Contribution of Human papillomavirus in neuroendocrine tumors from a series of 10,575 invasive cervical cancer cases

Papillomavirus Res. 2018 Jun;5:134-142. doi: 10.1016/j.pvr.2018.03.005. Epub 2018 Mar 17.


Aims: Neuroendocrine tumors (NET) of the cervix are rare tumors with a very aggressive course. The human papillomavirus (HPV) has been linked to its etiology. The objective of this study is to describe HPV prevalence and genotype distribution of NET.

Methods and results: Forty-nine tumors with histological neuroendocrine features were identified among 10,575 invasive cervical cancer (ICC) cases from an international study. HPV DNA detection was done using SPF10/DEIA /LiPA25 system. Immunohistochemical (IHC) staining for neuroendocrine markers (chromogranin A, synaptophysin, CD56) and for p16INK4a as a surrogate for HPV transforming infection was performed. In 13 samples with negative IHC for all 3 neuroendocrine markers studied, it was possible to conduct electron microscopy (EM). NET represented 0.5% of the total ICC series and HPV was detected in 42 out of 49 samples (85.7%, 95%CI:72.8%,94.1%). HPV16 was the predominant type (54.8%), followed by HPV18 (40.5%). p16INK4a overexpression was observed in 38/44 cases (86.4%). Neuroendocrine IHC markers could be demonstrated in 24/37 (64.9%) cases. EM identified neuroendocrine granules in 8 samples with negative IHC markers.

Conclusions: Our data confirms the association of cervical NET with HPV and p16INK4a overexpression. Specifically, HPV16 and 18 accounted together for over 95% of the HPV positive cases. Current HPV vaccines could largely prevent these aggressive tumors.

Keywords: Cervical Cancer; Human Papillomavirus; Immunohistochemistry; Neuroendocrine Tumor; PCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA, Viral / isolation & purification
  • Female
  • Genotype
  • Human papillomavirus 16 / pathogenicity
  • Human papillomavirus 18 / pathogenicity
  • Humans
  • Immunohistochemistry
  • Microscopy, Electron
  • Middle Aged
  • Neoplasm Invasiveness
  • Neuroendocrine Tumors / ultrastructure
  • Neuroendocrine Tumors / virology*
  • Papillomaviridae / pathogenicity*
  • Papillomavirus Infections / complications*
  • Polymerase Chain Reaction
  • Uterine Cervical Neoplasms / complications*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Viral