Laboratory Studies
A complete blood count (CBC) with differential may be elevated in cases with an underlying inflammatory process. This possibility must be excluded before definitive surgical intervention is initiated. For patients undergoing fine-needle aspiration (FNA), determination of prothrombin time (PT)/international normalized ratio (INR) may be indicated to assess for baseline coagulopathy.
Imaging Studies
Controversy exists regarding the routine use of imaging for small lesions of the minor salivary glands because radiographic imaging typically does not alter the management of these lesions.
Nevertheless, computed tomography (CT), magnetic resonance imaging (MRI), or both may be useful for suspected tumors of the parapharyngeal space. MRI and CT are also optimal for delineating the complete extent of the tumor and assessing for regional lymphadenopathy. In addition, these imaging modalities are useful for evaluating the possibility of invasion into surrounding tissues and facilitating the planning of definitive surgical resection.
Computed tomography
When bony erosion is a concern (eg, in palatal minor salivary gland tumors), CT may be required to assess the extent of locoregional involvement, which will play a role in planning for definitive resection as well as subsequent reconstruction. Similarly, CT is indicated for minor salivary gland neoplasms involving the paranasal sinuses to delineate the extent of the tumor and differentiate tumor from obstructive inflammatory changes.
Magnetic resonance imaging
MRI (see the image below) is superior in soft-tissue differentiation and is particularly helpful in assessing tumor extent, marrow infiltration, and perineural spread. It can also detect signal changes and extracapsular spread within regional lymph nodes while simultaneously avoiding exposure to ionizing radiation. The disadvantages of MRI include its relatively high cost in comparison with CT, its susceptibility to motion artifact, and its poor cortical bone delineation. [43]
Coronal magnetic resonance imaging (MRI) scan demonstrating a large, benign lesion of the right parapharyngeal space.
Ultrasonography
Minor salivary gland lesions in the mucosa of oral cavity, pharynx and tracheobronchial tree are not easily accessible or visualized via conventional ultrasonography (US). Accordingly, US is rarely employed in the management of minor salivary gland lesions.
Other Tests
Fine-needle aspiration cytology
FNA cytology was first developed as a diagnostic tool at the Memorial Sloan-Kettering Cancer Center in the 1930s. However, it is only in the past two decades that it has become a widely applied technique in the management of salivary gland tumors. [44] In general, the histopathology of salivary gland tumors is extremely varied and complex; therefore, correct cytologic typing of a primary salivary gland neoplasm can be difficult to perform. [45]
The utility of FNA was established by Eneroth and others, who advocated its routine use and reported accuracy rates in the range of 74-90%. [46] Although the procedure is somewhat operator-dependent, it is generally regarded as safe, simple to perform, relatively inexpensive, and low in morbidity. When a needle of appropriate size is used, the risk of seeding of the needle tract is negligible (0.003% and 0.009%). [47] Open biopsy is rarely performed, because of the risk of tumor spillage, associated infection, and tumor recurrence. [15]
The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC), implemented in 2018, is an evidence-based standardized reporting system for salivary gland FNA that aids in the determination of malignancy risk. [48]
Core needle biopsy
Currently, core needle biopsy (CNB) is not commonly employed in the management of salivary neoplasms, because of the risk of tumor spillage. The overall risk of tumor seeding with CNB is estimated to be in the range of 0-22%. [49] Factors implicated include needle size, use of a single vs coaxial needle, and tumor-related factors. There may, however, be a role for CNB in cases where prior FNA was nondiagnostic. Thus, surgeons must exercise discretion when considering CNB in the management of these lesions.
Immunohistochemical diagnostics
Immunohistochemical diagnostics have specific applications and may facilitate the delineation of different cell components. Various diagnostic markers can be utilized to make an accurate diagnosis. For example, Ki-67 can differentiate between benign basal cell adenomas and malignant basal cell adenocarcinomas, and PLAG1 is specific for pleomorphic adenomas. [50] PLAG1 and HMGA1 have been found to be increased in benign tumors and can aid in differentiating benign from malignant. [51] Although these markers are helpful for characterizing tumors, they are not essential for diagnosis.
Identification of genetic translocations and fusion genes
Identification of genetic translocations and fusion genes is another emerging adjunct in the diagnosis of salivary neoplasms. This can be accomplished via fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), or, more recently, targeted RNA sequencing (RNA-seq), [52] which is capable of identifying fusion genes with rearrangement of PLAG1 and HMGA2 in pleomorphic adenomas, for example.
