Kinetics of EBV antibody-based NPC risk scores in Taiwan NPC multiplex families.

Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein-Barr virus (EBV)-antibody testing have shown potential for screening of NPC; however, the long-term stability is unclear. Here, we investigated the kinetics of two EBV-antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2-marker enzyme-linked immunosorbent assay score and 13-marker multiplex serology score using the intra-class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20-year follow-up, the 2-marker score showed high stability over time, whereas the 13-marker score was more variable (p < .05). Case-control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2-marker score than the 13-marker score (p < .05). The 2-marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13-marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high-risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high-risk regions.

Feasibility of Using Needle Rinse Fluid for Cobas Human Papillomavirus (HPV) Assay in Diagnosing HPV+ Oropharyngeal Cancer with Neck Lymph Node Aspiration.

BACKGROUND: Human papillomavirus (HPV) is a crucial prognostic factor in oropharyngeal cancer (OPC). p16 is a surrogate marker for diagnosing HPV+ OPC, however it is not direct evidence of HPV existence. OBJECTIVE: The purpose of our study was to evaluate an HPV DNA test-Cobas HPV assay-in diagnosing HPV+ OPC through neck lymph node aspiration. METHODS: Patients with suspected neck mass who received fine needle aspiration (FNA) or core needle biopsy (CNB) at the National Taiwan University Hospital between January 2018 and December 2022 were reviewed. Besides routine cytology and pathology study, needle rinse fluid was collected for the Cobas HPV assay to detect high-risk HPV. RESULTS: We analyzed 137 patients with suspected lymph nodes, 32 (23.4%) of whom were HPV+ OPC patients and 105 (76.6%) of whom had non-HPV-related disease. FNA was performed in 31 patients and CNB was performed in 106 patients, according to the size and necrosis status of the lymph nodes. For diagnosing HPV+ OPC, CNB combined with p16 immunohistochemistry staining showed sensitivity of 93.3%, specificity of 97.8%, positive predictive value (PPV) of 87.5%, negative predictive value (NPV) of 98.9%, and accuracy of 97.2%. On the other hand, for the needle rinse Roche Cobas HPV assay, the test showed sensitivity of 96.9%, specificity of 100%, PPV of 100%, NPV of 99.1%, and accuracy of 99.3%. Compared with p16 IHC staining, the Cobas HPV test showed better PPV with statistical significance (p = 0.04). CONCLUSION: The Cobas HPV assay is a US FDA-approved, highly automated, and readily used technique to directly detect the presence of high-risk HPV. We recommend utilizing the Cobas HPV assay in combination with routine cytology or histopathology examination in the work-up of neck lymphadenopathy.

Is the N2A Category Still Necessary for Oral Cancer Patients After Extranodal Extension Upgrade?

BACKGROUND: The presence of single-node metastasis (Ns) sometimes could be encountered in patients with oral squamous cell carcinoma (OSCC). The survival outcome for different Ns should be worthy of discussion. METHODS: Patients diagnosed with OSCC at the National Taiwan University Hospital between January 2007 and December 2018 were reviewed. All patients with Ns were classified into two groups: with and without extranodal extension (ENE). RESULTS: We analyzed 311 OSCC patients with Ns: 77 (24.76%) with and 234 (75.24%) without ENE. Lymph node (LN) >3 cm was the only significant factor associated with ENE (odds ratio 17.21, p < 0.001). The 5-year, disease-free survival of N1/N2A and N3B patients was 60.5% and 49.4%, respectively (p = 0.04), and the 5-year overall survival was 63.1% and 33.6%, respectively (p = 0.0001). Four fifths of Ns patients with LN >3 cm were upgraded to N3B category as ENE+. Postoperative radiotherapy (PORT) could provide significant benefit in regional control for Ns patients with (p = 0.03) and without (p = 0.0004) other adverse features. After multivariant Cox analysis, ENE+ was a modest and significant risk factor for disease-free (p = 0.08) and overall survival (p = 0.001). By contrast, the LN>3cm and N2A category were not significant risk factors for disease-free and overall survival. CONCLUSIONS: For OSCC patients with Ns, the survival outcome between N3B category and N1/N2A category was significantly different. After ENE+ upgrades (>80%), there were fewer N2A patients, and these patients became more comparable to N1 patients. PORT could significantly improve regional control for Ns patients.

