Human Papillomavirus-Associated Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis.

Objective: Human papillomavirus (HPV) is known to affect head and neck sites beyond the oropharynx, including the nasopharynx. Unlike HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC), HPV-associated nasopharyngeal carcinoma (HPV+NPC) is not well characterized and the true prevalence in non-endemic regions is poorly described. Here, we sought to obtain a global point prevalence of HPV in NPC, stratified by geographic region. Data Sources: EMBASE, OVID Medline, and Web of Science were systematically searched for available evidence on September 21, 2022 for articles published between January 1, 1990 and September 21, 2022. Review Methods: We reviewed the literature for all studies examining NPC and HPV status in adult patients that provided a quantitative HPV prevalence. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main outcome and measures included HPV+NPC prevalence estimates stratified by geographic region, along with other clinical and demographic features. Results: Of the 1567 citations retrieved, 46 studies encompassing 6314 NPC patients were eligible for statistical analysis. The global prevalence of HPV+NPC was 0.18 (95% CI 0.14-0.23). When stratified by geographic region, prevalence was highest in North America (0.25, 95% CI 0.17-0.36), which is a non-endemic region for NPC and also has highest prevalence for HPV+OPSCC. Asia, an endemic area, had the lowest HPV prevalence estimate (0.13, 95% CI 0.08-0.22). HPV 16 (44%) and 18 (33%) were the predominant genotypes in HPV+NPC, dissimilar to HPV+OPSCC. Conclusion: This systematic review and meta-analysis provides a global point prevalence of HPV+NPC stratified by geographic region and suggests that HPV is a significant etiological factor of NPC in North America.

Human papillomavirus-associated nasopharyngeal carcinoma: A systematic review and meta-analysis.

OBJECTIVE: Human papillomavirus (HPV) is known to affect head and neck sites beyond the oropharynx, including the nasopharynx. Unlike HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC), HPV-associated nasopharyngeal carcinoma (HPV+NPC) is not well characterized and the true prevalence in non-endemic regions is poorly described. Here, we sought to obtain a global point prevalence of HPV in NPC, stratified by geographic region. DATA SOURCES: EMBASE, OVID Medline, and Web of Science were systematically searched for available evidence on September 21, 2022 for articles published between January 1, 1990 and September 21, 2022. REVIEW METHODS: We reviewed the literature for all studies examining NPC and HPV status in adult patients that provided a quantitative HPV prevalence. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main outcome and measures included HPV+NPC prevalence estimates stratified by geographic region, along with other clinical and demographic features. RESULTS: Of the 1567 citations retrieved, 46 studies encompassing 6314 NPC patients were eligible for statistical analysis. The global prevalence of HPV+NPC was 0.18 (95% CI 0.14-0.23). When stratified by geographic region, prevalence was highest in North America (0.25, 95% CI 0.17-0.36), which is a non-endemic region for NPC and also has highest prevalence for HPV+OPSCC. Asia, an endemic area, had the lowest HPV prevalence estimate (0.13, 95% CI 0.08-0.22). HPV 16 (44%) and 18 (33%) were the predominant genotypes in HPV+NPC, dissimilar to HPV+OPSCC. CONCLUSION: This systematic review and meta-analysis provides a global point prevalence of HPV+NPC stratified by geographic region and suggests that HPV is a significant etiological factor of NPC in North America.

ctDNA predicts recurrence and survival in stage I and II HPV-associated head and neck cancer patients treated with surgery.

Human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV+OPSCC) release circulating tumor HPV DNA (ctHPVDNA) into the blood which we, and others, have shown is an accurate real-time biomarker of disease status. In a prior prospective observational trial of 34 patients with AJCC 8 stage I-II HPV+OPSCC treated with surgery, we reported that ctHPVDNA was rapidly cleared within hours of surgery in patients who underwent complete cancer extirpation, yet remained elevated in those with macroscopic residual disease. The primary outcomes of this study were to assess 2-year OS and RFS between patients with and without molecular residual disease (MRD) following completion of treatment in this prospective cohort. MRD was defined as persistent elevation of ctHPVDNA at two consecutive time points, without clinical evidence of disease. The secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. We observed that patients with MRD after treatment completion were more likely to recur compared to patients without MRD, while there was no difference in recurrence rates between patients with MRD and without MRD on postoperative day 1. OS did not significantly differ between patients with MRD after surgery or treatment completion compared to patients without MRD; however, time to death was significantly different between the groups in both settings, suggesting that with a larger sample size OS would differ significantly between the groups or that the impact of MRD detection on survival is time dependent.

Immune Cell Densities Predict Response to Immune Checkpoint-Blockade in Head and Neck Cancer.

