HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications

Abstract

Cervical cancer is the fourth most common cancer in women. It is the leading cause of female deaths in developing countries. Most of these cervical neoplasms are represented by squamous lesions. Cervical adenocarcinoma causes about a quarter of cervical cancers. In contrast to squamous lesions, cervical glandular disease is HPV-negative in about 15–20% of cases. HPV-negative cervical adenocarcinomas typically present in advanced stages at clinical evaluation, resulting in a poorer prognosis. The overall and disease-free survival of glandular lesions is lower than that of squamous lesions. Treatment options require definitive treatments, as fertility-sparing is not recommended. Moreover, the impact of HPV vaccination and primary HPV screening is likely to affect these lesions less; hence, the interest in this challenging topic for clinical practice. An updated review focusing on clinical and molecular characterization, prognostic factors, and therapeutic options may be helpful for properly managing such cervical lesions.

Long-Term Follow-Up Outcomes in Women with In Situ/Microinvasive Adenocarcinoma of the Uterine Cervix Undergoing Conservative Treatment—Cervical Adenocarcinoma Study Group Italian Society of Colposcopy and Cervico-Vaginal Pathology

“…The latter has a worse prognosis, and conservative treatment is not recommended [ 34 ]. Unfortunately, given the study period, our data were based on the 2014 WHO classification, which did not consider the above subdivision [ 10 ]. Although we did not include cases of HPV-independent adenocarcinoma, we must underline that the 2014 WHO classification in the mucinous AC class includes HPV-associated and HPV-independent types [ 33 ].…”

“…It is well known that cervical glandular lesions can be multifocal, so even with negative margins, the possibility of residual disease is not negligible [ 8 ]. In contrast to squamous lesions, approximately 15–20% of glandular disease may be HPV-negative and therefore associated with a worse prognosis [ 9 , 10 ]. Furthermore, up to 4% of cases may show recurrence after three years of follow-up [ 8 ].…”

The Coexistence of Cervical Intraepithelial Neoplasia (CIN3) and Adenocarcinoma In Situ (AIS) in LEEP Excisions Performed for CIN3

“…In 2018, the International Endocervical Criteria and Classification (IECC) divided cervical glandular pathologies into HPV-positive lesions and HPV-negative lesions. Compared to the WHO classification, they suggested a classification based on pathogenesis that is more informative from a clinical point of view [ 12 ]. In total, 10–20% of glandular neoplastic pathologies are HPV-negative and have a worse prognosis than HPV-related lesions [ 9 , 13 ].…”

Development and assessment of an RNA editing-based risk model for the prognosis of cervical cancer patients

“…[3,6,7] Nevertheless, HPV testing is negative in a small number of CESC cases, which include true HPV-negative cancer patients and false-negative cases. [8][9][10] This has some detrimental implications for strategies based on HPV screening and vaccination to prevent CESC. In clinical practice, treatment methods for CESC patients mainly involve hysterectomy, chemotherapy, radiotherapy or adjuvant therapy.…”