumors are typically 3 to 4 cm.
MICROSCOPIC FEATURES MECs are thought to recapitulate the cell types seen in large excretory ducts, and are composed of 3 basic cell types: intermediate cells, epidermoid 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 dark nuclei with inconspicuous nuclei surrounded 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 types.14 Intermediate cells are often arranged in solid nests, although other elements may be interspersed. Mucous cells represent ductoacinar differentiation in MEC. They range from ovoid to columnar and characteristically line cystic spaces, although are occasionally seen singly. Epidermoid cells on the other hand represent squamous differentiation in MEC. These cells are larger and more polygonal than intermediate cells and have more densely eosinophilic cytoplasm. Welldeveloped squamous features, such as keratinization and prominent intercellular bridges, are highly uncommon.6 Columnar cells are also a form of ductal differentiation and are found only lining cysts or luminae. These are typically interspersed between mucous cells and have eosinophilic cytoplasm. In addition
Common Malignant Salivary Gland Epithelial Tumors Fig. 1. Cell types in MEC. MEC consist of a mixture of mucous cells (short broad arrow, top right), epidermoid cells (medium arrow, bottom left), and intermediate cells (double long slender arrows) (hematoxylin-eosin [H&E], original magnification 100). Clear-cell change is fairly common.
to these basic cell types, there are some fairly common modifications that can affect any cell type, namely clear-cell change and oncocytic change, leading to the designation of clear-cell MEC or oncocytic MEC variants when prominent.13 The stroma surrounding tumor nests is often sclerotic with varying levels of lymphoplasmacytic inflammation. Tumors with heavy sclerosis are often labeled as “sclerosing MEC.”15 Some MECs may show a prominent lymphoid stroma with germinal centers resembling that seen in Warthin tumor. These cytoarchitectural features, along with other features of oncologic potential, such as perineural invasion, angiolymphatic invasion, tumor border, necrosis, anaplasia, and mitotic activity, are integrated into a variety of commonly used grading schemes (Table 1).16 Although the specific grade of a tumor varies depending on grading system used, in general, cystic, well-demarcated tumors with a prominent mucous cell component are low grade (Fig. 2); solid, intermediate-cell predominant tumors are intermediate grade (Fig. 3); and infiltrative, anaplastic tumors with a prominent epidermoid component are high grade (Fig. 4). Immunohistochemically, mucous and columnar cells show a ductal staining pattern and are positive for low molecular weight cytokeratins (CK7, CK 18, CK 19) and negative for p63, whereas the epidermoid and intermediate cells are typically positive for high molecular weight cytokeratins
(ie, CK 5/6) and p63.2,5,13 Regarding mucin (MUC) proteins, the membrane-bound MUC1 and MUC4 are expressed in all cell types in MEC, although MUC1 increases with highergrade tumors, whereas MUC4 decreases with higher-grade tumors. Secretory MUC proteins, such as MUC 2, 5AC, 5B, 6, and 7, are variably expressed and tend to favor mucous and intermediate cells.17
DIFFERENTIAL DIAGNOSIS Classic low-grade and intermediate-grade MECs are diagnostically straightforward. However, highgrade MEC and tumors with variant morphologies may be diagnostically challenging. The main diagnostic challenges for high-grade MEC include adenosquamous carcinoma (primary or intra/periglandular lymph node metastases), and salivary duct carcinoma with mucin production. In the oral cavity, the overlying mucosa should be examined thoroughly to exclude the presence of a mucosal dysplasia or carcinoma in situ, which would point to a diagnosis of adenosquamous carcinoma. In the parotid, if a prior history of a cutaneous or mucosal carcinoma exists, this should be compared with the parotid lesion because it would likely represent a metastasis.6 Adenosquamous carcinomas tend to be more pleomorphic, infiltrative, mitotically active, and heavily keratinizing (Fig. 5). They lack a monomorphic intermediate
1179
1180
Seethala & Barnes
Table 1 Common grading schemes in MEC Modified Healey22
AFIP21
Brandwein23
Qualitative
Point Based
Point Based
Low Grade Macrocysts, microcysts, transition with excretory ducts Differentiated mucinproducing epidermoid cells, often in a 1:1 ratio; minimal to moderate intermediate cell population Daughter cyst proliferation from large cysts Minimal to absent pleomorphism, rare mitoses Broad-front, often circumscribed invasion Pools of extravasated mucin with stromal reaction Intermediate Grade No macrocysts, few microcysts, solid nests of cells Large duct not conspicuous Slight to moderate pleomorphism, 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 No macrocysts, predominantly solid but may be nearly all glandular Cell constituents range from poorly differentiated to recognizable epidermoid and intermediate 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
Intracystic component