Proactive Swallowing Rehabilitation in Patients with Recurrent Oral Cancer Receiving Salvage Treatment: Long-Term Swallowing-Related Outcomes.

The present study aimed to evaluate the impact of proactive swallowing rehabilitation on swallowing function and quality of life in patients with recurrent oral cancer in the first 2 years after salvage treatment. Consecutive adult patients with recurrent oral cancer who received salvage surgery and free flap reconstruction were recruited prospectively, to whom proactive swallowing rehabilitation was provided. Body weight (BW); fiberoptic endoscopic evaluation of swallowing (FEES), functional oral intake scale (FOIS), and diet level; 10-item eating assessment tool (EAT-10), and MD Anderson Dysphagia Inventory (MDADI); and adherence at baseline, 1, 3, 6, 12, 18 and 24 months were evaluated. A total of 50 patients were included during May 2018 to July 2020. Compared to the baseline, significant deterioration in BW, FOIS, and MDADI was noted at one month. However, a trend of recovery was observed in BW and FOIS from one month, and in MDADI from three months. All patients were free of tube feeding at 18-24 months and tolerated diet with special preparations or compensation. Safe swallowing could be achieved in approximately 80% participants after 12 months of diet modification or compensatory maneuvers. Proactive swallowing therapy was feasible in patients with recurrent oral cancer receiving salvage treatment. Although this patient population might have pre-existing dysphagia from previous treatments, rehabilitation could facilitate safe per oral intake and maintain adequate nutrition with adaptive maneuvers or compensatory strategies. Patients who underwent proactive swallowing rehabilitation had better recovery in the functional oral intake level.

Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common.

BACKGROUND: The incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan. METHODS: Between 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records. RESULTS: In our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999-2002), 30% (2003-2006), 30% (2007-2010), 29% (2011-2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999-2002), 1.06 (2003-2006), 1.52 (2007-2010) to 1.74 (2011-2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35-0.76), p = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p < 0.01). CONCLUSION: The incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC.

Epstein-Barr Virus-Based Nasopharyngeal Carcinoma (NPC) Risk Prediction Scores Are Elevated in NPC Multiplex Family Members in Taiwan.

Nasopharyngeal carcinoma (NPC) is caused by Epstein-Barr virus (EBV) and is more likely to occur in susceptible families. Whether genetic susceptibility operates through altered EBV control is incompletely understood. We used a NPC risk prediction model based on 14 EBV markers to compare risk score distribution in unaffected members from multiplex families with that in population-based controls. Despite the absence of NPC at the time of antibody measurement, we observed an upward shift in risk score among multiplex family members compared to the general population, consistent with the possibility that genetic factors affect NPC risk through alterations in EBV control.

Cancer patterns in nasopharyngeal carcinoma multiplex families over 15 years.

BACKGROUND: Genetic and environmental factors are important determinants of nasopharyngeal carcinoma (NPC). NPC is associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC, but evidence has been mixed for elevated rates of cancers other than NPC. METHODS: The authors reassessed their previous evaluation of familial aggregation of cancer in 348 high-risk Taiwanese multiplex families with 2 or more NPC cases enrolled between 1980 and 2003. Participants were linked to the Taiwan National Cancer Registry and National Death Registry to identify cancers. RESULTS: In all, 2590 individuals contributed 37,959 person-years over an average of 15 years of follow-up; 314 incident cancers were identified. The authors computed multiple primary standardized incidence ratios (MP-SIRs) to evaluate the overall risk and the risk of infection-associated, EBV-associated, and individual cancers. The overall MP-SIR was 1.24 (95% confidence interval [CI], 1.10-1.38). The exclusion of excess NPC risk led to an overall MP-SIR of 1.11 (95% CI, 0.98-1.25). Similarly, the risk of cancers associated with infectious agents was driven by the excess in NPC, and its exclusion led to an MP-SIR of 1.22 (95% CI, 0.99-1.48) for infection-associated cancers and to an MP-SIR of 1.18 (95% CI, 0.72-1.82) for EBV-associated cancers. The authors observed a significant excess of second cancers among NPC cases (oral cancer, mouth cancer, tongue cancer, gum cancer, nasal cavity cancer, bone cancer, and non-Hodgkin lymphoma). CONCLUSIONS: This reassessment of the largest NPC multiplex family study confirms the presence of NPC coaggregation within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. Among NPC cases, elevated rates of secondary cancers, mostly at the, head and neck and hematopoietic cancers suggest radiation treatment effects on subsequent cancer risk.

