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Head and Neck Pathology

, Volume 12, Issue 1, pp 13–21 | Cite as

Proceedings of the NASHNP Companion Meeting, March 18th, 2018, Vancouver, BC, Canada: Salivary Neuroendocrine Carcinoma—An Overview of a Rare Disease with an Emphasis on Determining Tumor Origin

  • Rebecca D. Chernock
  • Eric J. Duncavage
Proceedings of the North American Society of Head and Neck Pathology Companion Meeting, March 18, 2018, Vancouver, British Columbia, Canada

Abstract

Salivary neuroendocrine carcinomas are rare and the overwhelming majority is high-grade. The parotid gland is the most commonly involved site followed by the submandibular gland. Most arise de novo but rare examples occurring as a high-grade transformation of another type of salivary gland neoplasm exist. There is significant morphologic and immunophenotypic overlap with neuroendocrine carcinomas of other sites, especially the skin. Like cutaneous neuroendocrine (or Merkel cell) carcinomas, approximately three-fourths are cytokeratin 20 positive. Cytokeratin 20 positive salivary neuroendocrine carcinomas are often referred to as being of the ‘Merkel cell type’ since most other non-cutaneous neuroendocrine carcinomas are cytokeratin 20 negative. Salivary neuroendocrine carcinomas may be challenging to separate from Merkel cell carcinomas of the head and neck on pathologic grounds because the latter often metastasize to the parotid gland. Clinical history is often relied upon to separate primary salivary tumors from cutaneous metastases but may not be helpful in all cases. Here we review the clinical, pathologic and molecular features of salivary neuroendocrine carcinomas focusing on high-grade major salivary gland tumors. The difficulty in separating salivary tumors from metastatic Merkel cell carcinoma will be highlighted.

Keywords

Salivary Neuroendocrine carcinoma Small cell carcinoma Large cell neuroendocrine carcinoma Merkel cell polyomavirus Merkel cell carcinoma 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors have no sources of funding or conflicts of interest to disclose.

