Tumors of the salivary gland represent relatively rare neoplasms. Still, in spite of their scarcity, they demonstrate a wide spectrum of disease across both benign and malignant lesions. The purpose of this review is to provide a practical overview of the pathology of the more common salivary gland neoplasms, covering the morphologic, immunophenotypic, and molecular profiles with an emphasis on unique diagnostic challenges and prognostic indicators.
Keywords
Introduction
The histopathology of salivary gland tumors has always been complex and a difficult area for pathologists to reach consensus. This is related to the varied patterns of the neoplasms and the marked overlap among several lesions and between those that were benign versus malignant.
In the past 10 years, however, this complexity has grown as newer entities have been recognized and their clinical features and behavior have been described. Hence, secretory carcinoma (SC) has been separated from acinic cell carcinoma (AcCC) and its distinct molecular and clinical signatures have been noted. Similarly, salivary duct carcinoma (SDC) has been shown to represent an important percentage of “carcinoma ex mixed tumor” and its immunoprofile has allowed for comparison to invasive ductal carcinoma of the breast and its differences to other salivary gland malignancies.
Finally, just as the histologic morphology of these lesions is complex, the cytologic appearances are even more so. The recent “Milan System for Reporting Salivary Gland Cytology (MSRSGC)” is the latest attempt to allow for Fine-Needle aspiration (FNA) classification of these lesions to better assist in their preoperative diagnosis.
1.
The Milan System for Reporting Salivary Gland Cytology is a tiered classification scheme consisting of 6 diagnostic categories: nondiagnostic, non-neoplastic, atypical, neoplasm, suspicious for malignancy and malignant. The neoplasm category is further subdivided into 2 categories: benign neoplasm, and salivary gland neoplasm of uncertain malignant potential. Each diagnostic category is associated with ranges of rate of malignancy and possible clinical management recommendations.This review will describe and discuss the major salivary gland neoplasms, their morphology and, where known, their relevant immuno- and molecular profiles. The ever-expanding knowledge in this area offers hope for better diagnostic categorization and in the future for targeted therapeutic approaches to such tumors.
Benign salivary gland neoplasms
Pleomorphic adenoma
The most common salivary gland tumor in children and adults is the pleomorphic adenoma (PA, also known as benign mixed tumor), a benign neoplasm that occurs predominantly in the parotid gland, followed by the minor salivary glands (especially the palate) and the submandibular gland, among other sites. This neoplasm occurs in individuals of all ages, with a peak incidence in the fourth to fifth decade and a predilection for females (2:1). Although it can show a wide range of morphologic features, it is essentially a biphasic tumor composed of luminal ductal epithelial cells and abluminal myoepithelial cells embedded within a mesenchymal stroma. Depending on the proportion of the cellular constituents, PAs can be categorized as myxoid type (80% stroma), cellular type (80% cellular), or the classic mixed type. The myxoid type is more prone to recurrence, with recurrent tumors often presenting as multifocal nodules.
Grossly, like most benign neoplasms of the salivary gland, they present as:
- •A solitary, well-circumscribed, variably encapsulated, round-to-oval mass (Figure 1A).
![Fig 1]()
Figure 1Pleomorphic adenoma. Grossly, these tumors are well circumscribed with lobulated borders, firm and tan-white (A). Myoepithelial cells are seen streaming off tubular structures into a mucochondroid stroma (B). Recurrent pleomorphic adenoma presenting as multiple nodules, also known as satellitosis (C). - •The appearance of the cut surface depends on the elements comprising the tumor.
- ○Cellular tumors may have a firm, tan-white appearance.
- ○Myxoid tumors may be more gelatinous.
- ○A cartilaginous component may impart a translucent sheen to the interior.
- ○
By light microscopy:
- •Ductal epithelial cells form tubules and cysts, and overall comprise a small portion of the cell population.
- •The remaining cellularity consists of myoepithelial cells, often seen streaming off into the stroma as tubular structures, sheets, nests, trabeculae, or singly scattered cells (Figure 1B).
- •The stroma is typically mucochondroid and variably collagenized, ranging from loose and myxoid to hyalinized. Chondroid, fatty, or osseous elements may be seen.
- •A notable feature of PAs is the presence of pseudopodia, which are small transcapsular, myxoid, and hypocellular projections of tumor into surrounding tissue.
- •Pseudopodia can be transected during surgery, resulting in recurrence often in the form of multicentric nodules, a process called satellitosis (Figure 1C).
On fine-needle aspiration:
- •The biphasic nature of the tumor can be readily appreciated.
- •Bland ductal epithelial cells with round-to-ovoid nuclei, small nucleoli and moderately abundant cytoplasm form cohesive groups.
- •Myoepithelial cells can demonstrate a spectrum of appearances including spindled (most common), plasmacytoid, clear, stellate, and epithelioid, and may be individually scattered or arranged in loose clusters within a characteristically fibrillary matrix that stains bright magenta (“metachromatic”) on Romanowsky-stained preparations and pale purple or blue on Papanicolaou-stained smears.
- •Cellular PAs comprising mostly of cells with a limited stromal component are often diagnosed as a salivary gland neoplasm with basaloid features in FNA specimens.
Approximately 70% of PAs demonstrate intrachromosomal rearrangements or translocations involving transcription factor genes PLAG1 on 8q12 (>50% of cases) and HMGA2 on 12q14-15 (10%-15% of cases).
2.
As PLAG1 or HMGA2 fusions have not been identified in other salivary gland neoplasms, except for carcinoma ex PA,3.
these biomarkers may be helpful in the diagnosis of challenging cases showing overlapping morphologies with other salivary gland tumors (Table).TableGenetic alterations in salivary gland neoplasms
| Tumor Type | Genetic Alteration | Chromosome | Frequency, % |
|---|---|---|---|
| Benign lesions | |||
| Pleomorphic adenoma | PLAG1 rearrangement | 8q12 | >50 |
| HMGA2 rearrangement | 12q14-15 | 10-15 | |
| Basal cell adenoma | |||
| Tubulotrabecular pattern | CTNNB1 mutation | 3p22 | >50 |
| Membranous pattern | CYLD loss of heterozygosity | 16q12.1 | 75-80 |
| Malignant lesions | |||
| Mucoepidermoid carcinoma | CRTC1-MAML2 fusion | t(11;19)(q21;p13) | ∼70 |
| CRTC3-MAML2 fusion | t(11;15)(q21;q26) | 5 | |
| Adenoid cystic carcinoma | MYB-NFIB fusion | t(6;9)(q22-23;p23-24) | >50 |
| Polymorphous adenocarcinoma | PRKD1 E710D mutation | 14q12 | ∼75 |
| PRKD1, PRKD2, PRKD3 rearrangement | 14q12, 19q13.32, 2p21 | <10 | |
| Cribriform adenocarcinoma of minor salivary glands | PRKD1, PRKD2, PRKD3 rearrangement | 14q12, 19q13.32, 2p21 | ∼80 |
| PRKD1 E710D mutation | 14q12 | <10 | |
| Acinic cell carcinoma | MSANTD3 rearrangements | 9q31.1 | ∼15% |
| Secretory carcinoma | ETV6-NTRK3 fusion | t(12;15)(p13;q25) | >95 |
| Other ETV6 rearrangement | 12p13 | <5 | |
| Salivary duct carcinoma | ERBB2 amplification | 17q21.1 | ∼40 |
| TP53 mutation | 17p13.1 | ∼50 | |
| PIK3CA mutation | 3q26.32 | ∼20 | |
| Epithelial-myoepithelial carcinoma | HRAS mutation | 11p15.5 | ∼30 |
| Clear cell carcinoma | EWSR1-ATF1 fusion | t(12;22)(q21;q12) | 80-90 |
Warthin tumor
Warthin tumor (WT, also known as papillary cystadenoma lymphomatosum), almost exclusively seen in the parotid, is the second most common salivary gland tumor, typically affecting adults in their sixth to seventh decade with a slight male predominance. This neoplasm is frequently bilateral or multifocal and thought to arise from entrapped salivary duct remnants in intraparotid or periparotid lymph nodes during embryologic development, resulting in a tumor composed of epithelial and lymphoid cells.
