The Histologic and Molecular Spectrum of Highly Differentiated HPV-independent Cervical Intraepithelial Neoplasia

Recently, the World Health Organization (WHO) recognized the existence of human papillomavirus (HPV)-independent invasive cervical squamous cell carcinoma (SCC), but HPV-independent precursor lesions were not included due to the lack of description of this rare entity. We present the histologic spectrum of highly differentiated squamous HPV-negative and p16 ink4a -negative precursor lesions adjacent to and/or preceding invasive HPV-negative cervical SCC in 3 patients. The histologic features resembled those described for vulvar HPV-negative precursor lesions. One precursor featured a proliferation of atypical basal keratinocytes with mitotic activity, premature squamatization in elongated epithelial rete, and mostly regular superficial squamous differentiation with TP53 mutation and immunohistochemical p53 overexpression termed differentiated cervical intraepithelial neoplasia (d-CIN). The other 2 precursors included verruciform acanthosis with plump rete, minimal atypia, and an EGFR mutation that resembled vulvar acanthosis with altered differentiation, and an exophytic papillary proliferation with a PIK3CA mutation resembling the differentiated exophytic vulvar intraepithelial lesion. Two precursors that preceded the invasive SCC harbored an additional pathogenic SMARCB1 mutation. The cytologic smears of d-CIN revealed 3-dimensional branched basaloid tubular structures and eosinophilic squamous cell clusters mimicking the histologic features. In conclusion, highly differentiated cervical HPV-negative precursors are characteristic intraepithelial squamous lesions with somatic mutations that resemble those described in vulvar HPV-independent carcinogenesis. For optimal reproducibility, we propose a simplistic classification of these HPV-negative cervical precursors in TP53 -mutated d-CIN and p53 wild-type verruciform intraepithelial neoplasia.