References

  1. 1.
    Nagao T, Gaffey TA, Olsen KD, Serizawa H, Lewis JE. Small cell carcinoma of the major salivary glands: clinicopathologic study with emphasis on cytokeratin 20 immunoreactivity and clinical outcome. Am J Surg Pathol. 2004;28:762–70.CrossRefPubMedGoogle Scholar
  2. 2.
    Gnepp DR, Wick MR. Small cell carcinoma of the major salivary glands. An immunohistochemical study. Cancer. 1990;66:185–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Mair S, Phillips JI, Cohen R. Small cell undifferentiated carcinoma of the parotid gland. Cytologic, histologic, immunohistochemical and ultrastructural features of a neuroendocrine variant. Acta Cytol. 1989;33:164–8.PubMedGoogle Scholar
  4. 4.
    de Vicente Rodríguez JC, Fresno Forcelledo MF, Junquera Gutiérrez LM, Hernández Vallejo G, López Arranz JS. Small cell undifferentiated carcinoma of the submandibular gland with neuroendocrine features. Ann Otol Rhinol Laryngol. 2004;113:55–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Mulder DC, Rosenberg AJWP., Storm-Bogaard PW, Koole R. Spontaneous regression of advanced merkel-cell-like small cell carcinoma of the parotid gland. Br J Oral Maxillofac Surg. 2010;48:199–200.CrossRefPubMedGoogle Scholar
  6. 6.
    Fisher CA, Harms PW, McHugh JB, Edwards PC, Siddiqui J, Palanisamy N, et al. Small cell carcinoma in the parotid harboring Merkel cell polyomavirus. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118:703–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Kawaratani H, Tsujimoto T, Yoshikawa M, Kawanami F, Shirai Y, Yoshiji H, et al. Large cell neuroendocrine carcinoma presenting with neck swelling in the submandibular gland: a case report. J Med Case Rep. 2013;7:81.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lombardi D, Accorona R, Ungari M, Melocchi L, Bell D, Nicolai P. Primary merkel cell carcinoma of the submandibular gland: when CK20 status complicates the diagnosis. Head Neck Pathol. 2015;9:309–14.CrossRefPubMedGoogle Scholar
  9. 9.
    Cimino-Mathews A, Lin BM, Chang SS, Boahene KD, Bishop JA. Small cell carcinoma ex-pleomorphic adenoma of the parotid gland. Head Neck Pathol. 2012;6:502–6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    de Biase D, Ragazzi M, Asioli S, Eusebi V. Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA. Hum Pathol. 2012;43:980–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Chernock RD, Duncavage EJ, Gnepp DR, El-Mofty SK, Lewis JS. Absence of Merkel cell polyomavirus in primary parotid high-grade neuroendocrine carcinomas regardless of cytokeratin 20 immunophenotype. Am J Surg Pathol. 2011;35:1806–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Andreasen S, Persson M, Kiss K, Homøe P, Heegaard S, Stenman G. Genomic profiling of a combined large cell neuroendocrine carcinoma of the submandibular gland. Oncol Rep. 2016;35:2177–82.CrossRefPubMedGoogle Scholar
  13. 13.
    Ueo T, Kaku N, Kashima K, Daa T, Kondo Y, Yoshida K, et al. Carcinosarcoma of the parotid gland: an unusual case with large-cell neuroendocrine carcinoma and rhabdomyosarcoma. APMIS Acta Pathol Microbiol Immunol Scand. 2005;113:456–64.CrossRefGoogle Scholar
  14. 14.
    Vural C, Dogan O, Yavuz E, Ozcelik HS, Senvar A. Small cell neuroendocrine carcinoma of the parotid gland. Otolaryngol Head Neck Surg Off J Am Acad Otolaryngol Head Neck Surg. 2000;122:151–2.CrossRefGoogle Scholar
  15. 15.
    Siciliano S, Crevecoeur H, Weynand B, Reychler H. Primary neuroendocrine carcinoma of the parotid gland: a case report. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2001;59:1359–62.CrossRefGoogle Scholar
  16. 16.
    Fornelli A, Eusebi V, Pasquinelli G, Quattrone P, Rosai J. Merkel cell carcinoma of the parotid gland associated with Warthin tumour: report of two cases. Histopathology. 2001;39:342–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu M, Zhong M, Sun C. Primary neuroendocrine small cell carcinoma of the parotid gland: a case report and review of the literature. Oncol Lett. 2014;8:1275–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Casas P, Bernáldez R, Patrón M, López-Ferrer P, García-Cabezas MA. Large cell neuroendocrine carcinoma of the parotid gland: case report and literature review. Auris Nasus Larynx. 2005;32:89–93.CrossRefPubMedGoogle Scholar
  19. 19.
    Said-Al-Naief N, Sciandra K, Gnepp DR. Moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the parotid gland: report of three cases with contemporary review of salivary neuroendocrine carcinomas. Head Neck Pathol. 2013;7:295–303.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yamagata K, Ohki K, Uchida F, Kanno N, Hasegawa S, Yanagawa T, et al. A rare primary neuroendocrine tumor (typical carcinoid) of the sublingual gland. Case Rep Dent. 2016;2016:7462690.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Michaels L, Lee K, Manuja SL, Soucek SO. Family with low-grade neuroendocrine carcinoma of salivary glands, severe sensorineural hearing loss, and enamel hypoplasia. Am J Med Genet. 1999;83:183–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Petrone G, Santoro A, Angrisani B, Novello M, Scarano E, Rindi G, et al. Neuroendocrine tumors of the submandibular gland: literature review and report of a case. Int J Surg Pathol. 2013;21:85–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Clark J, Wang S. Metastatic cancer to the parotid. Adv Otorhinolaryngol. 2016;78:95–103.PubMedGoogle Scholar
  24. 24.
