Distant metastasis in oral squamous cell carcinoma: Does the neutrophil-to-lymphocyte ratio act as a surrogate of the host immune status?

OBJECTIVES: Distant metastasis (DM) is an important prognostic factor for oral squamous cell carcinoma (OSCC). The aim of this study is to evaluate the influence of host and tumor factors in development of DM. MATERIALS AND METHODS: After IRB approval, 1369 patients with OSCC undergoing primary surgery were eligible for the study. The primary endpoint was the development of distant metastasis (DM). Patients were pathologically staged according to the American Joint Committee on Cancer, 8th Edition. Pre-operative peripheral blood counts were used to calculate neutrophil-to-lymphocyte ratio (NLR). RESULTS: Median follow-up was 39 months (range 1-221). DM were identified in 126 patients during follow-up. When analyzed as a time-dependent covariate, neck recurrence (NR) was a significant predictor of DM (HR 16.35, 95% CI: 11.39-23.47, p < 0.001). NLR, margin status, vascular invasion, perineural invasion (PNI), grade, pT, number of metastatic lymph nodes, level IV involvement, and extra nodal-extension (ENE) were also significant. In multivariable analysis, NLR, margins, PNI, number of metastatic lymph nodes, and ENE maintained independent predictive capacity. Patients with NLR ≥ 5.7 were 3 times more likely to develop DM compared to NLR ≤ 2.9 (95% CI: 1.74-5.59, p < 0.001), patients with ≥ 5 metastatic lymph nodes were 2 times more likely to develop DM (95% CI: 1.18-3.60, p = 0.011), and those with ENE were 4 times more likely (95% CI: 2.67-8.20, p < 0.001) when compared to pNx/pN0 patients. CONCLUSIONS: NLR, number of metastatic lymph nodes, and ENE were the strongest independent predictors of DM in OSCC treated with primary surgery and appropriate adjuvant therapy.

Mucoepidermoid carcinoma: Evaluating the prognostic impact of primary tumor site.

Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland malignancies. Our aim was to evaluate the prognostic impact of primary tumor site in patients with MEC. MATERIAL AND METHODS: This cohort identified 308 patients with MEC who underwent primary surgery between 1985 and 2015. Survival outcomes were determined using the Kaplan-Meier method. Hazard ratios for primary site were determined using the Cox proportional-hazards model. RESULTS: One hundred eighty (58%) patients were diagnosed with minor and 128 (42%) with major salivary gland cancer. Primary site in the minor salivary gland group included 137 (44%) oral cavity, 38 (12%) pharynx, 3 (0.9%) nasal cavity, and 2 (0.6%) trachea and larynx. The major salivary gland group included 118 (38%) parotid, 8 (3%) submandibular, and 2 (0.6%) sublingual. With a median follow-up of 73 months, 5-year overall survival and disease-specific survival were 84% and 91%, respectively. Patients with tumors located in the hard palate and retromolar trigone had the best survival, while patients with tumors located in the paranasal sinuses and submandibular gland had the poorest survival. After controlling for tumor grade and stage, MEC primary site was not predictive of survival or recurrence. On multivariate analysis, worse DSS was associated with stage III-IV tumors (HR: 7,11; 95% CI: 1.19-26.43; p = 0.0034) and high-grade tumors (HR: 19.12; 95% CI: 2.26-162.77; p = 0.0068). CONCLUSIONS: While high grade and advanced overall stage were found to be independent predictors of worse survival, primary tumor site was not predictive of poor outcome.

Use of Ultrasmall Core-Shell Fluorescent Silica Nanoparticles for Image-Guided Sentinel Lymph Node Biopsy in Head and Neck Melanoma: A Nonrandomized Clinical Trial.

Importance: Sentinel lymph node (SLN) mapping agents approved for current surgical practice lack sufficient brightness and target specificity for high-contrast, sensitive nodal visualization. Objective: To evaluate whether an ultrasmall, molecularly targeted core-shell silica nanoparticle (Cornell prime dots) can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy. Design, Setting, and Participants: This nonrandomized clinical trial enrolled patients aged 18 years or older with histologically confirmed melanoma in whom SLN mapping was indicated. Exclusion criteria included known pregnancy, breast-feeding, or medical illness unrelated to the tumor. The trial was conducted between February 2015 and March 2018 at Memorial Sloan Kettering Cancer Center, with postoperative follow-up of 2 years. Data analysis was conducted from February 2015 to March 2018. Interventions: Patients received standard-of-care technetium Tc 99m sulfur colloid followed by a microdose administration of integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine-aspartic acid-tyrosine peptides (cRGDY-PEG-Cy5.5-nanoparticles) intradermally. Main Outcomes and Measures: The primary end points were safety, procedural feasibility, lowest particle dose and volume for maximizing nodal fluorescence signal, and proportion of nodes identified by technetium Tc 99m sulfur colloid that were optically visualized by cRGDY-PEG-Cy5.5-nanoparticles. Secondary end points included proportion of patients in whom the surgical approach or extent of dissection was altered because of nodal visualization. Results: Of 24 consecutive patients enrolled (median [interquartile range] age, 64 [51-71] years), 18 (75%) were men. In 24 surgical procedures, 40 SLNs were excised. Preoperative localization of SLNs with technetium Tc 99m sulfur colloid was followed by particle dose-escalation studies, yielding optimized doses and volumes of 2 nmol and 0.4 mL, respectively, and maximum SLN signal-to-background ratios of 40. No adverse events were observed. The concordance rate of evaluable SLNs by technetium Tc 99m sulfur colloid and cRGDY-PEG-Cy5.5-nanoparticles was 90% (95% CI, 74%-98%), 5 of which were metastatic. Ultrabright nanoparticle fluorescence enabled high-sensitivity SLN visualization (including difficult-to-access anatomic sites), deep tissue imaging, and, in some instances, detection through intact skin, thereby facilitating intraoperative identification without extensive dissection of adjacent normal tissue or nerves. Conclusions and Relevance: This study found that nanoparticle-based fluorescence-guided SLN biopsy in head and neck melanoma was feasible and safe. This technology holds promise for improving lymphatic mapping and SLN biopsy procedures, while potentially mitigating procedural risks. This study serves as a first step toward developing new multimodal approaches for perioperative care. Trial Registration: ClinicalTrials.gov Identifier: NCT02106598.

Fluorine-18 labeled poly (ADP-ribose) polymerase1 inhibitor as a potential alternative to 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography in oral cancer imaging.

OBJECTIVES: The evaluation of disease extent and post-therapy surveillance of head and neck cancer using 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET is often complicated by physiological uptake in normal tissues of the head and neck region, especially after surgery or radiotherapy. However, irrespective of low positive predictive values, [18F]FDG PET remains the standard of care to stage the disease and monitor recurrences. Here, we report the preclinical use of a targeted poly (ADP-ribose) polymerase1 (PARP1) binding PET tracer, fluorine-18 labeled poly (ADP-ribose) polymerase1 inhibitor ([18F]PARPi), as a potential alternative with greater specificity. METHODS: Using an orthotopic xenograft mouse model injected with either FaDu or Cal 27 (human squamous cell carcinoma cell lines) we performed PET/CT scans with the 2 tracers and compared the results. Gamma counts and autoradiography were also assessed and correlated with histology. RESULTS: The average retained activity of [18F]PARPi across cell lines in tumor-bearing tongues was 0.9 ±â€¯0.3%ID/g, 4.1 times higher than in control (0.2 ±â€¯0.04%ID/g). Autoradiography and histology confirmed that the activity arose almost exclusively from the tumor areas, with a signal/normal tissue around a ratio of 42.9 ±â€¯21.4. In vivo, [18F]PARPi-PET allowed delineation of tumor from healthy tissue (p < .005), whereas [18F]FDG failed to do so (p = .209). CONCLUSIONS AND IMPLICATIONS FOR PATIENT CARE: We demonstrate that [18F]PARPi is more specific to tongue tumor tissue than [18F]FDG. [18F]PARPi PET allows for the straightforward delineation of oral cancer in mouse models, suggesting that clinical translation could result in improved imaging of head and neck cancer when compared to [18F]FDG.

