High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV

Abstract

In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR and In Situ Hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11/40 (28%) cases, and 10/41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10/11 HPV-positive cases and 7/10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (p=0.01). High TP53 expression exhibited a trend for poorer survival (p=0.12), but among cases, association with poor survival reached statistical significance (p=0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls. Implications HIV infection did not increase risk of death from HNSCC, and HPV-positive tumors continued to be associated with a significantly improved survival, independent of HIV status.

Prognostic biomarkers in patients with human immunodeficiency virus‐positive disease with head and neck squamous cell carcinoma

“…In addition, current alcohol users were more likely to have HIV infection compared with nonalcohol or former alcohol users (OR 6.0; 95% CI 1.8‐20.0; P = .003), consistent with the high prevalence of lifestyle‐related cancer risk factors (smoking and alcohol intake) associated non‐AIDS‐defining malignancies among patients with HIV infection . The cases of HIV infection did not have significant impact on patients' OS, consistent with the findings of investigators who used specimens derived from similar cohorts …”

“…We chose a panel of oncogenic (NF‐κB, pAKT, pSTAT3, and Bcl‐2) and inflammatory (TGF‐β, IL‐6, and VEGF) tumor biomarkers known to play roles independently or cooperatively in tumor growth and progression and tumor‐host immune interaction . The subset of patients with HIV‐positive head and neck cancer largely retained the characteristics of the original patient cohort, particularly, consistent with the findings in the original study, we found that low CD4 count (<200 cells/μL) was significantly associated with poor OS in the HIV‐positive head and neck cancer cases when only clinical information was included (Supporting Information Table S4) . In addition, current alcohol users were more likely to have HIV infection compared with nonalcohol or former alcohol users (OR 6.0; 95% CI 1.8‐20.0; P = .003), consistent with the high prevalence of lifestyle‐related cancer risk factors (smoking and alcohol intake) associated non‐AIDS‐defining malignancies among patients with HIV infection .…”

Distinct pattern of TP53 mutations in human immunodeficiency virus–related head and neck squamous cell carcinoma

“…All these elements are also recognized as important risk factors for head and neck squamous cell carcinoma (HNSCC) development and may explain the higher incidence of these tumors among HIVIIs . HNSCC is diagnosed at an earlier age and at a more advanced stage in HIVIIs, and these tumors tend to be more aggressive and related to worse survival rates when they express high levels of TP53 in comparison with non‐HIVIIs . The efficacy of current treatment approaches to HIVII‐related HNSCC is still a matter of debate .…”

The tumor genome in human immunodeficiency virus–related head and neck cancer: Exploitable targets?

“…In this issue of Cancer , Gleber‐Netto et al report on the results of the next‐generation sequencing of a panel of 18 head and neck cancer–relevant genes in head and neck cancers from 20 HIV‐infected individuals and 32 HIV‐uninfected controls . Controls were selected by pathology record review, apparently without systematic serologic confirmation, and thus there is a theoretical possibility that the HIV‐negative cohort contained 1 or more individuals with an unrecognized HIV infection . However, it is unlikely that a case with HIV‐related immunosuppression and cancer would have remained unrecognized, and thus the clinical relevance of this concern is low.…”

“…The question of HPV misclassification is also raised by the atypically high proportion of HPV‐related cases from anatomic subsites outside the oropharynx. The previously published methodology used here for assigning the HPV status included both HPV DNA detection by in situ hybridization or polymerase chain reaction and staining for p16 expression . The expression of p16 is an accepted surrogate for HPV association because HPV oncoprotein–mediated degradation of wild‐type retinoblastoma removes a negative regulator of p16 and because p16 expression has repeatedly performed as well as or better than HPV detection in predicting favorable outcomes for oropharyngeal cancer patients in clinical trials .…”