Grossly, these tumors present as:
- •A well-circumscribed, soft, round-to-ovoid mass.
- •Cut sections reveal a multicystic interior containing thick, mucoid yellow-brown fluid that has been likened to “motor oil” (Figure 2A).
![Fig 2]()
Figure 2Grossly, note the brown motor oil-like material characteristic of this nodule (A). These tumors are characterized by papillary projections (B) composed of a bilayered oncocytic epithelium overlying a reactive lymphoid stroma (C).
By light microscopy:
- •WT manifests as cysts with papillary projections containing a reactive lymphoid core lined by a dual layer of oncocytic epithelial cells (Figure 2B).
- •The luminal layer of the epithelium consists of tall columnar cells that overlie a row of basal cuboidal cells, a parallel nuclear arrangement that resembles tram tracks (Figure 2C).
- •Within the cystic spaces, desquamated epithelial cells, lymphocytes, thick secretions, and debris may be seen.
On fine-needle aspiration:
- •A dominant population of polymorphous lymphocytes is admixed with varying amounts of oncocytes either in a honeycomb arrangement or less commonly, as papillary groups or a bilayer.
- •The oncocytes have uniformly round, large nuclei with variably prominent nucleoli, even chromatin, distinct cell borders and abundant granular cytoplasm that appears deep blue with the Romanowsky stain and orange-pink to blue on the Papanicolaou stain.
- •An aspirate will typically show granular debris in the background.
A rare subset of WTs has a t(11;19)(q21-22;p13) translocation resulting in a CRTC1-MAML2 fusion gene, the same translocation observed in mucoepidermoid carcinomas (MEC).
4.
, 5.
These tumors may signal the early development of a MEC within a WT or a misdiagnosed MEC.6.
, 7.
Basal cell adenoma
Basal cell adenoma is a very rare tumor mostly seen in the major salivary glands, in particular, the parotid, followed by the submandibular gland. This tumor tends to occur in elderly adults with a peak incidence in the sixth decade and a slight female predominance. This is a biphasic neoplasm composed of basaloid epithelial and myoepithelial cells, likely derived from intercalated or striated ducts.
Grossly, these tumors manifest as:
- •A well-circumscribed, encapsulated nodule with a homogeneous, solid, or partially cystic pink-tan cut surface.
By light microscopy:
- •Two basaloid cell populations are noted. Small basaloid myoepithelial cells with scant cytoplasm, indistinct cell borders, and deeply basophilic round-to-oval nuclei palisade peripherally around a cluster of cells that are larger with more abundant cytoplasm and pale nuclei (Figure 3A and B).
![Fig 3]()
Figure 3Basal cell adenoma. This well-circumscribed tumor (A) is composed of smaller basaloid cells with scant cytoplasm palisading around larger cells with more abundant cytoplasm (B). - •Several architectural subtypes are recognized—solid, trabecular, tubular, and membranous in order of decreasing frequency.
- •The membranous type, characterized by nests of basaloid cells containing and surrounded by eosinophilic hyaline material simulating a jigsaw puzzle-like pattern, is notable for frequently displaying multinodular, unencapsulated growth, which may mimic invasion.
On fine-needle aspiration:
- •Smears are cellular with sheets and syncytial fragments of uniformly bland basaloid cells, of which 2 populations may be appreciated.
- •Frequently associated with the cells is a dense nonfibrillary hyaline matrix that appears basophilic to metachromatic on Romanowsky stain and eosinophilic or blue on the Papanicolaou stain.
- •Small hyaline globules may also be present.
- •Due to the presence of basaloid cells and hyaline globules in an FNA specimen, it may be difficult to distinguish these from adenoid cystic carcinoma (AdCC).
The tubulotrabecular pattern is associated with activating CTNNB1 mutations, which may manifest as nuclear beta-catenin and/or lymphoid enhancer-binding factor 1 staining.
8.
, 9.
Loss of heterozygosity for the CYLD gene has also been demonstrated in the membranous subtype.10.
Myoepithelioma
Myoepithelioma is a very rare salivary gland tumor, often seen in the parotid gland, followed by the hard and soft palate. This neoplasm mostly occurs in adults with a peak incidence in the third decade and no sex predilection.
- •These tumors are well-circumscribed, variably encapsulated, and rubbery with a tan-yellow cut surface. As the name suggests, they are composed entirely of myoepithelial cells.
- •The cells are found in nests, cords, fascicles, or a reticular arrangement within a variably collagenized background (Figure 4).
![Fig 4]()
Figure 4Myoepithelioma. Embedded within a collagenized stroma are bland and epithelioid myoepithelial cells with varying amounts of eosinophilic cytoplasm. - •Abundant myxoid stroma occasionally may be present.
- •Cytology smears show bland spindled, plasmacytoid, epithelioid, or clear cells, singly scattered or in clusters, with fine-to-coarse chromatin and varying amounts of eosinophilic cytoplasm.
- •The cells resemble the myoepithelial cells seen in a PA but without the characteristic chondromyxoid matrix or any epithelial cells.
Oncocytoma
An oncocytoma is an uncommon neoplasm that usually presents as a discrete nodule, most commonly in the parotid but also in the submandibular and minor salivary glands. On occasion they may present as multifocal or bilateral disease. They tend to present in the sixth to eighth decade with an equivalent predilection for males and females.
- •They are made of oncocytes, which characteristically have ample granular, eosinophilic cytoplasm, sometimes with clear cell change, centrally located nuclei and occasionally prominent nucleoli (Figure 5A and B).
![Fig 5]()
Figure 5Oncocytoma. This well-circumscribed oncocytoma (A) is composed of cells with ample eosinophilic cytoplasm and centrally located nuclei with occasionally prominent nucleoli (B). - •Architectural patterns include solid, acinar, follicular, trabecular, papillary, or cystic.
- •The oncocytes are seen in abundance in smears as sheets, clusters, or single cells in a clean background with no lymphocytes.
- •The cytoplasm appears deep blue with the Romanowsky stain and orange-pink to blue with the Papanicolaou stain.
Canalicular adenoma
Canalicular adenoma is a very rare tumor occurring in the fourth to seventh decade with a slight predilection for males. This tumor is thought to originate from the excretory duct and characteristically occurs in the minor salivary glands, particularly those of the upper lip.
- •They present as a single or multiple well-delineated but unencapsulated nodules composed of chains or tubules of cuboidal to columnar cells with basophilic oval nuclei, finely dispersed chromatin, and scant to moderate amounts of eosinophilic cytoplasm.
- •The cords are seen running parallel to each other and then connecting and separating, creating a beaded appearance with canal-like spaces in between the points of attachment (Figure 6).
![Fig 6]()
Figure 6Canalicular adenoma. Basophilic cells are seen creating canal-like spaces. - •Most tumors are cystic and have a loose, myxoid, and fibrillary stroma.
Cystadenoma
Cystadenoma is a rare tumor of the minor and major salivary glands, typically presenting in the sixth to seventh decade and almost 2-3 times more common in women than men. The parotid gland is involved in up to 50% of cases, followed by the minor glands of the lip and buccal mucosa.
- •They present as well-circumscribed but variably encapsulated nodules composed of a single or multiple cysts, separated by thin fibrous tissue and containing intraluminal papillary projections (Figure 7).
![Fig 7]()
Figure 7Cystadenoma. This cystadenoma is multicystic with oncocytic papillary projections. - •The epithelial lining is bland cuboidal to columnar and may show oncocytic differentiation as well as apocrine or squamous differentiation with admixed mucous cells.
- •Eosinophilic material and epithelial, inflammatory or foamy cells may be seen inside the cysts.
Ductal papilloma
Ductal papilloma is a rare tumor of adults with no sex or age predilection, most common in the oral minor salivary glands but also seen in the parotid and other major salivary glands. Depending on the growth pattern, this entity can be categorized as intraductal or inverted.
- •Intraductal papillomas originate in the terminal portion of excretory ducts and are characterized by a cystic cavity containing broad, exophytic papillary fronds, lined by cuboidal to columnar cells with eosinophilic cytoplasm and mucocytes.