Patients with oral cancer do not undergo surgery as primary treatment: A population-based study in Taiwan.

BACKGROUND: There are still oral cancer patients without surgery. To improve the survival, it is necessary to know the causes of the oral cancer patients without surgery. METHODS: 23,217 patients with a newly-diagnosed oral cancer in Taiwan Cancer Registry (TCR) database between 2011 and 2015 were enrolled. Data from TCR database named "Reason for No Surgery of Primary Site" were extracted for analysis of the causes of those without surgery. Overall survival plots were presented using the Kaplan-Meier method with log-rank test. RESULTS: 3263 (14%) patients did not received surgery. Among them, there were 720 patients (group 3) without surgery although surgery was advised, 154 patients (group 2) because of poor condition or death before surgery, and 2389 patients (group 1) because of other causes. Twenty-four percent of the patients with surgery were treated one month and more after diagnosis. The 5-year overall survival rates were 68.7%, 25.2%, 9.1% and 17.3% for surgery group, group 3, 2 and 1, respectively (p < 0.001). The mean age of the patients with and without surgery were 54.8 and 59.3, respectively (p < 0.01). Female patients were commoner in group 3 (p < 0.01). The patients without surgery was commoner in the middle (15.7%) and southern (14.8%) than in Northern Taiwan (12.1%). All groups without surgery had more advanced stage and lower BMI (p < 0.01). CONCLUSION: One-sevenths of patients were not treated surgically because of refusal, poor condition, older age, low BMI, and advanced stage. It is necessary to encourage the patients to undergo surgery with shortening the diagnosis-to-treatment interval.

Prevalence of current oral HPV infection among 100 betel nut chewers or cigarette smokers in Northern Taiwan.

BACKGROUND: The incidence of HPV positive oropharyngeal cancer is increasing in Taiwan. Given this, it is critical to understand the prevalence of oral HPV infection since this cancer is potentially preventable. A community-based study was conducted to evaluate the prevalence of oral HPV infection and sexual behavior changes. METHODS: Between January and December 2016, 100 subjects between 20 and 70 years-old with current/ever betel nut chewing or current cigarette smoking visited the Department of Health, New Taipei City. Subjects with cancer history or known HIV/AIDS were excluded. Sexual behavior information was collected through a questionnaire. Oral rinse samples and oropharyngeal swabs were obtained for HPV genotyping using the EasyChip HPV genotyping array (King-Car, Taiwan). RESULTS: 92 men and 8 women were recruited. The prevalence of oral HPV infection was 3%, present between 60 and 70 (11%) and between 30 and 40 years old (4%). The prevalence of the first sexual contact at younger than 20 years old were 71.4%, 53.6%, 15.4% and 44% in <40, 40-49, 50-59 and 60+ years old, respectively (p for trend = 0.0036). The prevalence of 3 or more lifetime sexual partners were 60.7%, 57.1%, 23.1% and 16.7%, respectively for <40, 40-49, 50-59 and 60+ years old (p for trend = 0.0005). CONCLUSION: The prevalence of oral HPV infection is 3%, in current/ever betel nut chewers or current cigarette smokers in Northern Taiwan. Younger generation have more lifetime sexual partners and younger first sexual contact. This could explain the rising incidence of HPV positive oropharyngeal cancer in Taiwan.

Application of ultrasound-guided core biopsy to minimize the non-diagnostic results and the requirement of diagnostic surgery in extrapulmonary tuberculosis of the head and neck.

