SCNEC Diagnosis: Cytological Clues to a Rare Cervical Malignancy

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix occupies a narrow but formidable niche in gynecologic oncology. With a frequency of less than one percent of all gynecologic malignancies and fewer than five percent of cervical cancers, SCNEC is rare, but its aggressive behavior and diagnostic elusiveness warrants it clinical significance.

In a recent retrospective study by Odaka et al. published in Oncology Letters in June 2025, six patients with cervical SCNEC were evaluated, bringing fresh perspective to a cancer type that remains underrecognized and often misdiagnosed. Here’s a brief overview of the study and its findings.

A Rare Entity with Elusive Cytological Signatures

The study examined cytological specimens from six patients—three with pure SCNEC, two with combined SCNEC (co-occurring with adenocarcinoma), and one with carcinosarcoma comprising both SCNEC and sarcomatous elements. All patients had undergone preoperative cervical cytology, followed by histopathological confirmation through biopsy or surgical resection.

What stands out here is the reliable presence of SCNEC cells in all cytological specimens. These cells consistently presented as small, round neoplastic clusters with granular “salt-and-pepper” chromatin and absent or inconspicuous nucleoli, set against a background of inflammation or necrosis. Nuclear molding—a hallmark of SCNEC cytomorphology—was evident in all but one case.

Despite this, initial cytologic diagnosis still missed the mark in one patient, where SCNEC was misclassified as squamous cell carcinoma (SCC). This error underscores an inherent diagnostic challenge: SCNEC often mimics more common cervical pathologies like high-grade squamous intraepithelial lesions or SCC. In such contexts, cytological subtleties may be overshadowed or even masked entirely.

Combined and Biphasic Complexity

A compelling aspect of the study lies in its inclusion of combined SCNEC and carcinosarcoma. In one combined case, cytological analysis successfully identified both SCNEC and an adenocarcinoma component—columnar cells with mucin and peripheral nuclei. In contrast, another case of combined SCNEC showed no obvious adenocarcinoma cytologically, revealing a limitation in sampling or recognition. Similarly, in the case of carcinosarcoma, spindle-shaped sarcomatous cells were noted only upon retrospective review, though atypia was initially reported.

These findings underscore a broader truth: when SCNEC coexists with other malignant histologies, especially those with dominant cytological features, the neuroendocrine component may be underdiagnosed unless scrutiny is applied. Importantly, no liquid-based cytology was used in this study.

Immunohistochemical Anchors

Immunoprofiling played an important confirmatory role. All SCNEC components expressed CD56, while five of six also expressed chromogranin A and synaptophysin—well-established neuroendocrine markers. Additionally, p16 expression, a surrogate for high-risk human papillomavirus (HPV) infection, was diffusely positive across all SCNEC samples, strengthening the suspected link between SCNEC and high-risk HPV, particularly type 18.

This expression pattern supports the clinical hypothesis that cervical SCNEC is typically HPV-driven. Interestingly, direct HPV testing was not performed—leaving molecular confirmation open-ended and emphasizing the continued reliance on immunohistochemistry in this diagnostic pathway.

Implications for SCNEC Diagnosis

This paper serves as both a diagnostic guide and a reminder of SCNEC’s many disguises and reinforces the value of early detection in managing a malignancy that offers few therapeutic windows once advanced. It also encourages clinicians to consider SCNEC even when squamous or glandular components dominate the cytological picture.

Reference:

Odaka M, Ishida M, Okanishi H, et al. Cytological features of small cell neuroendocrine carcinoma of the uterine cervix. Oncol Lett. 2025;30(2):401. doi:10.3892/ol.2025.15147