Immune checkpoint blockade (ICB) is the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), yet efficacy remains low. The current approach for predicting the likelihood of response to ICB is a single proportional biomarker (PD-L1) expressed in immune and tumor cells (Combined Positive Score, CPS) without differentiation by cell type, potentially explaining its limited predictive value. Tertiary Lymphoid Structures (TLS) have shown a stronger association with ICB response than PD-L1. However, their exact composition, size, and spatial biology in HNSCC remain understudied. A detailed understanding of TLS is required for future use as a clinically applicable predictive biomarker. Methods: Pre-ICB tumor tissue sections were obtained from 9 responders (complete response, partial response, or stable disease) and 11 non-responders (progressive disease) classified via RECISTv1.1. A custom multi-immunofluorescence (mIF) staining assay was designed, optimized, and applied to characterize tumor cells (pan-cytokeratin), T cells (CD4, CD8), B cells (CD19, CD20), myeloid cells (CD16, CD56, CD163), dendritic cells (LAMP3), fibroblasts (α Smooth Muscle Actin), proliferative status (Ki67) and immunoregulatory molecules (PD1). Spatial metrics were compared among groups. Serial tissue sections were scored for TLS in both H&E and mIF slides. A machine learning model was employed to measure the effect of these metrics on achieving a response to ICB (SD, PR, or CR). Results: A higher density of B lymphocytes (CD20+) was found in responders compared to non-responders to ICB (p=0.022). A positive correlation was observed between mIF and pathologist identification of TLS (R 2 = 0.66, p-value= <0.0001). TLS trended toward being more prevalent in responders to ICB (p=0.0906). The presence of TLS within 100 µm of the tumor was associated with improved overall (p=0.04) and progression-free survival (p=0.03). A multivariate machine learning model identified TLS density as a leading predictor of response to ICB with 80% accuracy. Conclusion: Immune cell densities and TLS spatial location within the tumor microenvironment play a critical role in the immune response to HNSCC and may potentially outperform CPS as a predictor of ICB response.

Blood-based screening for HPV-associated cancers.

Background: HPV-associated oropharyngeal cancer (HPV+OPSCC) is the most common HPV-associated cancer in the United States yet unlike cervical cancer lacks a screening test. HPV+OPSCCs are presumed to start developing 10-15 years prior to clinical diagnosis. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC. Taken together, blood-based screening for HPV+OPSCC may be feasible years prior to diagnosis. Methods: We developed an HPV whole genome sequencing assay, HPV-DeepSeek, with 99% sensitivity and specificity at clinical diagnosis. 28 plasma samples from HPV+OPSCC patients collected 1.3-10.8 years prior to diagnosis along with 1:1 age and gender-matched controls were run on HPV-DeepSeek and an HPV serology assay. Results: 22/28 (79%) of cases and 0/28 controls screened positive for HPV+OPSCC with 100% detection within four years of diagnosis and a maximum lead time of 7.8 years. We next applied a machine learning model classifying 27/28 cases (96%) with 100% detection within 10 years. Plasma-based PIK3CA gene mutations, viral genome integration events and HPV serology were used to orthogonally validate cancer detection with 68% (19/28) of the cohort having multiple cancer signals detected. Molecular fingerprinting of HPV genomes was performed across patients demonstrating that each viral genome was unique, ruling out contamination. In patients with tumor blocks from diagnosis (15/28), molecular fingerprinting was performed within patients confirming the same viral genome across time. Conclusions: We demonstrate accurate blood-based detection of HPV-associated cancers with lead times up to 10 years before clinical cancer diagnosis and in doing so, highlight the enormous potential of ctDNA-based cancer screening.

Double trouble: Synchronous and metachronous primaries confound ctHPVDNA monitoring.

BACKGROUND: Human papillomavirus-associated head and neck squamous cell carcinoma (HPV + HNSCC) occurs in the oropharynx (HPV + OPSCC), sinonasal cavity (HPV + SNSCC), and nasopharynx (HPV + NPC). Circulating tumor HPV DNA (ctHPVDNA) is an accurate tool for diagnosis, treatment monitoring, and recurrence detection. An emerging challenge with ctHPVDNA is that ~7.4% of HPV + HNSCC patients develop synchronous or metachronous HPV+ primaries, which could confound ctHPVDNA monitoring. METHODS: We describe a 65-year-old patient with T2N1M0 HPV16 + OPSCC and a 55-year-old patient with T2N2M0 HPV16 + OPSCC. Both patients were enrolled in our prospective observational ctHPVDNA study with longitudinal blood collections throughout treatment. Both patients developed multiple HPV+ primaries. RESULTS: Detailed discussion of the patients' treatment courses, the subsequent diagnoses of their second HPV+ primaries, and their ctHPVDNA monitoring is presented. CONCLUSIONS: As ctHPVDNA use becomes more prevalent, it is important to recognize that an increase in ctHPVDNA can come not only from the primary tumor or metastatic clones, but also from synchronous or metachronous second primaries.