    Jorcano S, Casado A, Berenguer J, Arenas M, Rovirosa A, Colomo L. Primary neuroendocrine small cell undifferentiated carcinoma of the parotid gland. Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. 2008;10:303–6.Google Scholar
  25. 25.
    Thompson LD, Aslam MN, Stall JN, Udager AM, Chiosea S, McHugh JB. Clinicopathologic and immunophenotypic characterization of 25 cases of acinic cell carcinoma with high-grade transformation. Head Neck Pathol. 2016;10:152–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Saini AT, Miles BA. Merkel cell carcinoma of the head and neck: pathogenesis, current and emerging treatment options. OncoTargets Ther. 2015;8:2157–67.Google Scholar
  27. 27.
    Chan JK, Suster S, Wenig BM, Tsang WY, Chan JB, Lau AL. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. Am J Surg Pathol. 1997;21:226–34.CrossRefPubMedGoogle Scholar
  28. 28.
    Cheuk W, Kwan MY, Suster S, Chan JK. Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med. 2001;125:228–31.PubMedGoogle Scholar
  29. 29.
    Goyal B, Duncavage EJ, Martinez D, Lewis JS, Chernock RD. Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway. Exp Mol Pathol. 2014;97:572–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Nagao T, Sugano I, Ishida Y, Tajima Y, Munakata S, Asoh A, et al. Primary large-cell neuroendocrine carcinoma of the parotid gland: immunohistochemical and molecular analysis of two cases. Mod Pathol Off J U S Can Acad Pathol Inc. 2000;13:554–61.Google Scholar
  31. 31.
    Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–100.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Duncavage EJ, Zehnbauer BA, Pfeifer JD. Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma. Mod Pathol Off J U S Can Acad Pathol Inc. 2009;22:516–21.Google Scholar
  33. 33.
    Pan Z, Chen Y-Y, Wu X, Trisal V, Wilczynski SP, Weiss LM, et al. Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart. Mod Pathol Off J U S Can Acad Pathol Inc. 2014;27:1182–92.Google Scholar
  34. 34.
    Duncavage EJ, Le B-M, Wang D, Pfeifer JD. Merkel cell polyomavirus: a specific marker for Merkel cell carcinoma in histologically similar tumors. Am J Surg Pathol. 2009;33:1771–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Signorini L, Belingheri M, Ambrogi F, Pagani E, Binda S, Ticozzi R, et al. High frequency of Merkel cell polyomavirus DNA in the urine of kidney transplant recipients and healthy controls. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2014;61:565–70.CrossRefGoogle Scholar
  36. 36.
    Chen T, Hedman L, Mattila PS, Jartti T, Ruuskanen O, Söderlund-Venermo M, et al. Serological evidence of Merkel cell polyomavirus primary infections in childhood. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2011;50:125–9.CrossRefGoogle Scholar
  37. 37.
    Beasley MB, Lantuejoul S, Abbondanzo S, Chu W-S, Hasleton PS, Travis WD, et al. The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol. 2003;34:136–42.CrossRefPubMedGoogle Scholar
  38. 38.
    Cimino PJ, Robirds DH, Tripp SR, Pfeifer JD, Abel HJ, Duncavage EJ. Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma. Mod Pathol Off J U S Can Acad Pathol Inc. 2014;27:1073–87.Google Scholar
  39. 39.
    Lee JH, Kang KW, Lee HW. Expression of phosphorylated mTOR and its clinical significances in small cell lung cancer. Int J Clin Exp Pathol. 2015;8:2987–93.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374:2542–52.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Behera M, Ragin C, Kim S, Pillai RN, Chen Z, Steuer CE, et al. Trends, predictors, and impact of systemic chemotherapy in small cell lung cancer patients between 1985 and 2005. Cancer. 2016;122:50–60.CrossRefPubMedGoogle Scholar
  42. 42.
    Prewett SL, Ajithkumar T. Merkel cell carcinoma: current management and controversies. Clin Oncol. 2015;27:436–44.CrossRefGoogle Scholar
  43. 43.
    Ahmadi Moghaddam P, Cornejo KM, Hutchinson L, Tomaszewicz K, Dresser K, Deng A, et al. Complete spontaneous regression of Merkel cell carcinoma after biopsy: a case report and review of the literature. Am J Dermatopathol. 2016;38:e154–e8.CrossRefPubMedGoogle Scholar
  44. 44.
    Shuda M, Arora R, Kwun HJ, Feng H, Sarid R, Fernández-Figueras M-T, et al. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer. 2009;125:1243–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Leroux-Kozal V, Lévêque N, Brodard V, Lesage C, Dudez O, Makeieff M, et al. Merkel cell carcinoma: histopathologic and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus large T antigen correlated with viral load. Hum Pathol. 2015;46:443–53.CrossRefPubMedGoogle Scholar
  46. 46.
    Andersson MK, Stenman G. The landscape of gene fusions and somatic mutations in salivary gland neoplasms—implications for diagnosis and therapy. Oral Oncol. 2016;57:63–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Wong SQ, Waldeck K, Vergara IA, Schröder J, Madore J, Wilmott JS, et al. UV-associated mutations underlie the etiology of MCV-negative merkel cell carcinomas. Cancer Res. 2015;75:5228–34.CrossRefPubMedGoogle Scholar
  48. 48.
    Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu Y-M, Dhanasekaran SM, et al. The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res. 2015;75:3720–7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Chen KT, Papavasiliou P, Edwards K, Zhu F, Perlis C, Wu H, et al. A better prognosis for Merkel cell carcinoma of unknown primary origin. Am J Surg. 2013;206:752–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Otolaryngology Head and Neck SurgeryWashington University School of MedicineSt. LouisUSA

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