PURPOSE: Head and neck extrapulmonary tuberculosis (ETB) presenting as lymphadenopathy poses a great threat by potentially increasing the deterioration of clinical outcomes. Tissue sampling for diagnostic confirmation of ETB is the only invasive procedure during the entire clinical course. It is, therefore, necessary to establish ETB sampling methods with accuracy and minimal invasiveness. METHODS: From 2009 to 2014, consecutive patients suspected of ETB receiving ultrasound-guided core biopsy (USCB), fine needle aspiration (FNA), and open biopsy (OB) were enrolled for comparison. RESULTS: There were 52 cases in the USCB group, 58 cases in the FNA group, and 78 cases in the OB group. For USCB, FNA, and OB groups, the diagnostic rates were 84.6 %, 8.6 %, and 100 % and the positive rates of acid-fast stain were 28.6 %, 0 %, and 37.5 %, respectively. The diagnostic rates of culture were 9.6 %, 0 %, and 50 %, respectively. For head and neck ETB, USCB procedure is timesaving, without leaving poor-healing wounds, scars, and the need for general anaesthesia and hospitalization. CONCLUSIONS: This study helps to optimize the ETB sampling method in head and neck based on diagnostic accuracy and minimal invasiveness. USCB can serve as the first-line diagnostic tool for ETB by reducing non-diagnostic results and the need for diagnostic surgery. KEY POINTS: • USCB shows higher diagnostic accuracy of ETB than FNA (84.6 % vs. 8.6 %). • USCB diminishes wound complications caused by surgical intervention for ETB. • USCB avoids general anaesthesia and hospitalization for diagnosing ETB. • USCB saves time and reduces the medical costs of diagnosing ETB.

Use of transnasal endoscopy for screening of esophageal squamous cell carcinoma in high-risk patients: yield rate, completion rate, and safety.

BACKGROUND: Patients with head and neck squamous cell carcinoma are at high risk for synchronous and/or metachronous esophageal cancer. The present study aimed to evaluate the feasibility and safety of unsedated transnasal endoscopy (TNE) for screening these high-risk patients. PATIENTS AND METHODS: Consecutive high-risk patients including patients with suspicious or diagnosed head and neck cancer or patients with alarming symptoms received screening TNE. All endoscopic procedures, including sequential conventional white-light, narrow-band imaging, and Lugol chromoendoscopy, were done without sedation. All suspicious lesions in the esophagus were biopsied for histological evaluation. The completion rate, procedure time, and significant adverse events of all endoscopic procedures were recorded and analyzed. RESULTS: From May 2007 to August 2011, a total of 500 TNE were carried out in 441 high-risk patients. Among them, 294 patients (66.7%) had diagnosed head and neck squamous cellcarcinoma, and most were hypopharyngeal cancer (n = 186). Esophageal squamous cell carcinomas and high-grade intraepithelial neoplasms were detected in 10.1% and 7.3%, respectively, of the cases. Completion rate of TNE in head and neck cancer was 96.7%; tumor obstruction and stenosis of anastomosis site were the main reasons for incomplete procedures. Mean duration of the endoscopic procedure was 14.6 min. One patient had post-endoscopic epistaxis while another patient had post-biopsy hemoptysis, both of whom were treated conservatively. No procedure-related mortality or significant morbidity occurred. CONCLUSION: Unsedated TNE is safe and feasible for screening synchronous or metachronous esophageal neoplasms in high-risk patients, especially those with head and neck cancer.

Margin to depth of invasion ratio as an indicator for stratifying close margins in early-stage oral squamous cell carcinoma.

