Final Diagnosis & Discussions: Liquid-Based Slide on 57-Year-Old Woman

FINAL DIAGNOSIS: Small cell neuroendocrine carcinoma.


Neuroendocrine neoplasms of the cervix are rare. The mean annual incidence for small cell neuroendocrine carcinoma (SCNC) is 0.06 per 100,000 women, compared with 6.6 and 1.2 for squamous cell carcinoma (SCC) and adenocarcinoma, respectively (1). Morphologically, small cell carcinoma is similar to their counterpart in the lung and therefore same nomenclature has been adopted in the cervix. The diagnostic spectrum runs from well-differentiated carcinoid tumors to poorly differentiated small cell carcinomas. Human papillomavirus (HPV) subtype 18 has been predominantly identified in SCNC of the cervix, which is not typical of small cell carcinomas in other body sites such as lung.

As in other sites, the tumor is aggressive and tends to present in advanced stages. It frequently has metastasized at the time of presentation. SCNC has different treatment implications than typical SCC or adenocarcinoma and the prognosis is generally poor. Median overall survival for patients with advanced stages (IIB–IV) was 6.4 months versus 31.2 months for patients with early stage disease (IA1–IB2) (2). The same study showed that patients with early stage disease who received chemotherapy had an estimated 3-year overall survival rate of 83% versus 20% for patients who did not receive chemotherapy as part of their initial treatment. Therefore, early detection and diagnosis are essential.

Some of the salient cytologic features of SCNC are (3):

  • Tight clustering and singly scattered tumor cells exhibiting

    • Prominent nuclear molding
    • Smearing or crush artifact also known as "Azzopardi effect"
    • Finely granular chromatin pattern with inconspicuous nucleoli
    • Scant cytoplasm which imparts a high N:C (nuclear to cytoplasm) ratio
    • High cellular turnover results in tumor diathesis and abundant mitotic and apoptotic figures

In liquid-based preparation, crush artifact and nuclear molding can be less prominent with better visualized nucleoli.

Diagnosis of SCNC should be reserved for tumors composed of small cells in which squamous or glandular differentiation is absent or minimal (4). Diagnostic difficulties may arise because the cells can be fragile and often poorly preserved. The most common differential malignant diagnoses that should be considered include poorly-differentiated squamous cell carcinoma and adenocarcinoma. Small cell squamous cell carcinoma should have more and denser cytoplasm with better visualized cell borders and less crush artifact (4). Additionally the presence of prominent nucleoli would be unusual for neuroendocrine carcinoma. Prominent nucleoli may be seen in both squamous cell carcinoma and adenocarcinoma, but less likely in SCNC. Glandular differentiation (columnar shape, mucin, and gland formation) should raise the differential of an adenocarcinoma. In cases of an endometrial adenocarcinoma there can be more pleomorphism.

The differential diagnosis of small blue cell tumors is quiet broad and includes lymphomas and melanoma (5). Non-Hodgkin lymphoma is an important diagnosis that should be excluded. Usually the patient has involvement of the cervix and uterus at an advanced stage of their disease, therefore primary presentation would be unusual and clinical history should be helpful. Primary melanoma of the cervix is rare and since the cytologic pattern can be variable, it should be included on the differential diagnosis.

The possibility of a metastatic small cell carcinoma from another body site should be considered as well, although very few case reports have been published.

Of the benign entities, endometrial cells, atrophy, and follicular cervicitis should be included in the differential diagnosis. Fortunately nuclear smearing and molding are uncommon with endometrial cells and should steer one towards the diagnosis of SCNC. Atrophy will frequently have naked nuclei with fine chromatin, but there should be no molding, smearing or extensive tumor diathesis. Follicular cervicitis presents as small clusters of lymphoid cells in various stages of maturation admixed with tingible body macrophages. SCNC cells tend to be monomorphic and without tingible body macrophages.

Small cell neuroendocrine carcinoma of the cervix is a rare primary cervical malignancy with distinctive clinicopathologic features and similar histopathology and biologic behavior to its aggressive morphological counterpart in other body sites.


  1. Chen J. et al. Incidence, Mortality, and Prognostic Factors of Small Cell Carcinoma of the Cervix. Obstet Gynecol. 2008 Jun;111(6):1394-402

  2. Zivanovic O, et al., Small cell neuroendocrine carcinoma of the cervix: Analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy, Gynecol Oncol (2008), doi:10.1016/j.ygyno.2008.11.010

  3. Kim, M J et al. Differential Diagnostic Features of Small Cell Carcinoma in the Uterine Cervix. Diagn Cytopathol. 2008 Sep;36(9):618-23

  4. Solomon D., Nayar R. (editors). The Bethesda System for Reporting Cervical Cytology, Second Edition. New York: Springer-Verlag, 2004.

  5. DeMay, RM. The Pap test. ASCP Press, Chicago, 2005