Skip to main content
SpringerLink
Log in

NKX3.1 Expression in Salivary Gland “Intraductal” Papillary Mucinous Neoplasm: A Low-Grade Subtype of Salivary Gland Mucinous Adenocarcinoma

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

Background

Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently proposed entity characterized by a papillary-cystic proliferation of mucin-producing cells. Because of overlapping histologic features and a clonal AKT1 p.E17K variant, SG IPMN has been presumed to be a precursor or a low-grade subtype of mucinous adenocarcinoma. NKX3.1 is a tumor suppressor gene located on chromosome 8p and is a known immunohistochemical marker of prostate epithelium and mucinous acinar cells of the intraoral salivary glands.

Methods

We retrieved 12 SG IPMN cases, and performed histologic and genetic analysis. Given the association of SG IPMN with mucinous acinar cells, we also investigated the performance of NKX3.1 as a marker of this tumor entity.

Results

Diffuse and strong NKX3.1 expression was observed in all SG IPMN cases (12/12, 100%) as well as in normal mucinous acinar cells. In contrast, mucoepidermoid carcinoma and pancreatic IPMN cases as well as normal serous acinar cells were negative for NKX3.1. Genetically, 11 of 12 cases (92%) harbored an AKT1 p.E17K variant. A novel PTEN frameshift deletion (p.G36Dfs*18) was detected in the other single case. At least one of the histologic features implying malignant tumors, such as severe cellular atypia, brisk mitotic activity, high Ki-67 proliferating index, lymphovascular invasion, and lymph node metastasis, was detected in 6 SG IPMN cases (50%).

Conclusion

The findings suggest that SG IPMN is a low-grade subtype of mucinous adenocarcinoma which may be derived from mucinous acinar cells of the minor salivary gland.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author, MN, upon reasonable request.

Code Availability

Not applicable.

References

  1. Rooper LM, Agaimy A, Bishop JA, Gnepp D, Leivo I. Mucinous adenocarcinoma. In: WHO Classification of Tumours Online, Head and Neck Tumours (WHO classification of tumours series, 5th ed.; vol. 9). https://tumourclassification.iarc.who.int/chapters/52. Accessed 28 Apr 2022.

  2. Rooper LM, Argyris PP, Thompson LDR, Gagan J, Westra WH, Jordan RC, et al. Salivary mucinous adenocarcinoma is a histologically diverse single entity with recurrent AKT1 E17K mutations: clinicopathologic and molecular characterization with proposal for a unified classification. Am J Surg Pathol. 2021;45(10):1337–47.

    Article  Google Scholar 

  3. Agaimy A, Mueller SK, Bumm K, Iro H, Moskalev EA, Hartmann A, et al. Intraductal papillary mucinous neoplasms of minor salivary glands with AKT1 p.Glu17Lys mutation. Am J Surg Pathol. 2018;42(8):1076–82.

    Article  Google Scholar 

  4. Nakaguro M, Urano M, Ogawa I, Hirai H, Yamamoto Y, Yamaguchi H, et al. Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm. Histopathology. 2020;76(3):411–22.

    Article  Google Scholar 

  5. Skálová A, Hyrcza MD, Leivo I. Update from the 5th edition of the World Health Organization classification of head and neck tumors: salivary glands. Head Neck Pathol. 2022;16(1):40–53.

    Article  Google Scholar 

  6. Bishop JA. Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: emerging entities in salivary gland tumor pathology. Head Neck Pathol. 2022;16(1):179–89.

    Article  Google Scholar 

  7. Griffin J, Chen Y, Catto JWF, El-Khamisy S. Gene of the month: NKX3.1. J Clin Pathol. 2022;75(6):361–4.

    Article  CAS  Google Scholar 

  8. Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mech Dev. 2000;95(1–2):163–74.

    Article  CAS  Google Scholar 

  9. Gurel B, Ali TZ, Montgomery EA, Begum S, Hicks J, Goggins M, et al. NKX3.1 as a marker of prostatic origin in metastatic tumors. Am J Surg Pathol. 2010;34(8):1097–105.

    Article  Google Scholar 

  10. Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG, Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev Dyn. 2000;219(2):248–60.

    Article  CAS  Google Scholar 

  11. Yoshida KI, Machado I, Motoi T, Parafioriti A, Lacambra M, Ichikawa H, et al. NKX3-1 is a useful immunohistochemical marker of EWSR1-NFATC2 sarcoma and mesenchymal chondrosarcoma. Am J Surg Pathol. 2020;44(6):719–28.

