HPV impact on oropharyngeal cancer radiological staging: 7th vs 8th edition of AJCC TNM classification.

PURPOSE: To evaluate the agreement between pathological and radiological staging in oropharyngeal cancer by comparing the 7th and the 8th edition of the AJCC TNM system. METHODS: This retrospective cohort study included 57 cases of oropharyngeal cancer with lymph node metastases staged with the 7th and 8th editions of the AJCC TNM system. Comparison between clinical and radiological features and differences in agreement rates were calculated between radiological and pathological staging for the primary tumor (T) and lymph nodes (N) in HPVpos and HPVneg cases. RESULTS: Comparison of HPVpos and HPVneg revealed a significantly different distribution between early and advanced stages in the 8 th edition, with a relevant number of HPVpos patients redefined from advanced stages whit the 7 th ed. to early stages with 8 th ed. (p < 0.01); no significant differences were found when comparing all diagnostic methods for T and N. CONCLUSIONS: The 8th edition of the AJCC TNM seems to lead to better pretreatment staging. For both HPVpos and HPVneg, the agreement between pretreatment radiological and pathological staging.

Detection of HPV16/18 E6 Oncoproteins in Head and Neck Squamous Cell Carcinoma Using a Protein Immunochromatographic Assay.

OBJECTIVES/HYPOTHESIS: The accurate diagnostic assessment of clinically relevant human papillomavirus (HPV) infections in patients with head and neck squamous cell carcinoma represents an urgent unmet medical need. The aim of this study was to determine feasibility, accuracy, and clinical significance of HPV16/18 E6 oncoprotein detection on cytological specimens from oropharyngeal squamous cell carcinoma (OPSCC) and neck lymph node metastasis of SCC from unknown primary tumor (CUP) via a protein immunochromatographic assay. STUDY DESIGN: Cross-sectional study. METHODS: Cytological specimens from primary tumor and neck metastases were collected from 34 patients with OPSCC or CUP and applied to a lateral flow format test that detects HPV16 and HPV18 E6 oncoproteins. E6 oncoprotein positivity or negativity in these specimens was compared to the specimens' "HPV-driven" reference status, defined by presence of HPV-DNA in combination with p16INK4a overexpression and/or HPV E6 seropositivity. RESULTS: Eighteen of 29 OPSCC (62%) and three of five CUP (60%) were HPV-driven according to our reference method. The E6 oncoprotein lateral flow test had a sensitivity of 94% (95% CI: 70%-100%) and a specificity of 100% (95% CI: 66%-100%) on primary tumor, and a sensitivity of 88% (95% CI: 64%-99%) and a specificity of 100% (95% CI: 74%-100%) on neck metastases. Test agreement between the E6 lateral flow test and the clinical reference method, HPV-DNA plus p16INK4a was excellent, both for primary lesion and neck metastases. CONCLUSIONS: We found the detection of HPV16/18 E6 oncoproteins to be a feasible, highly reliable, and low-invasive method to assess "HPV-driven" status in OPSCC and CUP. LEVEL OF EVIDENCE: II Laryngoscope, 131:1042-1048, 2021.

Surgical Anatomy of the Marginal Mandibular Nerve: A Systematic Review and Meta-Analysis.

The high number of marginal mandibular nerve (MMN) anatomical variants have a well-known clinical significance due to the risk of nerve injury in several surgical procedures. The aim of this study was to find and systematize the available anatomical data concerning this nerve. The PubMed and Scopus databases were investigated in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. All studies reporting extractable data on the origin, course, splitting, anastomosis and relationship of the MMN with the mandible or the facial vessels were included. We included 28 studies analyzing 1861 halves. The MMN had one (PP = 35% 95% CI:18-54%), two (PP =35% 95% CI:18-54%), three (PP = 18% 95% CI:0-35%), or four branches (PP = 2% 95% CI:0-8%). Anastomosis with the great auricular nerve, transverse cervical nerve, mental nerve, and other branches of the facial nerve were defined. The origin of the MMN in relation to the parotid and the mandible was variable. The MMN nearly always crossed the anterior facial vein laterally (PP = 38% 95% CI:9-72% if single, PP = 57% 95% CI:22-90% when multiple); its relation with other vessels was less constant. At least one branch of the MMN was found below the inferior border of the mandible (IBM), with a PP of 39% (95% CI:30-50%). The MMN has high anatomical variability and it is more often represented by one or two branches; its origin is frequently described at the parotid apex and above the IBM, although in its course at least one branch often runs below the IBM. Its most frequent anastomosis is with the buccal branch of the facial nerve. Clin. Anat., 33:739-750, 2020. © 2019 Wiley Periodicals, Inc.

Absence of disruptive TP53 mutations in high-risk human papillomavirus-driven neck squamous cell carcinoma of unknown primary.

BACKGROUND: To enforce the evidence for causality between high-risk human papillomavirus (hrHPV) infections and neck squamous cell carcinoma from unknown primary (NSCCUP) and provide biological basis for treatment de-intensification, we searched for TP53 mutations in association with HPV status. METHODS: TP53 mutations were searched for by amplification of exons 4 to 10. RESULTS: Of the 70 NSCCUP, 27 (39%) harbored HPV infection. TP53 sequencing resulted in the identification of 19 patients harboring single mutations including 16 disruptive alterations (84%). The association of TP53 mutations and HPV could be evaluated in 48 NSCCUP including those with disruptive mutation in any exon (n = 16) and those without mutations but with complete sequence of exons 4 to 9 (n = 32): no disruptive mutations were found in the 17 HPV-driven NSCCUP but in 16 of the 31 non-HPV-driven NSCCUP (P = .0002). CONCLUSION: In a fraction of cases, NSCCUP is an HPV-driven entity harboring wild-type TP53 gene or nondisruptive TP53 mutations. HPV-driven NSCCUP might benefit from treatment de-intensification.

Oncogenic DNA viruses found in salivary gland tumors.

BACKGROUND: Previous investigations studying the association of DNA viruses with salivary gland tumors (SGTs) have led to conflicting results. The aim of this study was to determine the prevalence of different DNA viruses by using a highly sensitive assay in a multi-center series of over 100 fresh frozen salivary gland samples. METHODS: DNA was isolated from 84 SGTs (80 parotid tumors and 4 submandibular gland tumors) and 28 normal salivary tissue samples from 85 patients in Northeast Italy. Using a highly sensitive type-specific multiplex genotyping assay, we analyzed the samples for the presence of DNA from 62 different viruses including 47 papillomaviruses, 10 polyomaviruses, and 5 herpesviruses. RESULTS: We observed a high prevalence of beta human papillomavirus DNA in malignant tumors. In contrast, polyomavirus DNA was present in benign, malignant, and non-tumor control samples. Most striking was the significant distribution of herpesvirus DNA in the SGT samples, in particular the high prevalence of Epstein-Barr type 1 and type 2 DNA in Warthin's tumor samples. CONCLUSION: Our data provides evidence for the presence of DNA viruses in SGTs. Mechanistic studies are needed to further attribute tumor formation to these viruses.

Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study.

Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998-2004 to 23% during 2005-2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP.