June 2021 – Gynecological Pathology

A 50-year-old woman presents with lower abdominal pain and heavy vaginal bleeding. She has not had a Pap test for 20 years. CT scan reveals a 7 cm cervical mass with metastatic disease. Concurrent cervical and endometrial biopsies show sheets of malignant cells with scant cytoplasm, irregular hyperchromatic nuclei with conspicuous nucleoli. Crush artifact, nuclear molding, brisk mitotic activity and apoptotic cells are seen. Tumor cells stain with synaptophysin, chromogranin, keratin AE1/AE3 and P16. HPV RNA ISH is positive.

Figure 1: NEC

Based on the immunomorphologic findings, what is the diagnosis?

  • Metastatic small cell carcinoma
  • Poorly differentiated squamous cell carcinoma
  • Endometrioid carcinoma, FIGO grade III
  • High-grade neuroendocrine carcinoma, large cell type

The correct answer is ...

The correct answer is: High-grade neuroendocrine carcinoma, large cell type.

Neuroendocrine carcinoma (NEC) is a rarely encountered entity in the cervix, comprising less than 5 percent of diagnosed cervical cancer. Like the more commonly seen cervical squamous cell carcinoma and adenocarcinoma, most of these tumors are driven by human papillomavirus (HPV), particularly HPV18. However, NEC carries a much poorer prognosis due to its aggressive behavior and propensity for metastatic spread. Because NEC is uncommon and has no specific morphologic features to suggest the site of origin, it can be misdiagnosed as metastatic carcinoma, leading to an unnecessary work up in search of the primary site. In this case the endometrial metastases can erroneously point to an endometrial cancer with involvement of the cervix. As a surrogate marker for an HPV-mediated process, P16 immunohistochemical stain can aid in making the correct diagnosis, which can then be confirmed by in situ hybridization. Although NEC has no precursor lesion that would allow diagnosis of preinvasive disease during screening procedures, HPV-driven NEC can be prevented with the available vaccine. 


  1. Castle PE, Pierz A, Stoler MH. A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix. Gynecol Oncol. 2018 Feb;148(2):422-429. 
  2. Alejo M, et al; RIS HPV TT study group. Contribution of Human papillomavirus in neuroendocrine tumors from a series of 10,575 invasive cervical cancer cases. Papillomavirus Res. 2018 Jun;5:134-142. 
Maria Zayko profile

Maria Zayko, D.O.

Fellow, Surgical Pathology
Mayo Clinic

Michael Henry, M.D.

Emeritus Consultant, Anatomic and Clinical Pathology
Mayo Clinic

Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.