Human papillomavirus and p53 expression in cancer of unknown primary in the head and neck region in relation to clinical outcome

Abstract

Patients with cancer of unknown primary (CUP) in the head neck region are generally treated with neck dissection followed by radiotherapy at times combined with chemotherapy, a treatment associated with considerable side effects. Some of these tumors may originate as human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OSCC), with better clinical outcome than head neck squamous cell cancer (HNSCC) in general, and could potentially do well with less treatment. Here, we therefore investigated whether HPV status and p53-expression correlated to clinical outcome in patients with CUP in the head neck region. Fifty metastases were analyzed for presence of HPV DNA, and expression of p16INK4A and p53 and the data were correlated to clinical outcome. Patients with HPV DNA-positive (HPVDNA+) metastases had significantly better 5-year overall survival (OS) compared to those with HPVDNA− metastases (80.0% vs. 36.7%, respectively; P = 0.004), with a similar tendency for disease-free survival (DFS). These survival rates showed excellent concordance with those of HPVDNA+ and HPVDNA− OSCC in Sweden during the same time period, strengthening the hypothesis that HPVDNA+ head and neck CUP may originate from HPVDNA+ OSCC. In addition, having absent/intermediary-low as compared to high expression of p53 correlated to a better prognosis with a 69% as compared to 14% 5-year OS, respectively (P < 0.001), and for DFS the tendency was analogous. In conclusion, both HPV status and p53 expression are valuable prognostic factors in patients with CUP in the head and neck region and should be further explored for clinical use.

Validation of Human Papillomavirus as a Favourable Prognostic Marker and Analysis of CD8+ Tumour-infiltrating Lymphocytes and Other Biomarkers in Cancer of Unknown Primary in the Head and Neck Region

“…Other studies have however not been able to demonstrate a survival difference in a similar HNCUP setting (16,17). Here, in a HNCUP cohort from 2008-2013, the survival benefit for patients with HPV DNA + HNCUP previously found for patients with HNCUP diagnosed 2000-2007 was confirmed (11).…”

“…A multiplex polymerase chain reaction (PCR) assay identifying 27 HPV types, with a β-globin housekeeping gene as an amplification control, was run as previously described, with 10 μl of each sample per reaction, and SiHa cells as positive and RNAs-free water as negative controls (11,(21)(22).…”

“…As previously reported, a streptavidin-biotin peroxidase method was used for IHC, with: mAb p53 (clone: DO1; Santa Cruz Biotech, Santa Cruz, CA, USA), mAb CD8 (clone: 4B11; Leica Biosystems, Newcastle, UK) and mAb HC10/HLA class I (a kind gift from Dr Soldano Ferrone, University of Pittsburgh, Cancer Institute, PA, USA) (11,18,20). IHC evaluations were conducted as described previously (11,18,20). For detection of p16 INK4A , Ventana CINtec ® p16 Histology (Roche AB, Stockholm, Sweden) was used and samples were considered positive if >70% of tumour cells showed strong staining (6,23).…”

“…Recently, we and others have reported similarities in clinical behaviour between HPV-positive HNCUP and HPVpositive oropharyngeal SCC, with a significantly better clinical outcome for patients with HPV-positive HNCUP compared to those with HPV-negative HNCUP (11,(14)(15). However, other surveys have not found an impact of HPV status on survival, leaving the role of HPV in prognosis in HNCUP unresolved (16,17).…”

“…HPV-positive tonsillar and base of tongue SCC have increased in incidence in the past decades in the developed world and have better clinical outcomes than HNSCC in general [~80% vs. 40% 5-year overall survival (OS)] (5)(6)(7)(8). HPV is frequently found in HNCUP and such cases likely have an HPV-positive oropharyngeal SCC origin, which gives reasons for steering diagnostic procedures as well as radiotherapy towards the oropharynx (9)(10)(11).…”