Cervical Human Papillomavirus-independent squamous cell carcinoma: a clinicopathological review and outcomes analysis in comparison to Human Papillomavirus-associated squamous cell carcinoma.

Human papillomavirus (HPV)-independent cervical squamous cell carcinomas (HPVI SCC) represent a poorly characterized entity. We aimed to explore the clinicopathologic and survival features in the largest series of HPVI SCCs and compare them to HPV-associated (HPVA) SCCs. 89 cases of SCC previously tested negative for high-risk and low-risk-HPV were collected from 22 institutions. 363 HPVAs SCCs were retrieved from a previously published database. Demographic and clinicopathological features, including p16 and p53 immunohistochemistry, and follow-up data were recorded. 49 of 89 cases were classified as "true" HPVI SCC (HPV-/p16-), while 40 were equivocal HPVI SCC (HPV-/p16+ or HPV-/p16 not performed) and were excluded. The median age of true HPVI SCCs was 68 (range: 36-88) years and 38 (77.6%) patients were diagnosed aged 60 or older. Seven (14.2%) had a history of uterine prolapse. Compared with HPVA SCC, patients with HPVI SCCs were older (p<0.001), had larger tumors (p<0.001), were diagnosed at higher FIGO stage (p<0.001), recurred more frequently (p<0.001) and had worse survival (p<0.001). True HPVI SCCs also more frequently had keratinizing histology (p=0.001) and abnormal p53 (p<0.001). In a bivariate analysis adjusted for FIGO stage, HPVI p53-abnormal SCC had higher risk of recurrence (p=0.068; p<0.001) and death of disease (p=0.062; p<0.001) than HPVI p53-wild type SCC and HPVA SCC. Survival outcomes (recurrence and disease-specific survival) in HPVI SCC and HPVA SCC differed significantly when comparing surgically treated HPVI SCC and HPVA SCC (p<0.0001 for both). Even with the challenges associated with an analysis of a heterogeneous study set, we confirm that HPVI cervical SCCs have distinctive clinicopathological features. p53-abnormal and p53-wild type HPVI SCC neoplasms exist in the uterine cervix, and p53-abnormal tumors are more aggressive. Although HPVI SCC are more frequently keratinizing than HPVA SCC neoplasms, there is substantial morphological overlap, so HPV testing (or p16 at least) and p53 should be considered in cervical SCC, especially in patients over the age of 60 years.