New AJCC: How does it impact oral cancers?

PURPOSE OF REVIEW: The objective of this article is to critically review the rationale for the changes in the staging of the oral cavity cancers. RECENT FINDINGS: After reviewing many recent studies about oral cancer and analyzing multi-institutional data for outcomes, the staging system was updated to include new knowledge of the disease and its biological behavior. SUMMARY: This article reviews the changes in the staging of oral cavity cancers published in the 8th edition of the AJCC/UICC TNM cancer staging manual and discusses future directions.

Validation of the use of a fluorescent PARP1 inhibitor for the detection of oral, oropharyngeal and oesophageal epithelial cancers.

For oral, oropharyngeal and oesophageal cancer, the early detection of tumours and of residual tumour after surgery are prognostic factors of recurrence rates and patient survival. Here, we report the validation, in animal models and a human, of the use of a previously described fluorescently labelled small-molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) for the detection of cancers of the oral cavity, pharynx and oesophagus. We show that the fluorescent contrast agent can be used to quantify the expression levels of PARP1 and to detect oral, oropharyngeal and oesophageal tumours in mice, pigs and fresh human biospecimens when delivered topically or intravenously. The fluorescent PARP1 inhibitor can also detect oral carcinoma in a patient when applied as a mouthwash, and discriminate between fresh biopsied samples of the oral tumour and the surgical resection margin with more than 95% sensitivity and specificity. The PARP1 inhibitor could serve as the basis of a rapid and sensitive assay for the early detection and for the surgical-margin assessment of epithelial cancers of the upper intestinal tract.

Polymorphous adenocarcinoma of salivary glands.

OBJECTIVE: Polymorphous adenocarcinoma of salivary gland (PAC) is rare. Despite being described as a low risk histology, some patients develop regional and distant metastasis. More aggressive behavior has been attributed to a PAC subcategory called cribriform adenocarcinoma of minor salivary glands (CAMSG). We examined oncological outcomes of PAC. PATIENTS AND METHODS: Fifty-seven patients with PAC were identified from an institutional database of 884 patients surgically treated for salivary gland malignancies from 1985 to 2015. Detailed histopathological analysis was performed. Survival outcomes were calculated using the Kaplan-Meier method. Factors predictive of recurrence were identified using the Cox proportional hazard method. RESULTS: Fifty-four (95%) had tumors of minor salivary gland origin; the most frequent location was the oral cavity in 41 (76%), specifically the hard palate in 32 (55%). Forty-six patients (81%) were clinical T1-T2; 3 (5%) had a clinically positive neck. Thirty-two patients (56%) were classified as PAC and 14 (25%) as CAMSG. Forty-four patients (77%) had surgery alone; 13 (23%) had surgery and postoperative radiotherapy. The 5- and 10-year overall survival and disease-specific survival were 88% and 79% and 98% and 94%, respectively (median follow up 84 [1-159] months); 5- and 10-year recurrence-free survival were 93% and 88%, respectively. Univariate analysis showed male sex, III/IV stage, and CASMG variant had increased incidence of recurrence but were not statistically significant. CONCLUSION: PAC of the salivary glands is an indolent disease with good survival outcomes. Recurrence is uncommon and tends to occur late. Long-term follow-up is indicated in patients with this disease.

Sex disparities in salivary malignancies: Does female sex impact oncological outcome?

