A 78-year-old male with a history of right submandibular gland neoplasm treated with resection in 2018, presented with a 1.5 cm subcutaneous mass in the neck near the site of the prior surgical resection. A fine needle aspiration (FNA) of the right neck mass was performed, and specimen showed clusters of neoplastic cells morphologically and immunohistochemically similar to the tumor cells seen in the patient’s prior submandibular gland resection. Immunocytochemical stains performed on the cell block showed that the neoplastic cells were patchy positive for mammaglobin and S100 and negative for p63, SMA, DOG1 and TTF-1.

 

Authors

• Niki Shreshta, MD and Lagnajita Datta, MD
  University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio

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Figure 1	Figure 2	Figure 3
Figure 4	Figure 5	Figure 6
Figure 7	Figure 8	Figure 9

Images 1-9:

• Figure 1: FNA of the subcutaneous mass, aspirate smear, Diff-Quik stained, 100X magnification
• Figure 2: FNA of the subcutaneous mass, aspirate smear, Diff-Quik stained, 200X magnification
• Figure 3: FNA of the subcutaneous mass, aspirate smear, Papanicolaou stained, 100X magnification
• Figure 4: FNA of the subcutaneous mass, aspirate smear, Papanicolaou stained, 200X magnification
• Figure 5: FNA of the subcutaneous mass, aspirate smear, Papanicolaou stained, 400X magnification
• Figure 6:  Cell block, Hematoxylin and Eosin (H&E) stain, 200X magnification
• Figure 7: Cell block, Mammaglobin immunocytochemical stain, 400X magnification
• Figure 8: Surgical resection specimen, Hematoxylin and Eosin (H&E) stain, 100X magnification
• Figure 9: Surgical resection specimen, Mammaglobin immunocytochemical stain, 100X magnification

Questions:

1. What is the most likely diagnosis?
   
   
1. Cystadenocarcinoma
2. Intraductal carcinoma of the salivary gland
   
3. Mammary-analogue secretory carcinoma
4. Acinic cell carcinoma
5. Mucoepidermoid carcinoma



2. Further molecular and FISH studies were performed on both the surgical and cytology specimen to confirm the diagnosis. Which of the following molecular features is most associated with the tumor?
   
   
   1. MYB-NFIB translocation
   2. ETV6-NTRK3 fusion gene
   3. TP53 mutation
   4. HER2 amplification
   5. PLAG1 translocation
      

Answers:

Question 1: Correct answers is C Mammary-analogue secretory carcinoma.
The patient's history of right submandibular gland adenocarcinoma with a new subcutaneous mass near the prior surgical site raises concern for recurrence or metastasis and the FNA cytology findings favors the diagnosis of local recurrence of the patient's previously known mammary-analogue secretory carcinoma. Mammary analogue secretory carcinoma (MASC) is a recently identified low-grade carcinoma that shares both morphological and genetic characteristics with breast secretory carcinoma. Histologically, MASC exhibit a variety of growth patterns, with uniform round epithelioid cells that can form papillary, cystic, microcystic, tubular, cribriform, or solid structures. These tumors also contain abundant homogeneous, eosinophilic or bubbly extracellular secretory material.

It can be extremely challenging to diagnose salivary tumors including MASC on cytology smears with subtle features. They can resemble acinic cell carcinoma, polymorphous adenocarcinoma, mucoepidermoid carcinoma and other adenocarcinomas. However, secretory carcinoma presents as uniform, round-to-histiocytoid tumor cells with round or ovoid nuclei, small or indistinct central nucleoli, and abundant, variably vacuolated cytoplasm, which may occasionally appear oncocytic. The tumor cells may be arranged in sheets, papillary groups, or scattered individually. Some cells may contain a single enlarged cytoplasmic vacuole, and extracellular secretory material may be observed in the background. MASC has a characteristic immunophenotype with co-expression of mammaglobin and S100, even in cases showing high-grade transformation. Most cases exhibit strong and diffuse mammaglobin staining, although some may show focal positivity. S100 staining is more variable, with about half of the cases showing strong, diffuse staining. These tumors may also show positivity for CK7, GATA3, and pan-TRK. The tumor's extracellular and intracellular secretory material is PAS-positive, diastase-resistant, and stains with mucicarmine, distinguishing it from other salivary neoplasms.

Question 2: Correct answer is B ETV6-NTRK3 fusion gene.

Mammary analogue secretory carcinoma is characterized by the recurrent t(12;15)(p13;q25) translocation, leading to the ETV6-NTRK3 gene fusion which leads to abnormal tyrosine kinase activity promoting oncogenesis. ETV6-NTRK3 gene fusion has also been identified in secretory carcinoma of the breast, as well as in other rare cancers such as infantile fibrosarcoma, congenital mesoblastic nephroma, papillary thyroid cancer, and various hematologic malignancies. In this case, the presence of similar neoplastic cells to those in the prior submandibular resection specimen, along with the detection of the ETV6-NTRK3 gene fusion strongly supports recurrence of the original carcinoma. Other mutations, like TP53, MYB-NFIB translocation (identified in adenoid cystic carcinomas), or PLAG1 translocation (identified in pleomorphic adenomas) are not typical of MASC, and HER2 amplification is more commonly associated with breast cancers, particularly in HER2-positive subtypes. The molecular understanding of MASC has led to potential therapeutic strategies targeting the NTRK pathway, with TRK inhibitors like larotrectinib showing promising clinical results in patients with MASC harboring the ETV6-NTRK3 fusion. Thus, the ETV6-NTRK3 fusion is a hallmark molecular feature of MASC, providing both a diagnostic biomarker and a potential therapeutic target.

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