Answer: A. Secretory carcinoma vs Salivary duct carcinoma

Despite S100 negativity, given the strong GATA3, weaker androgen receptor uptake and presence of secretory features on cytomorphology, consideration of secretory carcinoma should be made, although a definitive distinction from salivary duct carcinoma is difficult on cytology alone.

Histology of the subsequent resection showed similar features, with high grade nuclear morphology and the presence of necrosis and high proliferative activity with Ki67 staining (20%). Immunohistochemistry performed showed similar results, with negativity for S100 and mammaglobin. A FISH analysis was positive for ETV6-NTRK3 gene fusion. Altogether, the final diagnosis was best in keeping with that of a high grade secretory carcinoma.

Both salivary duct carcinoma and secretory carcinoma of salivary gland can demonstrated compact tubular forms imparting a cribriform appearance (1). The key difference is that salivary duct carcinoma is a high grade tumour, typically with high grade nuclear morphology with prominent nucleoli and necrosis, while secretory carcinoma is usually a low grade tumour with more uniform nuclei and lacking necrosis and prominent nucleoli.

However, it has been reported that secretory carcinomas can undergo high grade transformation (2 to 4). Features of high grade transformation include more solid growth pattern, presence of necrosis, highger nuclear grade, evidence of increased proliferative activity and evidence of loss of secretory activity. Loss of expression of S100 and/or mammaglobin, highly sensitive markers for low grade secretory carcinoma, have also been reported rarely in literature (3, 4).

Given the significant morphological and immunohistochemical overlap between secretory and salivary duct carcinomas, molecular analysis can be used to aid in diagnosis. High grade secretory carcinomas will retain the molecular alterations associated with the low grade form; in a recent study by Thompson et al (2), all cases of secretory carcinoma assessed, including 29 high grade cases, showed ETV6-NTRK3 fusions in 81.8% and other translocations or breaks of ETV6 or RET genes in the remainder.

References:

1. 1. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO Classification of Head and Neck Tumours 4^th Edition. 2017.
   2. Baněčková M, Thompson LDR, Hyrcza MD, Vaněček T, Agaimy A, Laco J, Simpson RHW, Di Palma S, Stevens TM, Brcic L, Etebarian A, Dimnik K, Majewska H, Stárek I, O'Regan E, Salviato T, Helliwell T, Horáková M, Biernat W, Onyuma T, Michal M, Leivo I, Skalova A. Salivary Gland Secretory Carcinoma: Clinicopathologic and Genetic Characteristics of 215 Cases and Proposal for a Grading System. Am J Surg Pathol. 2023 Jun 1;47(6):661-677. 
   3. Suzuki K, Harada H, Takeda M, Ohe C, Uemura Y, Kawahara A, Sawada S, Kanda A, Sengupta B, Iwai H. Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report. BMC Med Genomics. 2022 Jan 6;15(1):6.
   4. Wang T, Yang X, Yao L, Wan Z, Zhao H, Zheng Z, Tang Y, Chen Y, Han Q. Clinicopathological analysis of 18 cases of secretory carcinoma of the salivary glands. Journal of Dental Sciences. Epub 2023 Jun.