OBJECTIVE: Previous population-based studies in salivary gland carcinomas have described a relationship between female sex and superior oncological outcome. PATIENTS AND METHODS: Our institutional database of 884 surgically treated patients with salivary gland malignancies from 1985 to 2015 was analyzed for the impact of sex on oncological outcomes. Histologies were classified in three risk groups, low, intermediate and high. Survival outcomes were determined using the Kaplan-Meier method. Hazard ratios for male sex were determined using the Cox proportional hazards model. RESULTS: Eight hundred sixty-seven patients were identified; median age was 59 years, and 51% had a minor salivary gland malignancy. Female patients were younger (58 versus 60 years; p = 0.040) and had a lower incidence of high-risk histologies (25% versus 40%, p < 0.001) and T3-T4 tumors compared to men (23% versus 31%, p < 0.001). With a median follow-up of 57 months, female patients had a superior 5-year disease-specific survival (DSS) (90% versus 79%; p < 0.001). The unadjusted hazard ratio showed male patients had a 2.15-fold increased risk of death (HR 2.15; 95% CI, 1.50-3.06, p < 0.001). After adjusting for Charlson comorbidity index, tobacco use, histological risk group, and overall pathological stage, males still had a statistically significant increased risk of death (HR 1.48; 95% CI 1.05-2.17; p = 0.047). Subgroup analysis showed DSS for females was significantly better in the high-risk histological group (5-year 68% versus 49%, p = 0.007). CONCLUSION: Our study shows that sex has an impact on cancer-specific survival and that female sex favors improved survival.

Feasibility of a Video-Mosaicking Approach to Extend the Field-of-View For Reflectance Confocal Microscopy in the Oral Cavity In Vivo.

BACKGROUND: Reflectance confocal microscopy (RCM) is a developing approach for noninvasive detection of oral lesions with label-free contrast and cellular-level resolution. For access into the oral cavity, confocal microscopes are being configured with small-diameter telescopic probes and small objective lenses. However, a small probe and objective lens allows for a rather small field-of-view relative to the large areas of tissue that must be examined for diagnosis. To extend the field-of-view for intraoral RCM imaging, we are investigating a video-mosaicking approach. METHODS: A relay telescope and objective lens were adapted to an existing confocal microscope for access into the oral cavity. Imaging was performed using metal three-dimensional-printed objective lens front-end caps with coverslip windows to contact and stabilize the tissue and set depth. Four healthy volunteers (normal oral mucosa), one patient (with an amalgam tattoo) in a clinical setting, and 20 anesthetized patients (with oral squamous cell carcinoma [OSCC]) in a surgical setting were imaged. Instead of the usual still RCM images, videos were recorded and then processed into video-mosaics. Thirty video-mosaics were read and qualitatively assessed by an expert reader of RCM images of the oral mucosa. RESULTS: Whereas the objective lens' native field-of-view is 0.75 mm × 0.75 mm, the video-mosaics display larger areas, ranging from 2 mm × 2 mm to 4 mm × 2 mm, with resolution, morphologic detail, and image quality that is preserved relative to that observed in the original videos (individual images). Video-mosaics in healthy volunteers' and the patients' images showed cellular morphologic patterns in the lower epithelium and at the epithelial junction, and connective tissue along with capillary loops and blood flow in the deeper lamina propria. In OSCC, tumor nests could be observed along with normal looking mucosa in margin areas. CONCLUSIONS: Video-mosaicking is a reasonably quick and efficient approach for extending the field-of-view of RCM imaging, which can, to some extent, overcome the inherent limitation of an intraoral probe's small field-of-view. Reading video-mosaics can mimic the procedure for examining pathology: initial visualization of the spatial cellular and morphologic patterns of the tumor and the spread of tumor margins over larger areas of the lesion, followed by digitally zooming (magnifying) for closer inspection of suspicious areas. However, faster processing of videos into video-mosaics will be necessary, to allow examination of video-mosaics in real-time at the bedside. Lasers Surg. Med. 51:439-451, 2019. © 2019 Wiley Periodicals, Inc.

Changes in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging of Head and Neck Cancer: Rationale and Implications.

PURPOSE OF REVIEW: The objectives of this article are to review the major changes in the staging of head and neck cancers and the rationale for the modifications. RECENT FINDINGS: Information gathered from various institutional reports lead to a better understanding of the clinical and biological behavior of head and neck tumors, resulting in distinct outcomes, which were used to update the staging system. This article reviews the changes in the staging of head and neck cancers published in the 8th edition of the AJCC/UICC TNM staging system.

Survival outcomes after treatment of cancer of the oral cavity (1985-2015).