- •Inverted ductal papillomas, in contrast, demonstrate an unencapsulated endophytic growth of monotonous squamoid and basaloid cells. The proliferation has thick, bulbous contours, centered around thin fibrovascular cores.
Sebaceous adenoma
Sebaceous adenoma is a very rare tumor of adults, slightly more common in males with a peak incidence in the sixth decade. The majority occurs in the major salivary glands with the remainder seen in the minor salivary glands of the buccal mucosa or lower molar region. Unlike cutaneous sebaceous adenomas, those occurring in the salivary gland are not associated with Muir-Torre syndrome.
- •These well-circumscribed tumors are made of variably sized nests of bland sebaceous cells, often with cystic change and squamous differentiation. The sebaceous component can vary from minimal to abundant, and occasional oncocytic metaplasia or mucocytes may be seen.
- •The background stroma is typically fibrous.
Lymphadenoma
Lymphadenoma is a rare tumor of children and adults with no sex or age predilection, most commonly seen in the parotid gland (>80% of cases). Most are in the form of sebaceous lymphadenomas, but up to a third of cases are nonsebaceous.
- •These tumors are solid or cystic and characterized by a dual population of epithelial and lymphoid cells. The epithelial component consists of basaloid cells forming nests, cords, or tubuloglandular structures, juxtaposed with reactive lymphoid follicles.
- •The cysts are variably sized with a cuboidal to columnar or squamoid lining, and may be associated with eosinophilic, basement membrane-like material.
- •Sebaceous lymphadenomas, like the name suggests, show sebaceous differentiation. After an FNA, sebum may leak out, inciting a granulomatous response in the surrounding tissue and triggering squamous differentiation.
Malignant tumors of salivary glands
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor, comprising about 30% of all salivary gland malignancies over a wide age distribution that includes children to adults.
11.
Roughly half of cases arise in the major salivary glands, with the majority of these occurring in the parotid gland.12.
, 13.
, 14.
The incidence is equal between genders12.
,15.
, 16.
, - Goode RK
- Auclair PL
- Ellis GL
Mucoepidermoid carcinoma of the major salivary glands: Clinical and histopathologic analysis of 234 cases with evaluation of grading criteria.
Cancer. 1998; 82: 1217-1224https://doi.org/10.1002/(SICI)1097-0142(19980401)82:7<1217::AID-CNCR2>3.0.CO;2-C
17.
; however, lesions in male patients tend to occur later in life and are more likely to be high grade.18.
Grossly, these tumors present as:
- •Different morphologies depending on the grade of the tumor.
- •Low-grade tumors are well circumscribed though only rarely encapsulated. Cut sections reveal gray-white to pink lobulated lesions with variable amounts of cystic change demonstrating mucoid material11.(Figure 8A).
![Fig 8]()
Figure 8Mucoepidermoid carcinoma. Grossly, low to intermediate grade lesions are often well circumscribed and demonstrate a gray-white lobulated cut surface (A). Histology reveals a tumor with the characteristic squamoid, intermediate, and mucinous cell types (B). - •Intermediate to high-grade lesions generally demonstrate more infiltrative borders and less lobulation on cut sections. Cystic regions are less prominent and are usually hemorrhagic when present.11.
By light microscopy:
- •This tumor is defined histologically by the presence of squamoid, intermediate (clear cell), and mucinous cells growing in cystic or solid patterns19.(Figure 8B). They present as well-circumscribed but variably encapsulated nodules composed of a single or multiple cysts separated by thin fibrous tissue and containing intraluminal papillary projections. The epithelial lining is bland cuboidal to columnar and may show oncocytic differentiation as well as apocrine or squamous differentiation with admixed mucous cells. Eosinophilic material and epithelial, inflammatory or foamy cells may be seen inside the cysts.
- •Several grading systems are available for MEC, most dividing lesions into 3 tiers.16.,
- Goode RK
- Auclair PL
- Ellis GL
Mucoepidermoid carcinoma of the major salivary glands: Clinical and histopathologic analysis of 234 cases with evaluation of grading criteria.Cancer. 1998; 82: 1217-1224https://doi.org/10.1002/(SICI)1097-0142(19980401)82:7<1217::AID-CNCR2>3.0.CO;2-C20.,21.In general, higher grade lesions tend to have less of a cystic component, increased mitoses, and greater nuclear pleomorphism. - •There is some overlap in the grading schema, and certain lesions might be graded differently depending on the system used; this is particularly significant when it comes to management of intermediate lesions. The Armed Forces Institute of Pathology (AFIP) system—a points-based scheme using intracystic component, perineural invasion, necrosis, mitotic rate, and anaplasia—tends to “downgrade” tumors and, therefore, intermediate lesions will tend to cluster with high-grade lesions. The Brandwein system is another points-based scheme utilizing intracystic component, tumor nesting, nuclear atypia, lymphatic or vascular invasion, perineural invasion, bone invasion, and mitotic count; this system will “upgrade” tumors and as a result intermediate lesions will cluster with low-grade lesions.21.
- •The pathology report for a MEC resection should describe the grading system used and the criteria determining the tumor's grade. Whatever grading system is used, it is critical that clinicians and pathologists agree of what the grade of an MEC means so that therapy is appropriate.
- •Differential diagnosis includes WT, oncocytoma, and cystadenoma for more low-grade lesions and SDC, squamous cell carcinoma, and adenosquamous carcinoma for high-grade lesions.12.,22.
- •In the setting of suspected high-grade MEC, mucicarmine stain can assist by highlighting mucous cells. Additionally, p63 (intermediate and epidermoid cells) and CK5/6 (epidermoid cells) will stain MECs, while androgen receptor is negative, distinguishing MEC from SDC.23.,24.
On fine-needle aspiration:
- •Clusters of epithelial cells including squamoid cells, intermediate cells, and mucin-secreting cells within a mucoid background are seen. High-grade lesions generally are markedly cellular with more pleomorphic and mitotically active cells with background necrosis, and the differential for these may include squamous cell carcinoma.25.
MEC is characterized by a recurrent t(11;19)(q21;p13) translocation involving the CRTC1 gene at 19p13 and the MAML2 gene at 11q21. This gene fusion is present in roughly two-thirds of tumors, and is more common in low to intermediate grade tumors.
5.
, 12.
,26.
In diagnostically difficult cases, tests to detect the CRTC1-MAML2 gene fusion can be performed.12.
The prognosis for MEC is generally favorable. The 5-year disease-specific survival is roughly 75%-80%.
13.
, 26.
Although initial studies found the presence of CRTC1/3-MAML2 gene fusion to be associated with better survival, this relationship was not identified in a study by Birkeland et al, which controlled for tumor grade; whether gene fusion status is independently associated with prognosis thus remains to be determined.27.
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma (AdCC) is the second most common malignant salivary gland tumor, accounting for 10% of salivary gland neoplasms overall.
28.
Although it may occur in major salivary glands, roughly 60% of cases occur in the minor salivary glands.- Bradley PJ.
Adenoid cystic carcinoma of the head and neck: A review.
Curr Opin Otolaryngol Head Neck Surg. 2004; 12: 127-132https://doi.org/10.1097/00020840-200404000-00013
29.
AdCCs occur with a slight female predominance (F:M of 1.5:1) over a wide age range with a peak in the fifth to sixth decades of life.30.
There are currently no known risk factors.31.
AdCCs often present as a slowly growing mass. Half of cases demonstrate pain due to perineural invasion.
30.
, 32.
Tumors occurring in the parotid gland may rarely present with facial nerve paralysis.- Vander Poorten VLM
- Balm AJM
- Hilgers FJM
- et al.
The development of a prognostic score for patients with parotid carcinoma.
Cancer. 1999; 85: 2057-2067https://doi.org/10.1002/(SICI)1097-0142(19990501)85:9<2057::AID-CNCR24>3.0.CO;2-F
32.
, - Vander Poorten VLM
- Balm AJM
- Hilgers FJM
- et al.
The development of a prognostic score for patients with parotid carcinoma.
