A Prospective Double-Blinded Comparison of Reflectance Confocal Microscopy with Conventional Histopathology for In Vivo Assessment in Oral Cancer.

PURPOSE: We investigated reflectance confocal microscopy (RCM) as a possible noninvasive approach for the diagnosis of cancer and real-time assessment of surgical margins. EXPERIMENTAL DESIGN: In a phase I study on 20 patients, we established the RCM imaging morphologic features that distinguish oral squamous cell carcinoma (OSCC) from normal tissue with a newly developed intraoral RCM probe. Our subsequent phase II prospective double-blinded study in 60 patients tested the diagnostic accuracy of RCM against histopathology. Five RCM videos from the tumor and five from normal surrounding mucosa were collected on each patient, followed by a 3-mm punch biopsy of the imaged area. An experienced RCM reader, who was blinded to biopsy location and histologic diagnosis, examined the videos from both regions and classified each as "tumor" or "not tumor" based on RCM features established in phase I. Hematoxylin and eosin slides from the biopsies were read by a pathologist who was blinded to RCM results. Using histology as the gold standard, we calculated the sensitivity and specificity of RCM. RESULTS: We report a high agreement between the blinded readers (95% for normal tissue and 81.7% for tumors), high specificity (98.3%) and negative predictive values (96.6%) for normal tissue identification, and high sensitivity (90%) and positive predictive values (88.2%) for tumor detection. CONCLUSIONS: RCM imaging is a promising technology for noninvasive in vivo diagnosis of OSCC and for real-time intraoperative evaluation of mucosal surgical margins. Its inherent constraint, however, stems from the diminished capability to evaluate structures located at more substantial depths within the tissue.

Young non-smokers with oral cancer: What are we missing and why?

OBJECTIVES: There has been an increase in young non-smokers (YNS) who develop oral cavity squamous cell carcinomas (OSCC). Oncological outcomes in YNS are controversial and etiology has not been well-defined. We hypothesize that the etiology of cancer development in YNS and their poor outcome is related to an impaired immune system. MATERIALS AND METHODS: From a database of 2073 OSCC patients treated with primary surgery between 1985 and 2015, 9% were young patients. We categorized patients as: ≤40 years-old/non-smokers (n = 100), ≤40 years-old/smokers (n = 80), >40 years-old/non-smokers (n = 595) and >40 years-old/smokers (n = 1298). Patient and tumor variables were used to calculate propensity scores and stabilized inverse probability of treatment weights were calculated. Weighted proportional hazard models were performed. Survival and recurrence outcomes of YNS were compared to the other 3 groups. Host immune status of YNS measured by peripheral blood neutrophil-to-lymphocyte ratio (NLR) was compared to 2 control groups (YNS with thyroid cancer and YNS with benign pathologies). RESULTS: After adjusting for tumor and host factors, YNS had a higher probability of death compared to young smokers. This was driven by a higher incidence of regional and distant recurrences. Host factors showed a strong association with outcomes suggesting YNS may have an impaired immune system. Compared to the control cohorts YNS with OSCC had a higher NLR (p = .006). CONCLUSION: When adjusted by relevant covariates, YNS with OSCC have poorer survival than their young smoker counterparts. Our results suggest that an impaired immune system may be partly responsible for OSCC development and poorer outcomes in YNS.

Histologic evaluation of host immune microenvironment and its prognostic significance in oral tongue squamous cell carcinoma: a comparative study on lymphocytic host response (LHR) and tumor infiltrating lymphocytes (TILs).

BACKGROUND: Host immune microenvironment is a key component of anti-tumoral immune response, influencing tumor progression, regression, and treatment responses. There is a need for simple and reliable histologic measurements of host immune response in routine histopathologic diagnosis. METHODS: The prognostic value of lymphocytic host response (LHR), a qualitative histologic grading scheme, was compared to stromal/intratumoral TIL (sTIL/iTIL) percentage, a quantitative measurement in a retrospective study of 329 patients with oral tongue squamous cell carcinoma (OTSCC) of 4 cm or less in size. RESULTS: High sTIL predicted improved distant recurrence free survival on univariate survival analysis and was an independent prognostic factor for better overall survival on multivariate analysis. LHR and iTIL were not associated with the risk of nodal metastasis or outcome. CONCLUSIONS: sTIL appears to be a superior quantitative histologic measurement for the host immune microenvironment compared with the qualitative LHR grading scheme. sTIL is an independent prognostic factor for overall survival in OTSCC.