OBJECTIVES: To present treatment results of oral squamous cell carcinoma (OSCC) at a tertiary cancer care center from 1985 to 2015. MATERIALS AND METHODS: A total of 2082 patients were eligible for this study. Main outcomes measured were overall survival (OS) and disease specific survival (DSS). Prognostic variables were identified with bivariate analyses using Kaplan-Meier curves and log-rank testing for comparison. A p-value < 0.05 was considered statistically significant and significant factors were entered into multivariate analysis. Median age was 62 years (16-100), 56% were men, 66% reported a history of tobacco use and 71% of alcohol consumption. The most common subsite was tongue (51%). Seventy-three percent of patients had cT1-2 and 71% had clinically negative necks (cN0). Surgery alone was performed in 1348 patients (65%), adjuvant postoperative radiotherapy in 608 patients (29%) and postoperative chemoradiation in 126 patients (6%). Neck dissection was performed in 920 patients with cN0, and in 585 patients with a clinically involved neck. The median follow-up was 37.6 months (range 1-382). RESULTS: The 5-year OS and DSS were 64.4% and 79.3%, respectively. Age, comorbidities, margin status, vascular invasion, perineural invasion, AJCC 8th edition pT, and pN were independent prognostic factors of OS (p < 0.05). History of alcohol consumption, margin status, vascular invasion, perineural invasion, pT, and pN were independent prognostic factors of DSS (p < 0.05). CONCLUSION: pN stage is the most powerful and consistent predictor of outcome in patients with OSCC treated with primary surgery and appropriate adjuvant therapy.

Do we need a different staging system for tongue and gingivobuccal complex squamous cell cancers?

OBJECTIVES: To determine the need for a separate staging system for gingivobuccal complex squamous cell cancers (GBCSCC) based on 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) data from one institution. PATIENTS AND METHODS: An Institutional Review Board (IRB)-approved retrospective analysis was performed on an oral cavity cancer patient database. Patients from 1985 to 2012 with primary surgical treatment for biopsy-proven squamous cell cancer (SCC) from either the oral tongue (TSCC Group) or gingivobuccal complex (GBCSCC Group), were selected as two separate subgroups. The clinicopathologic data were used to stage the patients based on the American Joint Committee on Cancer 7th edition. Survival outcomes including 5-year OS, RFS, and DSS were calculated and analyzed. A multivariate analysis was performed to identify if subsite was an independent predictor for the survival outcomes, adjusting for other variables. A p-value of less than .05 was considered statistically significant. RESULTS: 936 patients with TSCC and 486 patients with GBCSCC were considered eligible for the analysis. Patients with GBCSCC were more likely to be older (p < .001) and presented with more advanced disease (p < .001) compared to patients with TSCC. Unadjusted hazard ratio (HR) suggested GBCSCC had poor OS compared to TSCC. However, after adjusting for other variables, the adjusted HR was not significant (p = .593). There was no difference in 5-year DSS or RFS in either of the study groups. CONCLUSION: With similar survival outcomes by stage, there is no justification for using a different staging system for GBCSCC.

Validation of nomograms for overall survival, cancer-specific survival, and recurrence in carcinoma of the major salivary glands.

BACKGROUND: The purpose of this study was to investigate the performance of the Memorial Sloan Kettering Cancer Center salivary carcinoma nomograms predicting overall survival, cancer-specific survival, and recurrence with an external validation dataset. METHODS: The validation dataset comprised 123 patients treated between 2010 and 2015 at our institution. They were evaluated by assessing discrimination (concordance index [C-index]) and calibration (plotting predicted vs actual probabilities for quintiles). RESULTS: The validation cohort (n = 123) showed some differences to the original cohort (n = 301). The validation cohort had less high-grade cancers (P = .006), less lymphovascular invasion (LVI; P < .001) and shorter follow-up of 19 months versus 45.6 months. Validation showed a C-index of 0.833 (95% confidence interval [CI] 0.758-0.908), 0.807 (95% CI 0.717-0.898), and 0.844 (95% CI 0.768-0.920) for overall survival, cancer-specific survival, and recurrence, respectively. CONCLUSION: The 3 salivary gland nomograms performed well using a contemporary validation dataset, despite limitations related to sample size, follow-up, and differences in clinical and pathology characteristics between the original and validation cohorts.