Cancer. 1999; 85: 2057-2067https://doi.org/10.1002/(SICI)1097-0142(19990501)85:9<2057::AID-CNCR24>3.0.CO;2-F
33.
Grossly, these tumors present as:
- •A poorly circumscribed tumor with a white, extremely firm cut surface. They often invade surrounding soft tissues and bone30.(Figure 9A).
![Fig 9]()
Figure 9Adenoid cystic carcinoma. Grossly, this AdCCa of the submandibular gland revealed the classic firm, tan-white cut surface with infiltrative borders (A). On histology, this lesion with a tubular and solid growth pattern reveals the dual cell population with angulated basaloid cells admixed with rounder luminal cells with more open chromatin and eosinophilic cytoplasm (B). Perineural invasion is common, as demonstrated in this lesion with more cribriform growth (C).
By light microscopy:
- •AdCCs are biphenotypic tumors consisting of a dominant population of nonluminal basaloid cells with small to moderate cytoplasm admixed with a smaller population of luminal, cuboidal cells with eosinophilic cytoplasm (Figure 9B).
- •AdCCs can grow in tubular, cribriform, and solid growth patterns. Perineural invasion is extremely common (Figure 9C). High-grade transformation is characterized by the presence of large nuclear size and pleomorphism, a fibrocellular desmoplastic response, micropapillary or squamoid regions, a loss of the abluminal cell layer, and p53 overexpression.34.
On fine-needle aspiration:
Over half of AdCCs feature a t(6;9)(q22-23;p23-24) translocation resulting in a MYB-NFIB fusion.
38.
, 39.
, 40.
Fluorescent in situ hybridization (FISH) studies, when positive, may therefore be used to confirm a suspected diagnosis of AdCC. The presence of the MYB-NFIB fusion has not been found to have prognostic significance.41.
AdCCs are generally slowly growing tumors with a relentless course. Although the 5-year survival is roughly 70%, the 15-year survival rate is around 25%.
33.
, 42.
A number of grading systems has been proposed for AdCC, all based on the extent of the solid component.41.
,43.
, - Perzin KH
- Gullane P
- Clairmont AC
Adenoid cystic carcinomas arising in salivary glands. A correlation of histologic features and clinical course.
Cancer. 1978; 42: 265-282https://doi.org/10.1002/1097-0142(197807)42:1<265::AID-CNCR2820420141>3.0.CO;2-Z
44.
, 45.
, 46.
Any solid component whatsoever is associated with a lower disease-specific survival.41.
, 46.
Tumors with high-grade transformation have a significantly worse prognosis, with over half of patients demonstrating lymph node metastases and up to a third of patients dying of disease within the first 3 years following diagnosis.
34.
Polymorphous adenocarcinoma
Polymorphous adenocarcinoma (PolAdCa) is a rare malignant salivary gland tumor. The majority of cases (>90%) occur in the minor salivary glands, with a particular predilection for the palate.
47.
, 48.
While most cases present with asymptomatic swelling, they may also rarely present with ulceration and pain.49.
There is a 2:1 female predominance, and the majority of cases occur in the sixth to eighth decades of life.47.
Grossly, these tumors present as:
- •Firm, well-circumscribed, and unencapsulated ovoid masses with light yellow to tan parenchyma. Minor salivary gland lesions typically lie in proximity to overlying surface epithelium.50.
- Castle JT
- Thompson LDR
- Frommelt RA
- et al.
Polymorphous low grade adenocarcinoma: A clinicopathologic study of 164 cases.Cancer. 1999; 86: 207-219https://doi.org/10.1002/(SICI)1097-0142(19990715)86:2<207::AID-CNCR4>3.0.CO;2-Q
By light microscopy:
- •As suggested by its name, PolAdCa can present with a wide array of morphologic appearances, often within cases.
- •Tumors can demonstrate solid, trabecular, ductal, tubular, cribriform, and papillary growth patterns.51.
- •Perineural invasion is common, occurring in roughly half of cases.52.However, the tumors are low grade with a long natural history. Only about 10% will demonstrate regional node metastases.
- •Due to some shared architectural patterns, the differential for PolAdCa includes AdCC; however, PolAdCa can be distinguished by the characteristic round-to-ovoid nuclei with stippled chromatin and inconspicuous nucleoli. Moreover, PolAdCa represents a monomorphic tumor, whereas AdCC demonstrates a dual cell population53.(Figure 10A).
![Fig 10]()
Figure 10Polymorphous adenocarcinoma. While this lesion shows cribriform and tubular growth patterns, the monomorphic population of round-to-oval cells with vesicular nuclei distinguishes this PolAdCa from AdCCa. - •A distinct subset of PolAdCa referred to as cribriform adenocarcinoma of minor salivary glands has unique pathologic, molecular, and clinical characteristics. These lesions tend to occur in the base of the tongue and are characterized by round nuclei with open chromatin growing in solid, cribriform, microcystic, and glomeruloid patterns.54.These lesions are more likely to demonstrate cervical lymph node metastasis, often bilaterally.55.
On fine-needle aspiration:
- •Papillary to cribriform clusters of cells with bland nuclei with fine chromatin, nuclear grooves, and small nucleoli are seen. Occasional hyaline globules may be present.56.
Three-quarters of cases of PolAdCa demonstrate somatic mutations in the PRKD1 gene on chromosome 14.
57.
Interestingly, only a minority (∼10%) of cases of cribriform adenocarcinoma of minor salivary glands demonstrates these PRKD1 mutations, and they are instead characterized by PRKD1-3 rearrangements.58.
The prognosis of PolAdCa is favorable. About 1 in 5 cases will recur, with extrapalatal cases presenting the greatest risk of recurrence. Mitotic count has also been found to be of prognostic significance.48.
Lymph node metastasis is rare, occurring in 5%-15% of cases, and distant metastasis occurs in <5%.47.
Acinic Cell Carcinoma
Acinic cell carcinomas (AcCC) comprises about 10% of salivary gland malignancies overall.
59.
The vast majority (>80%) of cases occur in the parotid gland, where they account for roughly 15% of malignancies.60.
, 61.
Population studies consistently reveal a slight female predominance, with a F:M ratio around 1.5:1.- Hoffman HT
- Hynds Karnell L
- Robinson RA
- et al.
National cancer data base report on cancer of the head and neck: Acinic cell carcinoma.
Head Neck. 1999; 21: 297-309https://doi.org/10.1002/(SICI)1097-0347(199907)21:4<297::AID-HED2>3.0.CO;2-R
14.
, 59.
AcCCs occur over a wide age distribution and are one of the more common salivary gland cancers in children. They usually present as slowly growing and painless circumscribed masses, commonly <5 cm in size.Grossly, these tumors present as:
- •White to tan, usually solid and vaguely lobulated masses with variably cystic cut surface with foci of hemorrhage62.(Figure 11A).
![Fig 11]()
Figure 11Acinic cell carcinoma. Grossly, AcCCs generally show tan-white solid to vaguely lobulated cut surfaces, with this lesion further demonstrating FNA-site changes (A). This AcCC with high-grade transformation shows the typical low-grade component on the right side of the image and the high grade with nuclear pleomorphism, mitoses, and necrosis on the left side of the image (B).
By light microscopy:
- •AcCCs are defined by epithelial cells demonstrating serous acinar differentiation in the form of intracytoplasmic secretory granules. Tumors may demonstrate solid, microcystic, follicular, papillary, and cystic growth patterns.
- •High-grade transformation of AcCC has been defined histologically by the presence of nuclear pleomorphism, prominent nucleoli, necrosis, and increased mitotic activity and proliferation index63.,64.(Figure 11B).
- •The diagnosis of AcCC is most challenging when the tumor presents with a papillary cystic architecture, as this variant can share morphologic features with SC. This differential may be resolved by the use of immunohistochemistry, as AcCCs will generally demonstrate at least focal DOG1 staining and negativity for mammaglobin, which is consistently strongly positive in SC.65.
- •AcCCs will also fail to demonstrate the rearrangement of ETV6 by FISH, which defines SC.