The prognostic role of histologic grade, worst pattern of invasion, and tumor budding in early oral tongue squamous cell carcinoma: a comparative study.

Major pathology guidelines often mandate stating the histologic grade as a component of the pathology report for various types of cancer. However, the prognostic value of histologic grade in head and neck squamous cell carcinoma (HNSCC) is controversial at best, and there is a need for more reliable prognostic histologic factors to better stratify and manage patients with HNSCC. In this study, we compared three relevant histopathologic features (histologic grade, worst pattern of invasion (WPOI), and tumor budding) in a large single-center retrospective cohort of early oral tongue squamous cell carcinoma (OTSCC) with tumor greatest dimension ≤ 4 cm. Only histologic grade predicted distant metastasis free survival (DMFS) on univariate analysis. Tumor budding was associated with nodal metastasis, overall survival (OS), regional recurrence-free survival (RRFS), and DMFS and was a significant predictor for nodal metastasis on the multivariable logistic regression model. WPOI 5 was associated with high frequency of nodal metastasis and shortened OS and was an independent adverse prognostic factor for OS on multivariate analysis using the Cox proportional hazards model. WPOI and tumor budding were prognostically more relevant than histologic grade. Consideration should be given to include WPOI and tumor budding in the pathology reporting of OTSCC.

Nodal characteristics associated with adverse prognosis in oral cavity cancer are linked to host immune status.

BACKGROUND AND OBJECTIVE: Nodal metastasis is one of the strongest predictors of outcomes in oral cavity squamous cell carcinomas (OSCC). The aim was to analyze the interplay of nodal characteristics in OSCC prognosis. METHODS: In this retrospective cohort study we included OSCC patients treated with primary surgery including neck dissection between 2005 and 2015 (n = 619). Disease-specific survival (DSS) was the primary endpoint. Optimal cutoffs were identified using recursive-partitioning analysis (RPA). A novel characteristic-metastatic focus-to-lymph node size ratio (MLR)-was introduced. We compared the American Joint Committee on Cancer, Eighth Edition (AJCC8) pN categories to a new categorization. RESULTS: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. All nodal characteristics were significant predictors of DSS in univariable analysis. In multivariable analysis, only number of positive nodes and MLR remained significant. An RPA including all nodal covariates confirmed the results. Compared with AJCC8, our RPA categorization had better hazard discrimination (0.681 vs. 0.598), but poorer balance value (0.783 vs. 0.708). CONCLUSION: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. Total number of metastatic lymph nodes is the strongest predictor of outcomes in OSCC. MLR is a more powerful predictor than metastatic lymph node size or metastatic focus size alone.

Depth of invasion versus tumour thickness in early oral tongue squamous cell carcinoma: which measurement is the most practical and predictive of outcome?

AIMS: The 8th edition of the American Joint Committee on Cancer (AJCC) Staging introduced depth of invasion (DOI) into the pT category of oral cavity squamous cell carcinoma. However, we noted multiple practical obstacles in accurately measuring DOI histologically in our daily practice. METHODS AND RESULTS: To compare the prognostic effects of DOI and tumour thickness (TT), a meticulous pathology review was conducted in a retrospective cohort of 293 patients with AJCC 7th edition pT1/T2 oral tongue squamous cell carcinoma. Overall survival (OS) and nodal metastasis rate at initial resection were the primary and secondary outcomes, respectively. We found that TT and DOI were highly correlated with a correlation coefficient of 0.984. The upstage rate was only 6% (18 of 293 patients) when using TT in the pT stage compared with using DOI. More importantly, DOI and TT, as well as pT stage using DOI and pT stage using TT, performed identically in predicting risk of nodal metastasis and OS. CONCLUSIONS: We therefore propose to replace DOI, a complicated measurement with many challenges, with TT in the pT staging system.

Host Factors Independently Associated With Prognosis in Patients With Oral Cavity Cancer.