A case of concurrent occurrence of carcinoma showing thymus-like differentiation and follicular variant of papillary thyroid cancer in the same thyroid.

Carcinoma showing thymus-like differentiation (CASTLE) is a rare thyroid cancer. This is the first report of a case of concurrent occurrence of CASTLE with papillary thyroid carcinoma (PTC). A 66-year-old male patient had hoarseness with right vocal cord paralysis. Ultrasonography revealed a hypoechoic nodule in the inferior pole of the right thyroid lobe. Ultrasound-guided fine-needle aspiration cytology suggested differentiated thyroid cancer. The patient underwent total thyroidectomy with neck dissection. Pathological examination revealed two different thyroid cancers: a CASTLE and a follicular variant of PTC. Postoperative radiation therapy was performed. The patient was still alive after 5 year following the initial treatment without evidence of recurrence. The oncological management of patients with concurrent occurrence of different thyroid cancers should consider the biological behavior of both tumors.

Lateral approach contributes to shortened surgical time in video-assisted neck surgery (VANS) for thyroid nodule.

Background: Despite endoscopic thyroid surgery contributing to excellent cosmetic outcomes, it requires longer surgical time than open surgery. This study evaluates the factors associated with operative time in video-assisted neck surgery. Methods: We retrospectively reviewed patients who underwent hemithyroidectomy by video-assisted neck surgery at a single hospital between 2017 and 2021. The clinical parameters were evaluated: age, sex, body weight, body mass index, coexistence of Hashimoto thyroiditis, side of operation, surgical approach to thyroid (midline approach or lateral approach), operation time, amount of blood loss during surgery, maximum tumor diameter and tumor volume, and postoperative complications. These parameters were compared to investigate the association of operative time and surgical approach. Results: Seventy consecutive patients were enrolled in this study, the median age at operation was 50 years, and there were 6 (8.6%) men and 64 (91.4%) women. The median body weight and body mass index at operation were 56.6 kg and 21.5, respectively. Coexistence of Hashimoto thyroiditis was found in 17 (24.3%) patients. Significant differences were found between the groups with longer and shorter operation time than median 201 minutes in surgical approaches to the thyroid (P < .001) and the amount of bleeding during surgery (P = .039). There were no differences in other candidates between the groups. Median operation times were 242 minutes in midline approach and 131 minutes in lateral approach (P < .001). Conclusion: The lateral approach of video-assisted neck surgery to the thyroid can contribute to shortened surgical time in the case of benign thyroid nodules.

Synergistic Effects of Lenvatinib (E7080) and MEK Inhibitors against Anaplastic Thyroid Cancer in Preclinical Models.

E7080, known as lenvatinib, is an oral multitargeted tyrosine kinase inhibitor that has been shown to improve the survival rate of patients with radioiodine-refractory thyroid cancer. However, a majority of patients do not continue lenvatinib intake due to disease progression or significant toxicity. To improve treatment success rates, we propose the combination of lenvatinib with mitogen-activated protein kinase (MEK) inhibitors. To test this hypothesis, we tested the effects of lenvatinib with the MEK inhibitor U0126 in vitro using two human anaplastic thyroid cancer (ATC) cell lines, 8505C and TCO1, and with another MEK inhibitor, selumetinib (AZD6244), in an ATC mouse model. We found that the combination of lenvatinib with MEK inhibitors enhanced the antitumor effects of monotherapy with either agent in vitro and in vivo, and these effects may be through the AKT (Protein Kinase B) and extracellular signal-regulated kinase (ERK) signaling pathways. Furthermore, the combination does not have significant adverse effects in the ATC mouse models in terms of body weight, blood biochemical parameters, and histopathology. In conclusion, the combination of lenvatinib with an MEK inhibitor is a potentially viable therapeutic approach for ATC treatment.

A Rare Case of Thyroid Carcinoma Showing Thymus-Like Differentiation in a Young Adult.

Thyroid carcinoma showing thymus-like differentiation (CASTLE) is thought to originate from ectopic thymic tissue or remnants of the developing thymus within or adjacent to the thyroid. This case report describes a mass located on the left thyroid of a 28-year-old man. Fine-needle aspiration cytology revealed a number of lymphoid cells without atypia that were similar to those seen in a malignant lymphoma of the thyroid, and surgery was performed. Based on additional histopathological findings, the tumor was finally diagnosed as a CASTLE. It is difficult to diagnose this neoplasm using fine-needle aspiration cytology. However, it is possible to differentially diagnose CASTLE based on its histological features. CD5 is useful for diagnosing CASTLE with immunohistochemical staining.

Circulating Tumor HPV DNA in Patients With Stage I and II HPV-Associated Head and Neck Cancer After Surgery.

This cohort study examines the association of posttreatment circulating tumor human papillomavirus DNA (ctHPVDNA) with residual disease and 2-year overall survival and recurrence-free survival in patients with HPV-associated head and neck cancer.