HPV-negative Tumors in a Swedish Cohort of Cervical Cancer

Abstract

Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%–7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

Human Papillomavirus Distribution in Women with Abnormal Pap Smear and/or Cervical Intraepithelial Neoplasia in Vaccination Era. A Single-Center Study in the North Italian Population

“…The increase in the rates of HPV negative and HPV untypable specimens during the period of 2010–2019 in our study is puzzling. As reported by several studies, the prevalence of HPV negative specimens among women with abnormal pap smears, CIN or invasive cervical cancer is about 12–14% [ 24 , 25 ], a rate that is comparable to our data. Interestingly Petry et al reported that HPV-negative status in cervical cancer could be a false diagnosis or false-negative HR-HPV results, caused by use of HC2 method [ 26 ].…”

High prevalence of mixed and non-vaccine HPV oncogenic types and their association with higher mortality in Black women with cervical cancer

“…Among our patients with negative HPV PCR results, 8 of 9 had positive p16 expression. This contradictory pattern has been described in other studies which found the initial HPV PCR negativity – with p16 positive IHC – reduced from 19/209 to 5/209 cervical carcinomas after expanding molecular studies (targeting E6/E7 genes) 36 . The p16 positivity is therefore considered a more sensitive indicator of HPV-mediated carcinogenesis in cervical cancers.…”

Tetramethylpyrazine inhibits the proliferation, invasiveness and migration of cervical cancer C33A cells by retarding the Hedgehog signaling pathway

“…Screening and management of precancerous lesions contribute to the prognosis of CC, whereas HPV vaccinations prevent infection from certain strains of HPV; however these preventative measures have limitations (30). For example, a considerable number of CCs have been confirmed to be HPV negative (31). As aforementioned, TMP was found to serve an inhibitory role in numerous types of cancer (17)(18)(19).…”