Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma

Abstract

Background:Human papillomavirus (HPV) is a causal factor in virtually all cervical and a subset of oropharyngeal squamous cell carcinoma (OP-SCC), whereas its role in laryngeal squamous cell carcinoma (L-SCC) is unclear.Methods:Formalin-fixed paraffin-embedded (N=154) and deep-frozen tissues (N=55) of 102 L-SCC patients were analysed for the presence of 51 mucosal HPV types. HPV DNA-positive (HPV DNA+) cases were analysed for E6*I mRNA transcripts of all high risk (HR)/probably/possibly (p)HR-HPV identified, and for HPV type 16 (HPV16) viral load. Expression of p16INK4a, pRb, cyclin D1 and p53 was analysed by immunohistochemistry.Results:Ninety-two patients were valid in DNA analysis, of which 32 (35%) had at least one HPV DNA+ sample. Among the 29 single infections, 22 (76%) were HPV16, 2 (7%) HPV56 and 1 each (4%) HPV45, HPV53, HPV70, HPV11 and HPV42. Three cases harboured HPV16 with HPV33 (twice) or HPV45. Only 32% of HPV DNA+ findings were reproducible. Among HPV16 DNA+ L-SCC, 2 out of 23 (9%) had high viral loads, 5 out of 25 (21%) expressed E6*I mRNA and 3 out of 21 (14%) showed high p16INK4a and low pRb expression (all three HPV16 RNA-positive), immunohistochemical marker combination not identified in any other HPV DNA+ or HPV DNA-negative (HPV DNA−) L-SCC, respectively.Conclusion:HPV type 16 has a causative role in a small subgroup of L-SCC (<5% in this German hospital series).

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: What is New in the 2017 WHO Blue Book for Tumours of the Hypopharynx, Larynx, Trachea and Parapharyngeal Space

“…New data on etiopathogenesis, with a specific focus on the role of human papillomavirus (HPV) infection in precursor lesions, CSCC and subtypes, are discussed in this section [1][2][3][4][5][6]. The recently clarified probable pathogenetic mechanism of spindle cell SCC (SpSCC) is also presented [7,8].…”

Current Views and Perspectives on Classification of Squamous Intraepithelial Lesions of the Head and Neck

“…In an additional study, Halec and co-workers revealed that HPV 16 had a causative role only in a small subset of laryngeal SCC (\5 % of 102 tumors) [39]. Although the authors found at least one HPV DNA positive sample in 35 % of patients, they stressed that the mere detection of HPV DNA is not sufficient to identify HPV-driven cancers, since high-risk HPV has frequently been found in benign laryngeal lesions and in normal mucosa [39,41]. In this study, the authors looked for the presence of 51 HPV types, viral load, HPV mRNA expression and expression of p16, pRb, p53 and cyclinD1 to provide reliable findings of transcriptionally active HPV [39].…”

“…In contrast to anogenital SCC, the prevalence of HPV in laryngeal SCC varies considerably, from 3 to 60 % [38,39]. Li and co-workers [40] recently published a meta-analysis with 55 studies, addressing HPV prevalence in laryngeal SCC.…”

“…Fourth, the crude division of study population by geographic regions made the analyses prone to misclassification bias [40]. In an additional study, Halec and co-workers revealed that HPV 16 had a causative role only in a small subset of laryngeal SCC (\5 % of 102 tumors) [39]. Although the authors found at least one HPV DNA positive sample in 35 % of patients, they stressed that the mere detection of HPV DNA is not sufficient to identify HPV-driven cancers, since high-risk HPV has frequently been found in benign laryngeal lesions and in normal mucosa [39,41].…”

“…In addition to laryngeal carcinoma and SILs, HPV DNA has also been detected in a substantial proportion, 12-25 %, of individuals with clinically and histologically normal laryngeal mucosa [1]. A final answer on the role of HPV infection in the etiopathogenesis of laryngeal SILs can thus only be reliably provided by additional studies, in which biological evidence of the existence of truly HPV-driven SILs is presented [39].…”