Current Practice and Emerging Molecular Imaging Technologies in Oral Cancer Screening.

Oral cancer is one of the most common cancers globally. Survival rates for patients are directly correlated with stage of diagnosis; despite this knowledge, 60% of individuals are presenting with late-stage disease. Currently, the initial evaluation of a questionable lesion is performed by a conventional visual examination with white light. If a lesion is deemed suspicious, a biopsy is taken for diagnosis. However, not all lesions present suspicious under visual white light examination, and there is limited specificity in differentiating between benign and malignant transformations. Several vital dyes, light-based detection systems, and cytology evaluation methods have been formulated to aid in the visualization process, but their lack of specific biomarkers resulted in high false-positive rates and thus limits their reliability as screening and guidance tools. In this review, we will analyze the current methodologies and demonstrate the need for specific intraoral imaging agents to aid in screening and diagnosis to identify patients earlier. Several novel molecular imaging agents will be presented as, by result of their molecular targeting, they aim to have high specificity for tumor pathways and can support in identifying dysplastic/cancerous lesions and guiding visualization of biopsy sites. Imaging agents that are easy to use, inexpensive, noninvasive, and specific can be utilized to increase the number of patients who are screened and monitored in a variety of different environments, with the ultimate goal of increasing early detection.

A Proposal to Redefine Close Surgical Margins in Squamous Cell Carcinoma of the Oral Tongue.

Importance: Resection of the primary tumor with negative margins is the gold standard treatment for squamous cell carcinoma of the oral tongue (SCCOT). A microscopically positive surgical margin is clearly associated with a higher risk for local recurrence, whereas a negative margin has traditionally been defined as greater than 5.0 mm clearance from the tumor, with lesser margins arbitrarily designated as close. The precise cutoff at which the risk for local recurrence with a close margin approximates that of a microscopically positive margin remains unclear. Objective: To determine whether the arbitrarily defined close margin (<5.0 mm) would portend as high a risk for local recurrence as a positive margin after resection of SCCOT. Design, Setting, and Participants: In this retrospective study, head and neck pathologists reviewed archived tumor specimens from 381 patients with SCCOT who underwent primary surgical resection at a tertiary care center from January 1, 2000, through December 31, 2012. Data were analyzed from November 15, 2015, to January 5, 2016. Time-dependent receiver operating characteristic curve analysis was used in patients who did not have a microscopically positive margin to determine an optimal margin cutoff for local recurrence-free survival (LRFS). Pathologic factors were assessed for LRFS in a multivariate Cox proportional hazards regression model. Main Outcomes and Measures: The primary end point was evaluation of the margin distance associated with LRFS. Results: Among the 381 patients included in the analysis (222 men [58.3%] and 159 women [41.7%]; mean [SD] age, 58 [14.7] years), the optimal cutoff associated with LRFS was determined to be 2.2 mm. This cutoff was compared with the traditionally accepted cutoff of 5.0 mm. Patients with a margin of 2.3 to 5.0 mm had similar LRFS as patients with a margin of greater than 5.0 mm (hazard ratio [HR], 1.31; 95% CI, 0.58-2.96), and all other comparisons were significantly different (HR for positive margin, 9.03; 95% CI, 3.45-23.67; HR for 0.01- to 2.2-mm margin, 2.83; 95% CI, 1.32-6.07). Based on this result, negative margins were redefined as those with a clearance of greater than 2.2 mm. In a multivariate model adjusting for pathologic factors, positive margins (adjusted HR, 5.73; 95% CI, 2.45-13.41) and margins of 0.01 to 2.2 mm (adjusted HR, 2.00; 95% CI, 1.13-3.55) were the variables most significantly associated with LRFS. Conclusions and Relevance: In this study, local recurrence-free survival was significantly affected only with surgical margins of less than or equal to 2.2 mm in patients with SCCOT. This new definition of close margins stratifies the risk for local recurrence better than the arbitrary 5.0-mm cutoff that has been used.