On fine-needle aspiration:
- •Highly cellular collections of cells with slightly enlarged, eccentrically located nuclei, evenly distributed chromatin and occasionally conspicuous nucleoli with abundant cytoplasm demonstrating coarse zymogen granules are present. Occasional stripped nuclei are commonly seen.62.
The molecular pathogenesis of AcCC remains poorly understood. Animal models and immunohistochemical studies have suggested that an upregulated mTOR pathway may be involved in the development of AcCCs.
66.
, 67.
A 2017 study demonstrated recurrent rearrangements involving the Myb/SANT-like DNA binding domain containing 3 (MSANTD3) gene on chromosome 9q in 3 of 20 cases of AcCC.68.
The prognosis of AcCC is generally favorable, with an estimated 20-year overall survival of 80%-90%.
59.
At diagnosis, <10% of cases demonstrate nodal metastasis.69.
Roughly 10%-15% of cases will recur following surgery.69.
, 70.
Factors associated with decreased survival include age >45 years, male gender, tumor size >3 cm, and the presence of positive margins.70.
High-grade transformation is associated with a significantly poorer prognosis, with up to two-thirds of patients dying from the disease after a median overall survival of 4 years.63.
, 71.
Secretory Carcinoma
Secretory carcinoma (SC) occurs over a wide age range with a peak in the fifth and sixth decades, and occurs with a slight male predominance (roughly 1.3:1).
69.
,72.
, 73.
, 74.
, 75.
Roughly 70% of cases occur in the parotid, but they also commonly occur in the minor salivary glands of the oral cavity and the submandibular gland.76.
Grossly, these tumors present as:
- •Well-circumscribed and unencapsulated, rubbery masses with a gray-white to brown cut surface that might be variably cystic.77.
By light microscopy:
- •SC generally presents as a circumscribed mass divided into lobules by fibrous septa.
- •They may show microcystic, tubular, or solid growth patterns. Classically, the microcystic and tubular spaces will show bubbly secretions that stain positively for mucicarmine, Periodic Acid Schiff (PAS), and alcian blue55.,72.(Figure 12).
![Fig 12]()
Figure 12Secretory carcinoma. This SC demonstrates the characteristic oval-to-round nuclei with vesicular chromatin and prominent pinpoint nucleoli growing in microcystic and tubular patterns. - •SC cells have oval-to-round nuclei with vesicular chromatin and prominent but small centrally located nucleoli.73.As noted previously, these lesions also demonstrate a unique immunophenotype compared to AcCC.
On fine-needle aspiration:
- •Clusters of follicular and papillary structures featuring bland tumor cells with vacuolated cytoplasm and lacking intracytoplasmic zymogen granules are noted. The background is generally mucinous and may feature hemosiderin-laden macrophages.78.
SC is defined by a t(12;15)(p13;q25) translocation, which leads to an ETV6-NTRK3 fusion gene product, resulting in ligand-independent activation of a membrane receptor kinase.
73.
Rare cases with high-grade transformation are characterized by a typical low-grade component along with a distinct component demonstrating anaplastic cells arranged in trabeculae with foci of geographic and comedo-like necrosis.79.
SC is a low-grade tumor with a decent prognosis. Recurrences occur in up to 15% of cases, and lymph node metastases occur in up to 20%. Only rarely does distant metastasis occur.
73.
, 76.
Salivary Duct Carcinoma
Salivary duct carcinoma (SDC) represents roughly 1%-3% of salivary gland carcinomas.
80.
, 81.
SDC is most common in male patients (M:F ratio ∼4:1) and tends to occur in the sixth to seventh decade of life.82.
, 83.
It is the most common form of carcinoma to arise ex PA. Up to 80% of cases of SDC have either morphologic or molecular evidence of having arisen from a PA.83.
Most cases (∼80%) occur in the parotid gland, and minor salivary gland involvement is extremely rare.81.
Grossly, these tumors present as:
By light microscopy:
- •SDC is characterized by solid or cystic nodules of tumor forming papillary or cribriform patterns, often invasive into surrounding tissues (Figure 13A).
![Fig 13]()
Figure 13Salivary duct carcinoma. This SDC emerged as a carcinoma ex PA and invades beyond the PA capsule to involve surrounding salivary gland tissue (A). On high power, SDC shows atypical tumor cells with eosinophilic cytoplasm, numerous mitoses, and comedonecrosis (B). - •The tumor cells generally demonstrate at least moderate atypia and contain abundant, eosinophilic cytoplasm with occasional apocrine snouts (Figure 13B).
- •Comedonecrosis is common.
- •The differential diagnosis of SDC includes other salivary gland tumors (AdCC and AcCC) with high-grade transformation as well as metastatic squamous cell carcinoma. Androgen receptor is an extremely sensitive marker for SDC, staining up to 98% of cases.82.In addition, cases are consistently positive for CK7 and GATA3.86.
On fine-needle aspiration:
- •Three-dimensional clusters of round-to-oval cells with fine to slightly granular chromatin and occasional intracytoplasmic vacuoles form sheets, cribriform structures, or tubules. Occasional binucleate or multinucleated cells are common.87.
A subset of SDC cases demonstrates ERBB2 amplification by FISH, and these cases will demonstrate strong HER2 staining.
80.
, 86.
Amplification appears to be particularly common in cases that arise ex PA.83.
Some studies have suggested a poor prognosis with ERBB2 overexpression88.
, 89.
; however, several others have failed to identify such a relationship.80.
, 82.
,86.
, 90.
Roughly half of SDCs arising ex PA have TP53 mutations.91.
SDC arising ex PA will often demonstrate the PLAG1 and HMGA2 rearrangements characteristic of PA. De novo SDC commonly harbors combined mutations involving HRAS and PIK3CA.83.
The prognosis for SDC is generally poor. A majority of cases will have lymph node metastases at diagnosis and about half of cases will develop distant metastasis.
92.
, - Lewis JE
- McKinney BC
- Weiland LH
- et al.
Salivary duct carcinoma: Clinicopathologic and immunohistochemical review of 26 cases.
Cancer. 1996; 77: 223-230https://doi.org/10.1002/(SICI)1097-0142(19960115)77:2<223::AID-CNCR1>3.0.CO;2-N
93.
, 94.
, 95.
, 96.
The 5-year disease-specific survival is around 40%-50%.94.
, 95.
, 96.
Factors that have been associated with survival include lymph node status, lymphovascular invasion, and variant morphologies (micropapillary and sarcomatoid).86.
, 96.
Epithelial-myoepithelial carcinoma
Epithelial-myoepithelial carcinoma (EMC) is a rare neoplasm, comprising only 1% of all salivary gland tumors.
97.
Most (60%-80%) occur in the parotid gland; however, they can occur in any major or minor salivary gland throughout the aerodigestive tract.98.
, 99.
, 100.
, 101.
They occur with a female predominance (F:M of 1.5:1) and over a wide age distribution with a mean age at diagnosis in the early 60s.98.
, 101.
It is currently believed that there are 2 pathways for the development of EMC. The first involves a de novo tumor believed to arise from intercalated ducts of the salivary gland.
102.
The second involves transformation from a PA.103.
While this second pathway had long been considered a rare event, Hallani et al identified the evidence of prior PA in 80% (31 of 39) of cases of EMC, either through morphologic evidence alone (8 of 39, 21%) or through the presence of PLAG1 (9 of 39, 23%) or HMGA2 (10 of 39, 26%) alterations.104.
A subset of EMCs demonstrates HRAS mutations.104.
, 105.
Grossly, these tumors present as:
- •Well-circumscribed and partially to completely encapsulated masses with a firm, tan-white, multinodular cut surface demonstrating pushing borders.106.
By light microscopy:
- •Lesions demonstrate a multilobular growth pattern with intervening fibrotic stroma. Tumors are biphenotypic, with inner cuboidal ductal cells with eosinophilic cytoplasm surrounded by more polygonal myoepithelial cells with clear cytoplasm106.(Figure 14).
