Abstract
Simple SummaryAlthough cervical cancer is mainly caused by infection with human papillomavirus (HPV), some cervical cancers test negative for HPV. As these HPV-negative cervical cancers are often diagnosed at an advanced stage and have a poor prognosis, it is important to understand their molecular pathology. Here, we provide an overview of the potential causes of false-negative HPV tests, as well as the histology, genetic profile, and pathogenesis of HPV-negative cancers.Cervical cancer is the fourth most common cancer in women worldwide and is predominantly caused by infection with human papillomavirus (HPV). However, a small subset of cervical cancers tests negative for HPV, including true HPV-independent cancers and false-negative cases. True HPV-negative cancers appear to be more prevalent in certain pathological adenocarcinoma subtypes, such as gastric- and clear-cell-type adenocarcinomas. Moreover, HPV-negative cervical cancers have proven to be a biologically distinct tumor subset that follows a different pathogenetic pathway to HPV-associated cervical cancers. HPV-negative cervical cancers are often diagnosed at an advanced stage with a poor prognosis and are expected to persist in the post-HPV vaccination era; therefore, it is important to understand HPV-negative cancers. In this review, we provide a concise overview of the molecular pathology of HPV-negative cervical cancers, with a focus on their definitions, the potential causes of false-negative HPV tests, and the histology, genetic profiles, and pathogenesis of HPV-negative cancers.
Highlights
90% of cervical carcinomas are caused by high-risk human papillomavirus (HPV), with HPV-16 accounting for 50–60% and HPV-18 for 10–20%, and the remaining 10% caused by other oncogenic types [7,8]
We previously evaluated 14 adenosquamous carcinoma (ASC) samples using targeted DNA sequencing and identified genetic alterations in PIK3CA (2/14%), TP53 (1/14%), and KRAS (1/14%), HER2 amplification, and PTEN copy number loss [49], which partly resembles the genetic profile of HPV-positive Squamous cell carcinoma (SqCC) or adenocarcinoma
Several studies have reported that women with HPV-negative tumors are more frequently diagnosed at advanced stages, with a higher rate of lymph node metastasis and impaired disease-free survival (DFS) and overall survival (OS) [57,58,60,148,149]
Summary
Cervical cancer is the fourth most common cancer in women worldwide, accounting for approximately 6.5% of all female cancer cases [1]. The leading cause of cervical cancer is considered to be a persistent infection with human papillomavirus (HPV), high-risk HPVs. HPV has a double-stranded DNA genome of up to 8 kbp that encodes six early genes (E1, E2, E4, E5, E6, and E7) and two late genes (L1 and L2) that constitute the viral capsid [2]. 90% of cervical carcinomas are caused by high-risk HPV, with HPV-16 accounting for 50–60% and HPV-18 for 10–20%, and the remaining 10% caused by other oncogenic types [7,8]. The increased global availability of HPV vaccines has decreased the number of deaths from HPV-positive cervical cancer [9,10] and the sensitivity of HPV testing has significantly increased in recent years, a small but significant percentage of cervical carcinomas remain HPV-negative. It is important to understand the molecular pathology of HPV-negative cervical cancer to develop appropriate patient management strategies
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