Pleomorphic adenoma (PA) is the most common major salivary gland neoplasm, the vast majority arising in the parotid. It usually presents as a painless, slow growing, firm and well-defined solitary mass. While there are classic well-described cytomorphologic features that can help conclusively render a diagnosis of PA, there are unusual cytomorphologic variants of PA that can lead to an incorrect diagnosis and thus possible incorrect surgical treatment. In presenting our case we hope to broaden exposure to a challenging variant of a PA.

Classic PA demonstrates 3 components including: bland basaloid ductal epithelial cells, myoepithelial cells (loose cohesive groups or single cells, typically plasmacytoid or spindle-shaped), and fibrillary chondromyxoid stroma which stains magenta on MGG and pale blue on Pap stain. This last feature is often considered the most helpful diagnostic cytologic feature of a PA1. Myoepithelial cells are often seen embedded within the matrix. While the matrix material is classically fibrillary, it can also appear as hyaline stroma or hyaline globules with a dense circumscribed appearance resembling basement membrane material, as highlighted in our case. Various combinations of these 3 components can be present including; myoepithelial-dominant, epithelial-dominant, and matrix dominant neoplasms. Sampling from different regions of the tumor is critical to the cytomorphologic diagnosis of the neoplasm so that no single area with a predominant growth pattern is biasedly sampled.

Adenoid cystic carcinoma (AdCC) is the second most common malignant major salivary gland neoplasm and will often present with pain due to its neurotrophism. The cribriform subtype of AdCC is the most common variant and is characterized by clusters, sheets, and trabeculae of basaloid cells associated with globules of hyaline basement membrane-like matrix1. The presence of acellular hyaline globules is considered one of the most characteristic features, but it is not 100% specific2. The cell-stroma interface is described as distinct and sharply demarcated3, a feature to reflect on when reviewing FNA smears. Most commonly as a biphenotypic tumor with myoepithelial and occasional ductal components, the basaloid cells in an AdCC are described as having angulated hyperchromatic nuclei and very scant to no cytoplasm2,4, a feature that is often more prominent in the myoepithelial cells4. Numerous single cells with angulated or bipolar shaped nuclei and scant indiscernible cytoplasm have been described in the cytologic background5.

Both PA and AdCC can grow in a cylindromatous or cribriform pattern and contain dense (hyaline) globules6. In AdCC, the hyaline globules are basal lamina material produced by neoplastic myoepithelial cells5. In PA, although rare, hyaline globules are speculated to have two origins: inspissated secretions in duct-like structures and mucoid or hyaline stromal particles5. Typically, PA’s do not have an abundance of hyaline globules, but in our case, this feature was strikingly prominent, especially on MGG-stained smears (Pre-test image 2 and 3) hence the diagnostic overlap with AdCC. Cases with extensive AdCC-like matrix can serve as a significant diagnostic pitfall in classifying salivary gland neoplasms on FNA7-11. In such cases, careful examination of the cytomorphology is of utmost importance. Nuclei of an AdCC are most often small, hyperchromatic and angulated, compared to those of a PA which demonstrate smooth nuclear membranes and an open chromatin pattern. The presence of a plasmacytoid appearance to the tumor cells in a PA may also help with this distinction6.

The initial diagnosis in this case study was AdCC. In retrospective review, subtle features were appreciated that could have influenced a less conclusive malignant diagnosis: bland, hypochromatic basaloid cells, lack of angulated nuclei and focal fibrillary stroma (refer to post-test image 4). Although not seen in this FNA case, the presence of well-developed squamous metaplasia should also raise caution in making a diagnosis of AdCC, as this feature is more consistent with a PA or basal cell adenoma12. In our patient, given the location of the mass, there was fortunately no difference in the treatment plan; however, in a patient with a deep parotid mass, a diagnosis of AdCC can influence the surgical approach with more aggressive treatment and sacrifice of the facial nerve.

The complexity and shared morphologic similarities of salivary gland neoplasms has been recognized by many authors, and thus, FNA cytology has known limitations in accurately subclassifying salivary gland tumors. The Milan System for reporting salivary gland cytology was developed to better communicate to the clinician the risk of malignancy associated with each diagnostic category, and thus help guide clinical management2. The Milan System can be very helpful in classifying salivary gland neoplasm, especially with cellular basaloid neoplasms lacking significant matrix, or cases with overlapping features as seen in this case. In the Milan system, cases such as this should be placed in the subcategory of salivary gland neoplasm of uncertain malignant potential (SUMP)2.

In summary, PA and AdCC can have overlapping morphology; specifically, they can both grow in a cribriform or cylindromatous pattern and both can contain hyaline globule formation. Therefore, it is not only critical to sample various areas of the salivary gland lesion but also important to be aware of overlapping morphologic features to provide the most accurate diagnosis for the patient.