Fine-needle Aspiration Cytology of Mammary Analog Secretory Carcinoma of the Parotid Gland: A Diagnostic Conundrum.

Mammary analog secretory carcinoma (MASC) is a recently described salivary gland neoplasm with the parotid gland being the most common location, defined by the t (12;15) (q13;q25) translocation that results in ETV6-NTRK3 gene fusion product. Fine-needle aspiration cytology (FNA) can pose diagnostic difficulties due to the overlapping cytological features with acinic cell carcinoma (AciCC), mucoepidermoid carcinoma (MEC), oncocytic salivary neoplasms, low-grade cystadenocarcinoma, and pleomorphic adenoma (PA).[1] Herein, we highlight cytological features and ancillary studies that would help in a more precise preoperative diagnosis of MASC.

A 28-year-old male presented to the cytology department of our hospital, for FNA of a nontender parotid gland swelling which was progressively increasing in size for the past 2 years. Computed tomography scan showed a well-defined cystic lesion about 2 cm × 3.2 cm × 2.6 cm involving the left parotid gland. FNA showed several clusters of atypical epithelial cells, some of them in papillary groups [Figure 1a and b]. The cells possess moderate-to-abundant cytoplasm with multiple intracytoplasmic vacuoles, round nuclei with bland chromatin, and small nucleoli. There were few clusters of metaplastic squamous cells and numerous foamy macrophages in a mucinous background [Figure 1c and d]. A diagnosis of low-grade salivary gland neoplasm with the possibility of MEC/AciCC was made. A histological correlation was advised. Subsequently, the patient underwent superficial parotidectomy. The surgical specimen comprised the superficial lobe of the parotid gland (12 g, 4.5 cm × 3.3 cm × 1.5 cm) which on sectioning showed a well-delineated cystic tumor (1.8 cm × 1.5 cm × 0.6 cm). Histological evaluation revealed an extraductal unencapsulated solid and cystic neoplasm with varied architectural patterns such as tubular, papillocystic, microcystic, and cribriform patterns [Figure 2a]. The constituent cells were small-to-medium-sized with oval-to-round nuclei with pale chromatin, an occasional small nucleolus, and abundant pink to eosinophilic bubbly cytoplasm [Figure 2b]. The microcysts contained luminal eosinophilic colloid-like secretions [Figure 2b]. The tumor showed strong diffuse expression of CK8/18, PANCK, CK7, EMA, S-100, GCDFP-15, and negative for p63 and DOG-1 [Figure 2c and d]. Mucicarmine stain highlighted the intracellular and extracellular mucin vacuoles. Based on the histological and immunohistochemical studies, a diagnosis of MASC was made. Unfortunately, fluorescence in situ hybridization for the demonstration of ETV6-NTRK3 was not available in our hospital. The patient is well and under follow-up till date.

Figure 1

(a) Low-power view of fine-needle aspiration cytology smear showing clusters of epithelial cells in the papillary groups (Papanicolaou stain, ×200). (b) High-power view of the aspirate showing clusters of epithelial cells with intracytoplasmic vacuoles in a mucinous background, respectively (May–Grunwald–Giemsa stain, ×400). (c) The aspirate showing metaplastic squamous cells (May–Grunwald–Giemsa stain, ×400). (d) High-power view of fine-needle aspiration cytology smear showing clusters of cells with intracytoplasmic vacuoles (Papanicolaou stain, ×400)

Figure 2

(a) Solid and cystic tumor exhibiting microcystic and cribriform patterns (H and E, ×200). (b) High power showing tumor cells with uniform round nuclei, small nucleolus, eosinophilic cytoplasm, and luminal colloid-like secretions (H and E, ×400). (c) Tumor positive for S100 immunostain (×200). (d) The tumor cells are negative for DOG-1 (immunoperoxidase, ×200)

MASC typically occurs in the adult population over the wide age range of 14–77 years (average age of 45 years) with male predominance. In 70% of the cases, parotid glands are involved. Less common subsites include submandibular glands and other oral cavity subsites such as the soft palate, buccal mucosa, base of tongue, and lips.[2]

An upfront diagnosis of MASC on FNA is often difficult as their cytological features overlap with those of AciCC, MEC, Warthin's tumor, low-grade cystadenocarcinoma, and PA.

The salient cytological features of MASC described in the literature are monomorphic population of cells in clusters, papillary groups, and singly dispersed eosinophilic cells with round nuclei, small nucleoli, and multivacuolated cytoplasm. Extracellular and intracellular mucins were also described.[1]

MASC is most often confused with AciCC. The features that aid in the diagnosis of AciCC are the presence of basophilic cytoplasmic (zymogen) granules which are PAS diastase-resistant and the absence of mucin production.[2] Other helpful features of AciCC are nuclei with macronucleoli and abundant arborizing vessels. However, granular AciCC can be really challenging, which can be resolved using immunohistochemical studies. MASC shows positivity for S-100 and mammoglobulin and is negative for DOG-1. The reverse staining pattern is observed in AciCC. At molecular level, the demonstration of the ETV6-NTRK3 fusion gene is characteristic of MASC.[23]

The clear and vacuolated cells of MASC may be mistaken for low-grade MEC, particularly the presence of intracellular mucin in both tumors. However, MASC does not have the intimate mixture of epidermoid cells and intermediate cells that characterize MEC. On close scrutiny, MASC cells tend to be multivacuolated as opposed to univacuolation in MEC.

Salivary duct carcinoma and PA can rarely be confused with MASC. The former is characterized by greater nuclear pleomorphism and higher grade. The myxoid stroma of PA can be confused with mucin production in MASC, but the metachromatic nature of the material in PA should be helpful in differentiation.[34]

Finally, metastatic renal cell carcinoma (RCC) could be a consideration, given the low-grade appearance with common clear cells and histiocyte-like cells we observed in MASC. However, RCC is characterized by perivascular nesting, macronucleoli, and often cytoplasmic metachromatic stromal material. Certainly, a history of renal tumor would also be helpful in this differential diagnosis. If doubt remains, performing immunohistochemistry for renal markers such as RCC, CD10, and PAX8 on cell block material would resolve the diagnosis.[5]

MASC should also be in the differential diagnosis of FNA of salivary gland tumors, especially when AciCC and MEC are considered. The cytological features along with clinical findings, immunohistochemical studies complemented by molecular studies on cell block can produce a more accurate preoperative diagnosis of MASC.

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