Histologic Findings
Basal cell adenoma
Basal cell adenomas comprise a mixture of basal, myoepithelial, and ductal cells. Basal cells are morphologically subdivided into the following two main categories:
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Small dark cells with sparse cytoplasm and round hyperchromatic nuclei
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Larger pale cells that are more polygonal, with basophilic–to–slightly eosinophilic cytoplasm and vesicular nuclei
The small dark cells usually form the periphery of tumor nests and demonstrate peripheral palisading, whereas the larger cells rest on top of this peripheral layer. Within the center, tumor nests are composed of small ductules lined by cuboidal epithelium. [21] Architecturally, basal cell adenomas are divided into the following six growth pattern subtypes [53] :
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Solid
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Trabecular
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Tubular
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Membranous
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Cribriform
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Myoepithelial-derived stroma-rich
Canalicular adenoma
Canalicular adenomas may or may not be encapsulated and are composed of cuboidal-to-columnar cells containing dark and often elongated nuclei with light eosinophilic-to-amphophilic cytoplasm. These cells are characteristically arranged in anastomosing cords that are two cells thick; this alternating pattern of abutment and separation has been referred to as beading. [21]
Cystadenoma
Cystadenomas may be lined by a variety of epithelial types. Most commonly, the luminal epithelium is cystic to cuboidal with pale eosinophilic cytoplasm. The outer layer is lined by an indistinct layer of basal cells with scant cytoplasm and small ovoid nuclei. Oncocytic cystadenomas are a common variant, in which the lining is composed of columnar oncocytic epithelium. [21]
Ductal papilloma
The intraductal type is characterized by a papillary network of cell-lined (columnar-cuboidal cells present on dilated salivary ducts) vascular fronds. The papillae partly fill the cystic cavity, and there is no evidence of cytologic atypia and mitoses. The inverted type has histologic features similar to those of sinonasal inverted papilloma and is composed of epithelial cells forming a papillary projection. Columnar cells, mucous cells, and microcysts may be seen. [16]
Lymphadenoma
Lymphadenomas are generally subcategorized as either sebaceous or nonsebaceous. Sebaceous lymphadenomas are more common and consist of solid-to-cystic proliferations of squamoid nests with varying degrees of sebaceous differentiation. One unique finding in sebaceous lymphadenomas is a granulomatous reaction to keratin and sebum in the surrounding lymphoid stroma. The epithelial component of nonsebaceous lymphadenomas is often basaloid in appearance, ranging from a solid to a tubulotrabecular growth pattern. [21]
Myoepithelioma
Myoepitheliomas are composed primarily of spindle cells, plasmacytoid (hyaline) cells, or a combination of cells that grow in a solid, nodular, myxoid-mucinous, pseudoglandular, trabecular, or reticulated pattern. Epithelioid, clear cell, and oncocytic variants are less common pathologies.
The spindle cells are organized in sheets or swirls and have central oval-to-elongated nuclei with finely dispersed chromatin and blunt tapered ends. The plasmacytoid cells have glassy, dense eosinophilic cytoplasm and eccentric round-to-oval nuclei. In comparison with other subsites, plasmacytoid variants are found more frequently in the palate. [21]
Oncocytoma
Oncocytomas are composed of polygonal oncocytes that may be arranged in a solid, a trabecular, or occasionally a compressed tubular growth pattern. Nuclei are round and vary from hyperchromatic to slightly vesicular with visible nucleoli. The periphery of tumor nests consists of darker cells with more scant cytoplasm. Squamous metaplasia may be seen in traumatized areas, particularly near an FNA tract. [21]
Pleomorphic adenoma
Pleomorphic adenomas have the following four components:
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Capsule
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Epithelial cells
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Myoepithelial cells
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Mesenchymal-stromal elements
Most of these tumors are composed of approximately 50% epithelial-myoepithelial cells and 50% mesenchymal-stromal elements. Tumors in which the percentage of epithelial-myoepithelial cells is 80% or higher are referred to as cellular pleomorphic adenomas, whereas those in which the percentage of mesenchymal-stromal elements is 80% or higher are referred to as acellular pleomorphic adenomas.
The epithelial cells are cuboidal to polygonal and appear as small ducts and acini surrounded by a single layer of myoepithelial cells. Tumor cells have eosinophilic-to-amphophilic cytoplasm and central mildly chromatic nuclei with absent or barely discernible nucleoli. Skin adnexal differentiation is frequently observed in palate pleomorphic adenoma. [54]
Myoepithelial cells exhibit remarkable phenotypic variation and may appear spindled, plasmacytoid, epithelioid, clear, or oncocytic. The mesenchymal-stromal components range from fibrous to myxoid to chondroid to osseous to lipomatous. Mitoses and necroses are sparse to absent and may be related to prior FNA cytology. [21]
Necrotizing sialometaplasia
Necrotizing sialometaplasia is similar in appearance to pseudoepitheliomatous hyperplasia, which appears as epithelial infiltration into underlying tissue, much like the visualized pattern of a carcinoma. Features distinguishing this condition from a malignant process include the following:
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Absence of cellular pleomorphism
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Maintenance of salivary lobular morphology
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Nondysplastic appearance of squamous islands or nests
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Evidence of residual ductal lumina within the epithelial nests
Histologically, lymphoepithelial hyperplasia is composed of diffuse well-organized lymphoid tissue and lymphocytic interstitial infiltrate with obliteration of the acinar pattern. [31]
Sebaceous adenoma
Sebaceous adenomas are well-circumscribed encapsulated masses made up of solid nests of sebaceous cells within a fibrous stroma. [16]
Sialadenoma papilliferum
In sialadenoma papilliferum, the salivary duct epithelium demonstrates a biphasic growth pattern into the squamous keratotic epithelium, resulting in papillary epithelial hyperplasia. [16, 55]
Sialolipoma
Sialolipomas are admixed with lipomatous and salivary tissue, as well as lobules of mature adipocytes.
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Histologic architecture of the salivary gland unit.
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Coronal magnetic resonance imaging (MRI) scan demonstrating a large, benign lesion of the right parapharyngeal space.
