Introduction/Background Although our knowledge of HPV-independent squamous cell cancers (SCC) of the cervix is growing, the current 2020 WHO classification does not describe HPV independent cervical precancers. The main reason for this was that these exceedingly rare cervix HPV-independent precancerous lesions were not described at time of publication.

Methodology This review will focus on recent aspects of HPV-independent cervical carcinogenesis.

Results In 2020 we reported for the first time a preinvasive cervical lesion negative with 3 different HPV tests in a series of 474 cone specimens (Reich O. Gynecol Oncol 2020). In 2022 we demonstrated detailed characteristics of HPV-negative cervical intraepithelial precursors (Regauer S. Am J Surg Path 2022). HPV-negativity was defined as lack of both, DNA of 32 HPV subtypes and E6/E7 mRNA of 14 HPV subtypes, and additionally by the absence of HPV sequences in ~5 Mio´s WGS reads. The morphological hallmark of this cervical lesion was the presence of atypical keratinocytes confined to the basal and parabasal layers in squamous epithelium with hyper- and parakeratosis with elongated rete ridges. The subepithelial stroma had a dense inflammation with plasma cells and eosinophilic granulocytes. Finding an appropriate terminology for these differentiated intraepithelial precursor lesions, however, proves difficult. In analogy to terminology of vulvar carcinogenesis, differentiated cervical intraepithelial neoplasia (d-CIN) may be appropriate.

Conclusion The existence of primarily HPV-negative squamous cervical precancers (d-CIN type and basaloid type) needs to be recognized (Regauer S. Int J Gynecol Cancer 2022). In a future classification squamous intraepithelial cervical precancers should be grouped into two categories: HPV-associated and HPV-independent.