OBJECTIVES: In early-stage oral squamous cell carcinoma (OSCC) patients, whether the margin-to-depth-of-invasion ratio (MDR) can assist in stratifying the prognosis remains unclear. METHODS: Patients diagnosed with early stage OSCC at National Taiwan University Hospital between January 2007 and December 2021 were reviewed. Patients with margin > 1 mm were classified into two groups: MDR < 0.5 and MDR ≥ 0.5. RESULTS: We analyzed 911 pT1-2N0M0 OSCC patients, 723 (79.36 %) with MDR ≥ 0.5 and 188 (20.64 %) with MDR < 0.5. Patients in the MDR < 0.5 group displayed a significantly higher local recurrence rate (odds ratio 2.81, p = 0.002) compared with MDR ≥ 0.5 group. The 5-year disease-free survival were 80.8 % for clear margin, 76.3 % for close margin (MDR ≥ 0.5), and 65.2 % for close margin (MDR < 0.5). The overall survival displayed a similar pattern, with 5-year rates of 88.3 % for clear margin, 86.8 % for close margin (MDR ≥ 0.5), and 75.0 % for close margin (MDR < 0.5). There were no significant overall survival differences between the two MDR ≥ 0.5 groups, but both were significantly superior to patients with MDR < 0.5 (p = 0.001; p = 0.01). After multivariant cox analysis, MDR < 0.5 was a significant risk factor for disease-free survival (p < 0.001). CONCLUSION: For early stage OSCC patients without positive margin (≦1mm), the survival outcome between MDR ≥ 0.5 group and MDR < 0.5 group was significantly different. The MDR < 0.5 group had significantly higher risk of local recurrence that may warrant adjuvant treatment.

Cleaning and Harmonizing Medical Image Data for Reliable AI: Lessons Learned from Longitudinal Oral Cancer Natural History Study Data.

For deep learning-based machine learning, not only are large and sufficiently diverse data crucial but their good qualities are equally important. However, in real-world applications, it is very common that raw source data may contain incorrect, noisy, inconsistent, improperly formatted and sometimes missing elements, particularly, when the datasets are large and sourced from many sites. In this paper, we present our work towards preparing and making image data ready for the development of AI-driven approaches for studying various aspects of the natural history of oral cancer. Specifically, we focus on two aspects: 1) cleaning the image data; and 2) extracting the annotation information. Data cleaning includes removing duplicates, identifying missing data, correcting errors, standardizing data sets, and removing personal sensitive information, toward combining data sourced from different study sites. These steps are often collectively referred to as data harmonization. Annotation information extraction includes identifying crucial or valuable texts that are manually entered by clinical providers related to the image paths/names and standardizing of the texts of labels. Both are important for the successful deep learning algorithm development and data analyses. Specifically, we provide details on the data under consideration, describe the challenges and issues we observed that motivated our work, present specific approaches and methods that we used to clean and standardize the image data and extract labelling information. Further, we discuss the ways to increase efficiency of the process and the lessons learned. Research ideas on automating the process with ML-driven techniques are also presented and discussed. Our intent in reporting and discussing such work in detail is to help provide insights in automating or, minimally, increasing the efficiency of these critical yet often under-reported processes.

The impact of perineural invasion and/or lymphovascular invasion on the survival of early-stage oral squamous cell carcinoma patients.

BACKGROUND: For early-stage oral squamous cell carcinoma (OSCC) patients, the impact of perineural invasion (PNI) and lymphovascular invasion (LVI) on disease control and survival has not been clarified. METHODS: The medical records of all early-stage OSCC patients who underwent curative surgery between 2004 and 2009 were reviewed. RESULTS: A total of 442 early stage patients were included in this study. There were 360 patients in group A (without PNI or LVI) and 82 patients in group B (with PNI and/or LVI). Between groups A and B patients, there were no significant differences in the 5-year disease-free survival (73.8 vs 68.7 %, p = 0.48) and overall survival (90.9 vs 86.1 %, p = 0.25). Between groups A and B patients without postoperative radiotherapy (PORT), there were no significant differences in the 5-year disease-free survival (73.8 vs 70.2 %, p = 0.51) and overall survival (90.9 vs 85.2 %, p = 0.18). Between group B patients with and without PORT, there was no significant difference in either the disease-free survival (61.1 vs 70.2 %, p = 0.98) and overall survival (88.9 vs 85.2 %, p = 0.64). Multivariate analyses revealed that PNI, LVI, and PORT could not provide significant effect on treatment outcome. CONCLUSIONS: PNI and LVI were not significant risk factors for the disease control and overall survival for early stage OSCC patients. Furthermore, PORT could not provide an additional benefit for the disease control and overall survival for stages I and II OSCC patients with PNI and/or LVI.

The expression of nicotinic acetylcholine receptor subunits and their associations with local immune cells and prognosis in oral squamous cell carcinoma.

BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that may be responsible for cancer cell proliferation, epithelial-mesenchymal transition (EMT), and immune regulation. However, little is known about the associations of different nAChR subunits with tumor microenvironment in oral squamous cell carcinoma (OSCC). METHODS: We retrospectively reviewed pathology samples from 75 OSCC patients by immunohistochemistry. In addition, a cohort of 307 OSCC patients in The Cancer Genome Atlas was analyzed. RESULTS: Subunit α1 was specific to peri-OSCC skeletal muscle. Increased α1 was associated with increased CD44 (cancer stem cells), increased CD3 and 8 (T cells), increased CD56 and 16 (natural killer cells), a decreased T stage, and an increased N stage. Increased α3 was associated with increased CD56 and 16. Increased α5 was associated with decreased CD3, 8, and 56, a decreased T stage, an increased N stage, worse survival, and decreased epithelial features. Increased α7 was associated with increased CD3, 8, 56, and 16, decreased tumor/peritumor ratios of CD3, 8, and 56 immune cells, and increased epithelial features. Increased local immune cells were associated with a better prognosis. CONCLUSIONS: α5 is the only subunit associated with decreased local immune cells and worse survival, while α1, α3, and α7 are associated with increased local immune cells in OSCC. α5 and α7 are correlated with different EMT states to be mesenchymal-like and epithelial-like OSCC, respectively. Protein expression data of the nAChR subunits, complementary to gene expression data, could provide meaningful information regarding the EMT status of OSCC associated with immune responses and prognosis.

Chemoprevention of oral cancer: A review and future perspectives.

BACKGROUND: Oral cancer causes significant morbidity and mortality. Chemoprevention utilizes medication or natural compounds to reverse oral premalignant lesions and to prevent second primary tumors. METHODS: A comprehensive PubMed database and Cochrane Library search from 1980 to 2021 was performed using the keywords "leukoplakia," "oral premalignant lesion," and "chemoprevention." RESULTS: Chemopreventive agents included retinoids, carotenoids, cyclooxygenase inhibitor, herbal extracts, bleomycin, tyrosine kinase inhibitors, metformin, and immune checkpoint inhibitors. Although some agents demonstrated effect in reducing premalignant lesions and preventing second primary tumors, the results among different studies were highly variable. CONCLUSIONS: The results of different trials, albeit inconsistent, provided substantial information for future studies. In the era of personalized medicine, future studies will focus on identifying specific biomarkers and molecular profile to monitor and to prevent malignant transformation. Larger trials are warranted to validate the effect of chemopreventive agents.

Spindle Cell Carcinoma of the Head and Neck: Clinical Characteristics and Molecular Signatures.

OBJECTIVE/HYPOTHESIS: Spindle cell carcinoma of the head and neck (HNSpCC) is a rare variant of head and neck squamous cell carcinoma (HNSCC). This study evaluated the clinical characteristics and molecular signatures of such tumors. STUDY DESIGN: Retrospective analysis. METHODS: Medical records of patients diagnosed with HNSpCC from 1996 to 2018 were reviewed. The clinicopathologic features, treatment modalities, and survival status were carefully recorded. Whole exome sequencing (WES) was performed to evaluate the genetic signatures of HNSpCC. RESULTS: We found that among all 71 patients included in this study, the majority of them were male, with tumors developing predominantly in the oral cavity. The 1-, 3-, and 5-year disease-specific survival (DSS) rates were 64.6%, 49.5%, and 43.9%, respectively. A high local recurrence (LR) and distant metastasis (DM) rate (47.9%-25.3%, respectively) were observed. A significant proportion (28.2%) of patients with the worst prognosis had history of previous head and neck cancer (HNC) and had been treated with radiotherapy (RT). WES revealed that those post-RT SpCC shared common mutations with their previous HNC (pre-RT SCC), but gained additional genetic traits, such as hypoxia and cell-ECM interaction that were favorable for survival in an irradiated microenvironment. Distinct genetic landscapes in primary and post-RT SpCC were also found. CONCLUSIONS: This study demonstrates that HNSpCC is a unique entity with more aggressive behavior than conventional HNSCC. HNSpCC arising from a previously irradiated field is a predictor of dismal survival. Both genetic and microenvironmental factors contribute to this highly invasive tumor. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2183-2191, 2023.