Importance: The association and interaction of host characteristics with prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are poorly understood. There is increasing evidence that host characteristics are associated with treatment outcomes of many cancers. Objectives: To examine the host factors associated with prognosis in patients with OSCC and their interactions to create a numerical index that quantifies the prognostic capacity of these host characteristics. Design, Setting, and Participants: This retrospective cohort study included patients with OSCC treated surgically at a tertiary care center from January 1, 1998, to December 31, 2015. From a departmental OSCC database of 1377 previously untreated patients, 68 patients with missing data on any host variable of interest within a month before the start of treatment were excluded, leaving 1309 patients. Data analysis was performed from October 21, 2019, to December 10, 2019. Exposure: Primary surgery for OSCC. Main Outcomes and Measures: Overall survival (OS) was the primary end point, and disease-specific survival (DSS) was the secondary end point. Optimal cutoffs for each variable were identified using recursive-partitioning analysis with the classification and regression tree method using OS as the dependent variable. Body mass index (BMI) and pretreatment peripheral blood leukocyte count, platelet count, hemoglobin level, and albumin level were analyzed. A host index (H-index) was developed using independent factors associated with OS. Results: A total of 1309 patients (731 [55.8%] male; mean [SD] age, 62 [14.3] years) participated in the study. When including all the host-related factors in a multivariable analysis, all except BMI (hazard ratio [HR], 1.14; 95% CI, 0.80-1.63) were independently associated with outcomes. For example, compared with a hemoglobin level of 14.1 g/dL or greater, the HR for a level of 12.9 to 14.0 g/dL was 1.42 (95% CI, 1.13-1.77) and for a level of 12.8 g/dL or less was 1.51 (95% CI, 1.18-1.94), and compared with an albumin level of 4.3 g/dL or greater, the HR for a level of 3.7 to 4.2 g/dL was 1.18 (95% CI, 0.95-1.45) and for a level of 3.6 g/dL or less was 3.64 (95% CI, 2.37-5.58). An H-index of 1.4 or less was associated with a 74% 5-year OS, an H-index of 1.5 to 3.5 with a 65% 5-year OS, and an H-index of 3.6 or higher with a 38% 5-year OS; for DSS, the 5-year survival was 84%, 80%, and 64%, respectively. Compared with patients with an H-index score of 1.4 or less, patients with H-index scores of 1.5 to 3.5 (hazard ratio, 1.474; 95% CI, 1.208-1.798) and 3.6 or higher (hazard ratio, 3.221; 95% CI, 2.557-4.058) had a higher risk of death. Conclusions and Relevance: The findings suggest that pretreatment values of neutrophils, monocytes, lymphocytes, hemoglobin, and albumin are independently associated with prognosis in patients with OSCC. The interactions between these host factors were incorporated into a novel H-index that quantified the prognostic capacity of host characteristics associated with OSCC.

Pretreatment peripheral blood leukocytes are independent predictors of survival in oral cavity cancer.

BACKGROUND: Inflammation and immune surveillance evasion are cancer hallmarks. Peripheral blood leukocytes (PBLs) represent both. The aim of the current study was to examine PBLs as predictors of outcomes in oral cavity squamous cell carcinoma (OSCC), and to find specific cutoffs with the goal of including PBLs as host factor in patients' preoperative risk assessment. METHODS: Previously established head and neck squamous cell carcinoma (HNSCC) cutoffs were examined in an independent cohort of 1369 OSCC patients. Then optimal OSCC cutoffs were found and validated in the subset of patients with OSCC (n = 119) from the external HNSCC cohort. The PBLs analyzed were neutrophils, monocytes, and lymphocytes individually, the neutrophil-to-lymphocyte ratio (NLR), and a combined index using all PBLs called Systemic Inflammation Response Index (SIRI). RESULTS: All parameters were significant predictors of survival using the previous cutoffs. However, OSCC cutoffs stratified survival outcomes better. Considering neutrophils ≤4.8 × 109 /L as reference, patients with 4.8-9.1 × 109 /L neutrophils had 1.536 times higher risk of death (95% CI, 1.295-1.822), and patients with ≥9.1 × 109 /L had 3.076 times higher risk (95% CI: 2.170-4.360). All PBLs maintained independent prognostic capacity in multivariable analysis. Neutrophils, NLR, and SIRI were significant predictors of survival when validating OSCC cutoffs in the external validation cohort. CONCLUSIONS: Pretreatment peripheral blood neutrophils, NLR, and SIRI are the most robust independent predictors of overall survival among all PBLs in OSCC. The authors report externally validated cutoffs that demonstrate the feasibility of including PBLs as host features in the preoperative prognostication of OSCC.