    Article  Google Scholar 

  12. Takada N, Nishida H, Oyama Y, Kusaba T, Kadowaki H, Arakane M, et al. Immunohistochemical reactivity of prostate-specific markers for salivary duct carcinoma. Pathobiology. 2020;87(1):30–6.

    Article  CAS  Google Scholar 

  13. Yang RK, Zhao P, Lu C, Luo J, Hu R. Expression pattern of androgen receptor and AR-V7 in androgen-deprivation therapy-naïve salivary duct carcinomas. Hum Pathol. 2019;84:173–82.

    Article  CAS  Google Scholar 

  14. Agaimy A. Papillary neoplasms of the salivary duct system: a review. Surg Pathol Clin. 2021;14(1):53–65.

    Article  Google Scholar 

  15. Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Lynch KD, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20(12):1479–84.

    Article  CAS  Google Scholar 

  16. Chu YH, Wirth LJ, Farahani AA, Nosé V, Faquin WC, Dias-Santagata D, et al. Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization. Mod Pathol. 2020;33(12):2458–72.

    Article  CAS  Google Scholar 

  17. Urano M, Nakaguro M, Yamamoto Y, Hirai H, Tanigawa M, Saigusa N, et al. Diagnostic significance of HRAS mutations in epithelial-myoepithelial carcinomas exhibiting a broad histopathologic spectrum. Am J Surg Pathol. 2019;43(7):984–94.

    Article  Google Scholar 

  18. Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto M, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci Rep. 2011;1:161.

    Article  Google Scholar 

  19. Nakaguro M, Tada Y, Faquin WC, Sadow PM, Wirth LJ, Nagao T. Salivary duct carcinoma: updates in histology, cytology, molecular biology, and treatment. Cancer Cytopathol. 2020;128(10):693–703.

    Article  CAS  Google Scholar 

  20. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.

    Article  CAS  Google Scholar 

  21. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.

    Article  CAS  Google Scholar 

  22. Yang S, Zeng M, Chen X. Intraductal papillary mucinous neoplasm of the minor salivary gland with associated invasive micropapillary carcinoma. Am J Surg Pathol. 2019;43(10):1439–42.

    Article  Google Scholar 

  23. Miura A, Mori T, Yoshida A, Watanabe Y, Sunami K, Watanabe S, et al. Primary adenocarcinoma of the trachea revealing a mucinous bronchial gland cell origin. Pathol Res Pract. 2018;214(5):796–9.

    Article  Google Scholar 

Download references

Acknowledgements

None

Funding

This study was funded by NIH/NHS 1P01CA240239-01 (WCF, PMS).

Author information

Authors and Affiliations

  1. Department of Pathology, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA

    Masato Nakaguro, Peter M. Sadow & William C. Faquin

  2. Department of Pathology and Laboratory Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan

    Masato Nakaguro

  3. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Rong Hu

  4. Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan

    Hikaru Hattori

  5. Department of Pathology and Clinical Laboratories, Komaki City Hospital, Komaki, Japan

    Kyoko Kuwabara

  6. Department of Surgical Pathology, Aichi Medical University, Nagakute, Japan

    Toyonori Tsuzuki

  7. Department of Diagnostic Pathology, Bantane Hospital, Fujita Health University, Nagoya, Japan

    Makoto Urano

  8. Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan

    Toshitaka Nagao

Authors
  1. Masato Nakaguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter M. Sadow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hikaru Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyoko Kuwabara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toyonori Tsuzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Makoto Urano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshitaka Nagao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William C. Faquin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MN, PMS, and WCF contributed to the study conception and design. Material preparation, data collection and analysis were performed by MN, PMS, RH, KK, TT, MU, TN, and WCF. The first draft of the manuscript was written by MN, PMS, and WCF. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masato Nakaguro.

Ethics declarations

Conflict of interest

The other authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

The present study was approved by the Institutional Review Board (IRB) of each collaborating institution (Mass General Brigham IRB 2015P001749, Nagoya University IRB 2018–019014195).

Consent to Participate

The need to obtain informed consent was waived due to the retrospective nature of the analysis.

Consent for Publication

The need to obtain informed consent was waived due to the retrospective nature of the analysis.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 63 KB)

Supplementary file2 (PDF 42 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakaguro, M., Sadow, P.M., Hu, R. et al. NKX3.1 Expression in Salivary Gland “Intraductal” Papillary Mucinous Neoplasm: A Low-Grade Subtype of Salivary Gland Mucinous Adenocarcinoma. Head and Neck Pathol 16, 1114–1123 (2022). https://doi.org/10.1007/s12105-022-01471-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-022-01471-4

Keywords

Search

Navigation