![Fig 14]()
Figure 14Epithelial-myoepithelial carcinoma. This EMC demonstrates a dual cell population of cuboidal ductal cells with eosinophilic cytoplasm and surrounding myoepithelial cells with clear cytoplasm. - •Immunohistochemistry can reveal the biphenotypic nature of lesions, with ductal cells staining with AE1-3, CAM 5.2, and pancytokeratin and myoepithelial cells staining with p63, S100, and SMA.98.
On fine-needle aspiration:
- •Cellular samples containing single cells, naked nuclei, and cell clusters composed of small, bland basaloid epithelial cells with scant cytoplasm and larger myoepithelial cells with pale, fragile cytoplasm are seen. Hyaline globules may also be present.107.Due to the generally bland nature of biphenotypic lesional cells as well as the frequently abundant stromal component, lesions may be misdiagnosed as PA.108.
Rare cases of EMC with high-grade transformation have been reported in the literature, with 2 forms appreciated. The first represents a transformation of the myoepithelial component, with myoepithelial anaplasia as well as overt myoepithelial carcinoma arising from EMC described. The other represents a poorly differentiated carcinoma arising from the ductal component.
109.
The prognosis for EMC is generally good, though recurrences occur in up to one-third of cases, often several years following surgery.
98.
, 104.
The disease-specific survival of EMC is 80%-90% at 10 years.101.
Roughly 5% of cases will demonstrate distant metastasis over the course of disease.98.
, 101.
Factors associated with a poor prognosis include size >4 cm, necrosis, positive resection margin status, angiolymphatic invasion, and myoepithelial anaplasia and/or high-grade transformation.98.
, 109.
Disclosures
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References
- : The Milan System for Reporting Salivary Gland Cytopathology.Springer International Publishing AG, Cham, Switzerland2018
- Fusion oncogenes and tumor type specificity—insights from salivary gland tumors.Semin Cancer Biol. 2005; 15: 224-235https://doi.org/10.1016/j.semcancer.2005.01.002
- High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes.Oncogene. 2008; 27: 3072-3080https://doi.org/10.1038/sj.onc.1210961
- 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: 21-28https://doi.org/10.1016/j.yexcr.2003.09.007
- CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin’s tumors: Implications for histogenesis and biologic behavior.Genes Chromosomes Cancer. 2007; 46: 708-715https://doi.org/10.1002/gcc
- A closer look at Warthin tumors and the t(11;19).Cancer Genet Cytogenet. 2008; 180: 135-139https://doi.org/10.1016/j.cancergencyto.2007.10.007
- The MECT1-MAML2 gene fusion and benign Warthin's tumor—is the MECT1-MAML2 gene fusion specific to mucoepidermoid carcinoma?.J Mol Diagn. 2006; 8: 394-396https://doi.org/10.2353/jmoldx.2006.060020
- Nuclear beta-catenin expression in basal cell adenomas of salivary gland.J Oral Pathol Med. 2011; 40: 460-466https://doi.org/10.1111/j.1600-0714.2011.01010.x
- A comparative analysis of LEF-1 in odontogenic and salivary tumors.Hum Pathol. 2015; 46: 255-259https://doi.org/10.1016/j.humpath.2014.10.018
- Molecular analysis of chromosome 16q regions in dermal analogue tumors of salivary glands: A genetic link to dermal cylindroma?.Am J Surg Pathol. 2002; 26: 778-783https://doi.org/10.1097/01.PAS.0000015962.68135.30
- Mucoepidermoid carcinoma of salivary gland origin. A clinicopathologic study of 367 cases.Am J Surg. 1978; 136: 461-468https://doi.org/10.1016/0002-9610(78)90262-3
- A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas.Am J Surg Pathol. 2010; 34: 1106-1121https://doi.org/10.1097/PAS.0b013e3181de3021
- Predictors of recurrence and survival for head and neck mucoepidermoid carcinoma.Otolaryngol Head Neck Surg. 2014; 149: 402-408https://doi.org/10.1177/0194599813489659.Predictors
- Incidence of carcinoma of the major salivary glands according to the WHO classification, 1992 to 2006: A population-based study in the United States.Cancer Epidemiol Biomarkers Prev. 2009; 18: 2899-2906https://doi.org/10.1158/1055-9965.EPI-09-0638
- Prognostic factors in head and neck mucoepidermoid carcinoma.Arch Otolaryngol Neck Surg. 2004; 130: 174https://doi.org/10.1001/archotol.130.2.174
- Mucoepidermoid carcinoma of the major salivary glands: Clinical and histopathologic analysis of 234 cases with evaluation of grading criteria.Cancer. 1998; 82: 1217-1224https://doi.org/10.1002/(SICI)1097-0142(19980401)82:7<1217::AID-CNCR2>3.0.CO;2-C
- Prognostic factors in head and neck mucoepidermoid carcinoma: Experience at a single institution based on 64 consecutive patients over a 28-year period.Int J Oral Maxillofac Surg. 2017; : 1-6https://doi.org/10.1016/j.ijom.2017.09.005
- Histologic grade as prognostic indicator for mucoepidermoid carcinoma: A population-level analysis of 2400 patients.Head Neck. 2014; 36: 1391https://doi.org/10.1002/HED
- Mucoepidermoid carcinoma.in: El-Naggar A Chan J Grandis J WHO Classification of Head and Neck Tumors. ed 4. International Agency for Research on Cancer, Saint Ismier, France2017: 163-164
- Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading.Am J Surg Pathol. 2001; 25: 835-845https://doi.org/10.1097/00000478-200107000-00001
- An update on grading of salivary gland carcinomas.Head Neck Pathol. 2009; 3: 69-77https://doi.org/10.1007/s12105-009-0102-9
- Prognostic features in mucoepidermoid carcinoma of major salivary glands with emphasis on tumour histologic grading.Histopathology. 2014; 65: 793-804https://doi.org/10.1111/his.12488
- Oncocytic mucoepidermoid carcinoma of the parotid gland with CRTC1-MAML2 fusion transcript: Report of a case with review of literature.Hum Pathol. 2011; 42: 2052-2055https://doi.org/10.1016/j.humpath.2011.02.021
- Update on selected salivary gland neoplasms.Arch Pathol Lab Med. 2009; 133: 1763-1774https://doi.org/10.1043/1543-2165-133.11.1763
- Mucoepidermoid carcinoma of salivary gland: Limitations and pitfalls on FNA.J Clin Diagn Res. 2017; 11: 10-12https://doi.org/10.7860/JCDR/2017/25341.9941
- Role of CRTC1/MAML2 translocation in the prognosis and clinical outcomes of mucoepidermoid carcinoma.JAMA Otolaryngol Neck Surg. 2016; 142: 234https://doi.org/10.1001/jamaoto.2015.3270
- Correlation of Crtc1/3-Maml2 fusion status, grade and survival in mucoepidermoid carcinoma.Oral Oncol. 2017; 68: 5-8https://doi.org/10.1016/j.oraloncology.2017.02.025
- Adenoid cystic carcinoma of the head and neck: A review.Curr Opin Otolaryngol Head Neck Surg. 2004; 12: 127-132https://doi.org/10.1097/00020840-200404000-00013
- Adenoid cystic carcinoma of the head and neck—a 20 years experience.Int J Oral Maxillofac Surg. 2004; 33: 25-31https://doi.org/10.1054/ijom.2003.0448
- Adenoid cystic carcinoma of salivary glands: A study of 61 cases with clinicopathologic correlation.Cancer. 1986; 128: 312-319
- Management of salivary gland adenoid cystic carcinoma: Institutional experience of a case series.São Paulo Med J. 2006; 124: 26-30https://doi.org/10.1590/S1516-31802006000100006
- The development of a prognostic score for patients with parotid carcinoma.Cancer. 1999; 85: 2057-2067https://doi.org/10.1002/(SICI)1097-0142(19990501)85:9<2057::AID-CNCR24>3.0.CO;2-F
