HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Abstract

Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.

Molecular Analysis of HPV-independent Primary Endometrial Squamous Cell Carcinoma Reveals TP53 and CDKN2A Comutations

“…Interestingly, a mutation in TP53 was not detected in case 5; however, immunohistochemistry for p53 demonstrated diffuse nuclear positivity, a finding which has previously been shown to be highly correlated with TP53 mutations 23. However, rare cases of an aberrant p53 staining pattern without TP53 mutations have been described 55. The significance of this finding is unclear.…”

Human papillomavirus-independent cervical cancer

“…However, it was recently reported that two of three HPV-independent pre-invasive Review cervical lesions showed diffuse p16 ink4a staining, similar to the pattern shown in HPV-associated lesions. The authors excluded somatic or germline mutations in the RB gene or the CDKN2A gene encoding the p16 ink4a protein, 61 which could suggest the action of the 'hit-and-run' mechanism.…”

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.…”