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NKX3.1 Expression and Molecular Characterization of Secretory Myoepithelial Carcinoma (SMCA): Advancing the Case for a Salivary Mucous Acinar Phenotype

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Abstract

Background

Secretory myoepithelial carcinomas (SMCA) are rare, mucinous, signet ring predominant tumors with primitive myoepithelial features. While many mucinous salivary gland tumors have now been molecularly characterized, key drivers in SMCA have yet to be elucidated. Recently, NKX3.1, a homeodomain transcription factor implicated in salivary mucous acinar development was also shown in a subset of salivary mucinous neoplasms, salivary intraductal papillary mucinous neoplasms (SG-IPMN). To date, NKX3.1 expression has not been characterized in other mucinous salivary lesions. Here, we report molecular and extended immunophenotypic findings in SMCA and NKX3.1 expression in the context of other head and neck lesions.

Methods

We retrieved 4 previously reported SMCA, performed additional immunohistochemical and targeted next-generation sequencing (NGS). We also investigated the use of NKX3.1 as a marker for SMCA in the context of its prevalence and extent (using H-score) in a mixed cohort of retrospectively and prospectively tested head and neck lesions (n = 223) and non-neoplastic tissues (n = 66).

Results

NKX3.1 positivity was confirmed in normal mucous acini as well as in mucous acinar class of lesions (5/6, mean H-score: 136.7), including mucinous adenocarcinomas (3/4), SG-IPMN (1/1), and microsecretory adenocarcinoma (MSA) (1/1). All SMCA were positive. Fluorescence in situ hybridization for SS18 rearrangements were negative in all successfully tested cases (0/3). NGS was successful in two cases (cases 3 and 4). Case 3 demonstrated a PTEN c.655C>T p.Q219* mutation and a SEC16A::NOTCH1 fusion while case 4 (clinically aggressive) showed a PTEN c.1026+1G>A p.K342 splice site variant, aTP53 c.524G>A p.R175H mutation and a higher tumor mutation burden (29 per Mb). PTEN immunohistochemical loss was confirmed in both cases and a subset of tumor cells showed strong (extreme) staining for P53 in Case 4.

Conclusion

Despite a partial myoepithelial phenotype, SMCA, along with mucinous adenocarcinomas/SG-IPMN and MSA, provisionally constitute a mucous acinar class of tumors based on morphology and NKX3.1 expression. Like salivary mucinous adenocarcinomas/SG-IPMN, SMCA also show alterations of the PTEN/PI3K/AKT pathway and may show progressive molecular alterations. We document the first extramammary tumor with a SEC16A::NOTCH1 fusion.

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Funding

Trainee Research Advancement Award (Department of Pathology at University of Pittsburgh, Pittsburgh, PA).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Simmi Patel, Abigail I. Wald, Simon I. Chiosea, Aatur D. Singhi & Raja R. Seethala

  2. Al-Sabah Hospital and Kuwait Cancer Control Center, Ministry of Health, Kuwait City, Kuwait

    Jassem M. Bastaki

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  1. Simmi Patel
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  2. Abigail I. Wald
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  3. Jassem M. Bastaki
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  4. Simon I. Chiosea
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  6. Raja R. Seethala
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Contributions

Conceptualization: SP, RRS; Methodology: AIW, JMB, SIC, ADS, RRS; Formal analysis and investigation: SP, RRS; Writing—original draft preparation: SP; Writing—review and editing: JMB, SIC, ADS, RRS; Funding acquisition: SP, RRS; Resources: AIW, SIC, ADS, RRS; Supervision: RRS.

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Correspondence to Simmi Patel.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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This study has obtained IRB approval from (University of Pittsburgh Human Research Protection Office) and the need for informed consent was waived.

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Part of this study was awarded a Leon Barnes award as a poster at the USCAP 2022 Annual Meeting in Los Angeles (Abstracts from USCAP 2022: Head and Neck Pathology (833) Mod Pathol 2022; 35: 897). Dr. Seethala is currently a member of the Editorial Board for Head and Neck Pathology Journal.

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Patel, S., Wald, A.I., Bastaki, J.M. et al. NKX3.1 Expression and Molecular Characterization of Secretory Myoepithelial Carcinoma (SMCA): Advancing the Case for a Salivary Mucous Acinar Phenotype. Head and Neck Pathol 17, 467–478 (2023). https://doi.org/10.1007/s12105-023-01524-2

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