Human papillomavirus-independent cervical cancer

Abstract

Cervical cancer is the fourth most frequent cancer in women worldwide, representing nearly 8% of all female cancer deaths every year. The majority of cases of cervical cancer are caused by human papillomavirus (HPV); however, up to 5% of tumors are not associated with HPV-persistent infection and, moreover, the new WHO Female Genital Tumors classification subdivided cervical squamous and adenocarcinomas into HPV-associated and HPV-independent tumors. Based on this new information, the aim of this review is to provide an overview of HPV-independent cervical cancer, evaluating diagnostic techniques, molecular profiles, and clinical outcomes. The HPV-independent tumors are characterized by a differentiated molecular profile with lower proliferative activity, a p53 immunostaining, a decreased expression of cyclin-dependent kinase inhibitor proteins, such as p16, p14, and p27, and alterations in PTEN, p53, KRAS, CTNNB1, ARID1A, and ARID5B. HPV-independent tumors are associated with both adenocarcinomas and squamous histologic subtypes, with lymph node involvement in the early stages, more distant metastasis, and generally worse oncological outcomes. Thus far, no specific therapeutic strategies have been developed based on HPV status; however, with advancing knowledge of differences in the molecular profiles and possible targetable alterations, novel approaches may offer potential options in the near future. Investigators should report on clinical outcomes, evaluating the overall response rates to specific treatments, and consider new biomarkers to establish more accurate prognostics factors.

Human papillomavirus-independent cervical cancer: what are the implications?

“…We would like to congratulate Dr Fernandes and colleagues on their excellent and thorough review of human papillomavirus (HPV)-independent cervical cancer. 1 While the majority of cervical cancers have been shown to be caused by HPV, several studies have reported HPV-independent disease. It is thought that these tumors are more often associated with lymph node involvement in early stages, more distant metastases, and worse prognosis.…”

Correspondence on "Human papillomavirus-independent cervical cancer" by Fernandeset al

“…The authors of the review on human papillomavirus (HPV)-independent cervical cancer1 cited our recent publication on HPV-negative squamous precursor lesions2 as support for the ‘hit-and-run theory’ of primarily HPV-driven precancers that—during cancer progression—lose HPV-oncogene expression 3. Our data, however, were misinterpreted.…”

Clinicopathological characteristics and survival outcomes in human papillomavirus independent cervical cancer: a propensity score matched analysis

“…With increasingly improved HPV detection methods, a gradual decrease in the rate of HPV-negative samples was noted between 1990 and 2010 2. However, despite the development of highly sensitive tests for molecular detection of HPV in recent years, a small proportion of cervical cancer cases are consistently negative for HPV in almost all studies 3 4…”

“…According to recently published data and a 2017 meta-analysis that included 17 studies about HPV-negative cervical cancer worldwide, HPV-negative cervical cancer was considered a distinct subgroup that showed poor prognosis, and its mechanism of action still remains unclear 6 7. Researches have demonstrated that HPV-negative cervical cancer is more frequently associated with lympho-vascular invasion, lymph node metastasis, and local or distant recurrence than HPV-positive cervical cancer 4 8. Therefore, in 2020, the fifth WHO classification of female genital tumors officially divided cervical cancer into HPV-associated and HPV-independent tumors according to the HPV status 9…”

“…False-negative results can arise from a panel of factors, including but not limited to histological misclassification, latent HPV infection, and HPV testing methods 10. The detection rate of HPV is largely dependent on the testing methods, which have been reported to vary across vendors 4…”