- Adenoid cystic carcinoma of the head and neck: A single-center analysis of 105 consecutive cases over a 30-year period.Oral Oncol. 2013; 49: 824-829https://doi.org/10.1016/j.oraloncology.2013.05.004
- Adenoid cystic carcinoma with high-grade transformation: A report of 11 cases and a review of the literature.Am J Surg Pathol. 2007; 31: 1683-1694https://doi.org/10.1097/PAS.0b013e3180dc928c
- Cytological spectrum of salivary gland lesions and their correlation with epidemiological parameters.J Oral Maxillofac Pathol. 2017; 21: 203-210https://doi.org/10.4103/jomfp.JOMFP
- Diagnostic role of fine needle aspiration cytology (FNAC) in the evaluation of salivary gland swelling: An institutional experience.BMC Res Notes. 2015; 8: 5-9https://doi.org/10.1186/s13104-015-1048-5
- Role of fine-needle aspiration cytology in the diagnosis of major salivary gland tumors: A study with histological and clinical correlation.J Oral Maxillofac Pathol. 2016; 20: 224https://doi.org/10.4103/0973-029X.185899
- MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation.Am J Surg Pathol. 2011; 35: 92-99https://doi.org/10.1097/PAS.0b013e3182002777.MYB
- Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms.Mod Pathol. 2011; 24: 1169-1176https://doi.org/10.1038/modpathol.2011.86
- Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck.Proc Natl Acad Sci. 2009; 106: 18740-18744https://doi.org/10.1073/pnas.0909114106
- Predictors of outcome in adenoid cystic carcinoma of salivary glands.Am J Surg Pathol. 2017; 41: 1422-1432https://doi.org/10.1097/PAS.0000000000000918
- Factors influencing survival rate in adenoid cystic carcinoma of the salivary glands.Int J Oral Maxillofac Surg. 1997; 26: 435-439https://doi.org/10.1016/S0901-5027(97)80008-2
- Adenoid cystic carcinomas arising in salivary glands. A correlation of histologic features and clinical course.Cancer. 1978; 42: 265-282https://doi.org/10.1002/1097-0142(197807)42:1<265::AID-CNCR2820420141>3.0.CO;2-Z
- Adenoid cystic carcinoma of salivary origin. A clinicopathologic study of 242 cases.Am J Surg. 1974; 128: 512-520https://doi.org/10.1016/0002-9610(74)90265-7
- Histologic grading of adenoid cystic carcinoma of the salivary glands.Cancer. 1984; 54: 1062-1069https://doi.org/10.1002/1097-0142(19840915)54:63.0.CO;2-E
- Histopathological grading of adenoid cystic carcinoma of the head and neck: Analysis of currently used grading systems and proposal for a simplified grading scheme.Oral Oncol. 2015; 51: 71-76https://doi.org/10.1016/j.oraloncology.2014.10.007
- Polymorphous low-grade adenocarcinoma of the head and neck: A population-based study of 460 cases.Laryngoscope. 2015; 125: 1644-1649https://doi.org/10.1002/lary.25266
- Polymorphous low-grade adenocarcinoma: The University of Pittsburgh experience.Arch Otolaryngol Neck Surg. 2010; 136: 385-392https://doi.org/10.1097/01.pcr.0000143777.29141.ea
- Retrospective study and review of polymorphous low-grade adenocarcinoma.Laryngoscope. 2006; 116: 2145-2149https://doi.org/10.1097/01.mlg.0000243200.35033.2b
- Polymorphous low grade adenocarcinoma: A clinicopathologic study of 164 cases.Cancer. 1999; 86: 207-219https://doi.org/10.1002/(SICI)1097-0142(19990715)86:2<207::AID-CNCR4>3.0.CO;2-Q
- Polymorphous adenocarcinoma.in: El-Naggar AK Chan JKC Takata T WHO Classification of Head and Neck Tumors. ed 4. International Agency for Research on Cancer, Saint Ismier, France2017: 167-168
- Polymorphous low-grade adenocarcinoma: A Danish national study.Oral Oncol. 2016; 55: 6-10https://doi.org/10.1016/j.oraloncology.2016.02.005
- Polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma: A review and comparison of immunohistochemical markers.J Oral Sci. 2002; 51: 509-514
- Cribriform adenocarcinoma of the tongue: A hitherto unrecognized type of adenocarcinoma characteristically occurring in the tongue.Histopathology. 1999; 35: 495-501https://doi.org/10.1046/j.1365-2559.1999.00792.x
- Newly described entities in salivary gland pathology.Am J Surg Pathol. 2017; 41: e33-e47https://doi.org/10.1097/PAS.0000000000000883
- Fine needle aspiration cytology of metastatic polymorphous low-grade adenocarcinoma of the palate in a cervical lymph node.Cytopathology. 2013; 24: 63-65https://doi.org/10.1111/j.1365-2303.2011.00921.x
- Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands.Nat Genet. 2014; 46: 1166-1169https://doi.org/10.1038/ng.3096
- Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin.Genes Chromosomes Cancer. 2014; 53: 845-846https://doi.org/10.1002/gcc
- Demographic trends and disease-specific survival in salivary acinic cell carcinoma: An analysis of 1129 cases.Laryngoscope. 2014; 124: 172-178https://doi.org/10.1002/lary.24231
- Long-term outcomes and quality of life of 186 patients with primary parotid carcinoma treated with surgery and radiotherapy at the Daniel den hoed cancer center.Int J Radiat Oncol Biol Phys. 2012; 84: 189-195https://doi.org/10.1016/j.ijrobp.2011.11.045
- National cancer data base report on cancer of the head and neck: Acinic cell carcinoma.Head Neck. 1999; 21: 297-309https://doi.org/10.1002/(SICI)1097-0347(199907)21:4<297::AID-HED2>3.0.CO;2-R
- Acinic cell carcinoma of the salivary gland: A continuing medical education case.Diagn Cytopathol. 2008; 36: 380-385https://doi.org/10.1002/dc.20852
- Acinic cell carcinoma with high-grade transformation: A report of 9 cases with immunohistochemical study and analysis of TP53 and HER-2/neu genes.Am J Surg Pathol. 2009; 33: 1137-1145https://doi.org/10.1097/PAS.0b013e3181a38e1c
- High grade transformation of salivary gland acinic cell carcinoma with emphasis on histological diagnosis and clinical implications.Pathol Res Pract. 2016; 212: 1059-1063https://doi.org/10.1016/j.prp.2016.08.005
- Combined DOG1 and mammaglobin immunohistochemistry is comparable to ETV6-breakapart analysis for differentiating between papillary cystic variants of acinic cell carcinoma and mammary analogue secretory carcinoma.Int J Surg Pathol. 2017; 25: 127-140https://doi.org/10.1177/1066896916670005
- Mammalian target of rapamycin-dependent acinar cell neoplasia after inactivation of Apc and Pten in the mouse salivary gland: Implications for human acinic cell carcinoma.Cancer Res. 2010; 70: 9143-9152https://doi.org/10.1158/0008-5472.CAN-10-1758
- The PI3K/AKT/mTOR signalling pathway is active in salivary gland cancer and implies different functions and prognoses depending on cell localisation.Oral Oncol. 2012; 48: 822-830https://doi.org/10.1016/j.oraloncology.2012.02.021
- Recurrent rearrangements of the Myb/SANTlike DNA-binding domain containing 3 gene (MSANTD3) in salivary gland acinic cell carcinoma.PLoS One. 2017; 12: 1-18https://doi.org/10.1371/journal.pone.0171265
- Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands.Histopathology. 2012; 61: 387-394https://doi.org/10.1111/j.1365-2559.2012.04232.x
- Prognostic factors associated with decreased survival in patients with acinic cell carcinoma.JAMA Otolaryngol Neck Surg. 2013; 139: 1195https://doi.org/10.1001/jamaoto.2013.4728
- The profile of acinic cell carcinoma after recognition of mammary analog secretory carcinoma.Am J Surg Pathol. 2012; 36: 343-350https://doi.org/10.1097/PAS.0b013e318242a5b0
- Mammary analogue secretory carcinoma of salivary glands: A clinicopathologic study of 11 cases.Ann Diagn Pathol. 2016; 22: 49-53https://doi.org/10.1016/j.anndiagpath.2016.04.003
