HPV-Negative Cervical Cancer: A Narrative Review

Abstract

Cervical cancer (CC) is the fourth most frequent cancer in women worldwide. HPV infection is associated with the majority of CC cases, but a small proportion of CCs actually test negative for HPV. The prevalence of HPV among CC histotypes is very different. It has been suggested that HPV-negative CC may represent a biologically distinct subset of tumors, relying on a distinct pathogenetic pathway and carrying a poorer prognosis, than HPV-positive CCs. Although, the discordance in terms of sensitivity and specificity between different HPV tests as well as the potential errors in sampling and storing tissues may be considered as causes of false-negative results. The identification of HPV-negative CCs is essential for their correct management. The aim of this narrative review is to summarize the clinical and pathological features of this variant. We also discuss the pitfalls of different HPV tests possibly leading to classification errors.

Keywords: HPV DNA test; HPV-negative cervical cancers; cervical cancer; false-negative results; human papillomavirus.

Figure 1

Mucinous adenocarcinoma, gastric type. Hematoxylin-Eosin, 10× magnification. This mucinous adenocarcinoma shows gastric-type differentiation. Invasion of the endocervical stroma with variably sized simple cystic glands, some solid areas, and infolded papillae. These tumors are composed of cells with abundant clear or pale eosinophilic cytoplasm and distinct cell borders, displaying enlarged and hyperchromatic nuclei.

Figure 2

Mesonephric carcinoma, Hematoxylin-Eosin, 20× magnification. This panel shows a typical mesonephric carcinoma composed of tubular glands lined by mucin-free cuboidal epithelium containing eosinophilic, hyaline secretion in their lumina. Haphazard infiltrative growth, elevated mitotic activity, the presence of intraluminal cellular debris, and nuclear atypia are also peculiar features.

Figure 3

Endometroid carcinoma, Hematoxylin-Eosin, 10× magnification. The panel shows endometroid carcinoma of the cervix whose morphology is similar to endometrioid adenocarcinoma arising in the uterine corpus. In particular, key features are the confluent or back-to-back glands lacking intervening stroma, with cribriform or microacinar configurations and complex papillary, micropapillary, or villoglandular structures. Nuclear rounding, enlargement with large nucleoli, and loss of polarity and cytoplasmic eosinophilia are also visible.