Parotid  

A 59-year-old man presents with a left parotid mass that had been present for five years. On physical examination, a firm, fixed, 2.5 cm mass with overlying skin changes was noted in the left parotid, along with weak facial mobility on the left side. Multiple lymph nodes (level 11 and level V) were palpable. A fine–needle aspiration (FNA) of the parotid mass is performed. The tumor is positive for CK7 and AR immunohistochemistry that was performed on the sections of the cell block.

Master List of Diagnoses:

• Acinic cell carcinoma
• Mucoepidermoid carcinoma (MEC)
• Salivary duct carcinoma (SDC)
• Secretory carcinoma 

This case first appeared as Fine-Needle Aspirate Program (FNA) 2023, Case 04, and is salivary duct carcinoma in the parotid gland. The information provided in this case was accurate and correct at the time of publication in 2023. Any changes in terminology since the time of publication may not be reflected in this case.

The aspirate smears are hypercellular with cells arranged in irregular, variably sized clusters and dispersed singly. The tumor cells are polygonal with mild to moderate pleomorphism, a moderate amount of finely granular and occasionally vacuolated cytoplasm, and central to focally eccentric, round to ovoid nuclei with smooth to focally irregular nuclear contours, coarse chromatin, and prominent nucleoli. H&E-stained sections of the cell block show tumor cells cytologically similar to those seen in the smears. The presence of a single population of tumor cells and moderate pleomorphism, the history of parotid mass for five years, nerve involvement, and neck lymphadenopathy are clues to the diagnosis of salivary duct carcinoma (SDC) which is confirmed with a positive immunostain for androgen receptor (AR).  

SDC is a high-grade, malignant tumor that most commonly arises in the parotid gland of older men. There is no formal grading system for SDCs; all SDCs are regarded as high-grade. High pathological stage is identified as a factor contributing to a worst prognosis and as the main indicator for treatment failure.

Macroscopically, SDCs are usually poorly circumscribed with an irregular and infiltrative periphery. The cut surface is firm and scirrhous and often shows areas of calcification, cystic change, and necrosis Histologically, a tumor is characterized by variable-sized, rounded, solid, or cystic nodules of tumor cells, often with central comedonecrosis separated by fibrosis. The tumor cells are generally large and show moderate to marked pleomorphism. Mitotic figures are easily identified. The major variants include sarcomatoid, mucin-rich, micropapillary, oncocytic, osteoclastic-giant cell, basal-like, squamous, and rhabdoid types. Identification of the variants is important because they may be the only histologic type present at the site of metastasis.  

Diffuse androgen receptor (AR) expression can help confirm the diagnosis of SDC.  

Establishing an accurate preoperative diagnosis of SDC by FNA is important as aggressive clinical management, including radical surgery and postoperative radiation therapy in the early stage of the tumor, appears to be the only hope for long-term survival. Androgen deprivation therapy (ADT) has shown a response rate of 18% to 42% in SDC. Approximately 30% of SDCs show HER-2::ERBB2 amplification, a potential target for ERBB inhibitors.

More recently, comprehensive molecular profiling of SDC has revealed other actionable targets, including PIK3CA, HRAS, BRAF, PTEN, NTRK, and RET, in cases of advanced and unresectable SDC.

Acinic cell carcinoma (AciCC) aspirate smears are hypercellular with monotonous polygonal tumor cells arranged in loose aggregates or as single isolated cells. The tumor cells have smooth and rounded, uniform nuclei with delicate to coarsely granular (blue-dot) basophilic cytoplasm. Immunocytochemically, AciCC is generally positive for SOX10 and DOG-1 but negative for S100, mammaglobin, and myoepithelial markers. The majority of AciCC shows a recurrent (t[4;9][q13;q31]) rearrangement resulting in upregulation of the nuclear receptor subfamily 4 group A (NR4A3) member 3/NOR1, which can be detected by immunohistochemistry. Other helpful stains are DOG1 with a unique apical-luminal positivity and PAS-diastase which highlights the Zymogen granules.  

Mucoepidermoid carcinoma (MEC) is characterized by the presence of three different cell types: mucocytes with intracytoplasmic mucin), intermediate cells resembling immature squamous cells, and epidermoid cells in varying proportions. The variability in the presence of the cell type depends upon the grade of the tumor, which can make the diagnosis challenging. Low-grade MEC is cystic, has abundant mucin, and is paracellular with single cells resembling macrophages floating in mucin.  In contrast, aspirates of high-grade MEC are highly cellular and are characterized by cytologic atypia, anisonucleosis, keratotic cells, and rare to absent mucinous cells. CRTC1::MAML2 and CRTC3::MAML2 gene fusions are highly specific for the diagnosis of MEC; they occur in 40%–90% and 6% of cases respectively.

Aspirate smears of secretory carcinoma (SC) are hypercellular and contain aggregates of uniform neoplastic cells with rounded smooth nuclei or with minimal irregularities, small visible nucleoli, and a moderate amount of granular to often multiple/septated vacuolated cytoplasm resembling macrophages. The background may show proteinaceous secretions and or granular debris. Secretory carcinoma is characterized by the presence of gene fusions involving ETV6::NTRK3, resulting from a balanced translocation t(12;15) (p13:q25). Demonstration of an ETV6 rearrangement is a useful adjunct in confirming the diagnosis. Immunohistochemical co-expression for S-100 and mammaglobin and negative expression for p63 and DOG1 is helpful in differential is helpful in differential diagnosis from morphologic mimics. More recently pan-TRK immunostaining has been reported as a cheap, fast, and accessible nuclear marker for diagnosis of secretory carcinoma and also as a screening tool for selecting patients to undergo confirmative molecular testing for clinical trials using TRK inhibitors. 

1. Which of the following markers can help guide therapeutic strategy in a salivary duct carcinoma (SDC)?  
   
    
   1. NR4A3
   2. P63
   3. Pan-TRK
   4. AR and Her 2
2. Which of the following immunostains is diagnostic for acinic cell carcinoma? 
   
    
   1. NR4A3/NOR1
   2. S-100
   3. Mammaglobin
   4. DOG1
3. Secretory carcinoma is characterized by which of the following molecular alterations? 
   
    
   1. ETV6::NTRK3
   2. HER-2::ERBB2 amplification  
   3. CRTC1::MAML2
   4. t(4;9) (q13; q31) rearrangement 

1. El-Naggar AK, Chan J, Takata T, Grandis J, Blootweg P. Who classification of Tumors. Pathology and Genetics of Head and Neck Tumors. 4th ed. Lyon, France : IARC Press;2022
2. Faquin WC, Rossi ED, Baloch Z, et al. eds. The Milan System for Reporting Salivary Gland Cytopathology, Second edition. Cham, Switzerland; Springer  
3. Carillo AM, De Luca C, Pisapia P, Vigliar E, Ikenberg K, Freiberger SN, Troncone G, Rupp NJ, Bellevicine C. Molecular testing in salivary gland cytopathology: A practical overview in conjunction with the Milan system. Cytopathology. 2024 May;35(3):330-343 

1. AR and Her 2
2. NR4A3/NOR1
3. ETV6::NTRK3