- Mammary analogue secretory carcinoma of salivary glands, containing the etv6-ntrk3 fusion gene: A hitherto undescribed salivary gland tumor entity.Am J Surg Pathol. 2010; 34: 599-608https://doi.org/10.1097/PAS.0b013e3181d9efcc
- Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: Expanded morphologic and immunohistochemical spectrum of a recently described entity.Am J Surg Pathol. 2012; 36: 27-34https://doi.org/10.1016/j.humpath.2013.06.010
- Papillary-cystic pattern is characteristic in mammary analogue secretory carcinomas but is rarely observed in acinic cell carcinomas of the salivary gland.Virchows Arch. 2015; 467: 145-153https://doi.org/10.1007/s00428-015-1786-8
- Unmasking MASC: Bringing to Light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands.Head Neck Pathol. 2013; 7: 35-39https://doi.org/10.1007/s12105-013-0429-0
- Mammary analogue secretory carcinoma.Arch Pathol Lab Med. 2016; 140: 997-1001https://doi.org/10.5858/arpa.2015-0075-RS
- Cytological features of mammary analogue secretory carcinoma of salivary gland: Fine-needle aspiration of seven cases.Diagn Cytopathol. 2014; 42: 846-855https://doi.org/10.1002/dc
- Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: Report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes.Am J Surg Pathol. 2014; 38: 23-33https://doi.org/10.1097/PAS.0000000000000088
- A 20-year review of 75 cases of salivary duct carcinoma.JAMA Otolaryngol Neck Surg. 2015; 344: 1173-1178https://doi.org/10.1126/science.1249098.Sleep
- Characterization, treatment and outcomes of salivary ductal carcinoma using the National Cancer Database.Oral Oncol. 2017; 71: 41-46https://doi.org/10.1016/j.oraloncology.2017.05.005
- Salivary duct carcinoma: The predominance of apocrine morphology, prevalence of histologic variants, and androgen receptor expression.Am J Surg Pathol. 2015; 39: 705-713https://doi.org/10.1097/PAS.0000000000000413
- Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations.Cancer. 2016; 122: 3136-3144https://doi.org/10.1002/nbm.3369.Three
- Expression of HER-2/neu gene and protein in salivary duct carcinomas of parotid gland as revealed by fluorescence in-situ hybridization and immunohistochemistry.Histopathology. 2003; 42: 348-356https://doi.org/10.1046/j.1365-2559.2003.01600.x
- Expression of androgen receptor and prostatic specific markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature.Am J Surg Pathol. 2000; 24: 579-586
- Salivary duct carcinoma: Clinicopathologic features, morphologic spectrum, and somatic mutations.Head Neck. 2016; 10: 1838-1847https://doi.org/10.1002/HED
- Salivary duct carcinoma cytologically diagnosed distinctly from salivary gland carcinomas with squamous differentiation.Diagn Cytopathol. 2008; 36: 485-493https://doi.org/10.1002/dc
- The role of molecular testing in the differential diagnosis of salivary gland carcinomas.Am J Surg Pathol. 2017; 42: e11-e27https://doi.org/10.1097/PAS.0000000000000980
- Clinical and immunohistologic typing of salivary duct carcinoma: A report of 50 cases.Cancer. 2005; 103: 2526-2533https://doi.org/10.1002/cncr.21116
- Biomarker immunoprofile in salivary duct carcinomas: Clinicopathological and prognostic implications with evaluation of the revised classification.Oncotarget. 2017; 8: 59023-59035
- Intraductal carcinoma is the precursor of carcinoma ex pleomorphic adenoma and is often associated with dysfunctional p53.Histopathology. 2007; 51: 362-371https://doi.org/10.1111/j.1365-2559.2007.02736.x
- Salivary duct carcinoma: Clinicopathologic and immunohistochemical review of 26 cases.Cancer. 1996; 77: 223-230https://doi.org/10.1002/(SICI)1097-0142(19960115)77:2<223::AID-CNCR1>3.0.CO;2-N
- Management and outcome of salivary duct carcinoma in major salivary glands.Eur Arch Otorhinolaringol. 2013; 270: 281-285https://doi.org/10.1007/s00405-012-1997-4
- Salivary duct carcinoma: Treatment, outcomes, and patterns of failure Meredith.Head Neck. 2016; 10: 820-826https://doi.org/10.1002/HED
- Letter to the editor : Prognostic factors and oncologic outcomes of 56 salivary duct carcinoma patients in a single institution: High rate of systemic failure warrants targeted therapy.Oral Oncol. 2014; 50: e64-e66https://doi.org/10.1016/j.oraloncology.2014.08.010
- Salivary duct carcinoma: A Danish national study.J Oral Pathol Med. 2016; 45: 664-671https://doi.org/10.1111/jop.12426
- Epithelial-myoepithelial carcinoma.in: El-Naggar AK Chan JKC Grandis JR WHO Classification of Head and Neck Tumors. ed 4. International Agency for Research on Cancer, Saint Ismier, France2017: 175-176
- Epithelial-myoepithelial carcinoma: A review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract.Am J Surg Pathol. 2007; 31: 44-57https://doi.org/10.1097/01.pas.0000213314.74423.d8
- Epithelial-myoepithelial carcinoma of the minor salivary glands: Immunohistochemical and morphological features.Anticancer Res. 2009; 29 (29/11/4703 [pii]): 4703-4709
- Epithelial-myoepithelial tumour of the lung: A case report referring to its molecular histogenesis.Diagn Pathol. 2011; 6: 71https://doi.org/10.1186/1746-1596-6-71
- Epithelial-myoepithelial carcinoma of the salivary glands: An analysis of 246 cases.Otolaryngol Neck Surg. 2015; 153: 569-574https://doi.org/10.1177/0194599815594788
- Intercalated duct hyperplasia: Possible relationship to epithelial-myoepithelial carcinoma and hybrid tumours of salivary gland.Histopathology. 2000; 37: 260-263https://doi.org/10.1046/j.1365-2559.2000.00976.x
- Carcinoma ex pleomorphic adenoma of minor salivary glands with major epithelial-myoepithelial component: Clinicopathologic and immunohistochemical study of 3 cases.Ann Diagn Pathol. 2015; 19: 164-168https://doi.org/10.1016/j.anndiagpath.2015.03.011
- Frequent morphologic and molecular evidence of preexisting pleomorphic.Am J Surg Pathol. 2018; 42: 18-27
- HRAS mutations in epithelial-myoepithelial carcinoma.Head Neck Pathol. 2014; 8: 146-150https://doi.org/10.1007/s12105-013-0506-4
- Salivary epithelial-myoepithelial carcinoma: Clinical, morphological and molecular features.Pathologica. 2017; 109: 1-8
- Going beyond “basaloid neoplasm” fine needle aspiration cytology of epithelial-myoepithelial carcinoma of the parotid gland.Diagn Cytopathol. 2016; 44: 422-425https://doi.org/10.1002/dc
- Epithelial myoepithelial carcinoma of head and neck region.Indian J Otolaryngol Head Neck Surg. 2013; 65: 163-166https://doi.org/10.1007/s12070-011-0414-4
- Epithelial-myoepithelial carcinoma with high grade transformation.Am J Surg Pathol. 2010; 34: 1258-1265https://doi.org/10.1016/j.ijom.2011.12.012
Article info
Publication history
Published online: July 18, 2018
Footnotes
This work is original and has not been published elsewhere nor is it currently under consideration for publication elsewhere. None of our authors has any conflicts of interest to declare.
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
30031-9&id=gr1.jpg){kind=link}
30031-9&id=gr2.jpg){kind=link}
30031-9&id=gr3.jpg){kind=link}
30031-9&id=gr4.jpg){kind=link}
30031-9&id=gr5.jpg){kind=link}
30031-9&id=gr6.jpg){kind=link}
30031-9&id=gr7.jpg){kind=link}
30031-9&id=gr8.jpg){kind=link}
30031-9&id=gr9.jpg){kind=link}
30031-9&id=gr10.jpg){kind=link}
30031-9&id=gr11.jpg){kind=link}
30031-9&id=gr12.jpg){kind=link}
30031-9&id=gr13.jpg){kind=link}
30031-9&id=gr14.jpg){kind=link}