Oral Tongue Squamous Cell Carcinoma Research Articles

Prognostic Value of Perineural Invasion in Oral Tongue Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

ObjectivesA significant number of recently published research has outlined the contribution of perineural invasion (PNI) to clinical outcomes in oral tongue squamous cell carcinoma (OTSCC), but some results remain conflicting. This study aimed to determine whether patients with OTSCC with PNI have a worse prognosis than those without PNI.Materials and MethodsPubMed, Embase, and the Cochrane Library were queried for potentially eligible articles published up to December 2020. The primary outcomes were the hazard ratio (HR) for locoregional recurrence, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). The random-effect model was used in all analyses.ResultsSeventeen studies (4445 patients) were included. Using adjusted HRs, the presence of PNI was associated with a higher risk of locoregional recurrence (HR=1.73, 95%CI: 1.07-2.79, P=0.025, I2 = 33.1%, Pheterogeneity=0.224), worse OS (HR=1.94, 95%CI: 1.39-2.72, P<0.001, I2 = 0.0%, Pheterogeneity=0.838), worse DFS (HR=2.13, 95%CI: 1.53-2.96, P<0.001, I2 = 48.4%, Pheterogeneity=0.071), and worse CSS (HR=1.93, 95%CI: 1.40-2.65, P<0.001, I2 = 25.5%, Pheterogeneity=0.251). PNI had an impact on locoregional recurrence in early-stage OTSCC but not in all stages, and on OS, DFS, and CSS in all-stage and early-stage OTSCC. The sensitivity analyses showed that the results were robust.ConclusionThe presence of PNI significantly affects the locoregional recurrence and survival outcomes among patients with OTSCC.

Surgical treatment for oral tongue squamous cell carcinoma: A retrospective study of 432 patients.

The incidence of oral cancer in Japan accounts for 1% of all cancers, with oral tongue cancer accounting for 60% of oral cancers based on the subsite. The most common histologic type is squamous cell carcinoma. This study aimed to evaluate the series of surgical treatments for 432 patients with oral tongue squamous cell carcinoma (OTSCC). Initial surgical treatments for the primary site included partial glossectomy, hemiglossectomy, and total or subtotal glossectomy in 348, 58, and 26 patients, respectively. Therapeutic neck dissection, elective neck dissection, and subsequent neck dissection were performed in 74, 53, and 37 patients, respectively. Patients with advanced cases had level IIb, IV, and V metastasis and outside regional lymph node metastases. The cumulative 5-year disease-specific survival rate for OTSCC was 92.8%, and the rates for each stage were 96.6%, 93.9%, 84.1%, and 79.0% in stages I, II, III, and IV, respectively. The recurrence rate, overall salvage rate for recurrent cases, and rate for the additional surgical group were 10.4%, 46.7%, and 78.6%, respectively. Patients with multiple cervical lymph node metastases, extranodal extension, metastases to multiple levels, and lower neck metastases had poor prognosis. In conclusion, careful follow-up is necessary to detect recurrence of primary tumors at a stage when surgical treatment can be performed, and cervical lymph node status is one of the most important prognostic factors in OTSCC.

Prognostic value of tertiary lymphoid structures in early clinical stage oral tongue squamous cell carcinoma.

Tertiary lymphoid structures have been observed in several solid tumors and suggested to be a favorable prognostic factor. However, the prognostic value of tertiary lymphoid structures for early clinical stage (cT1/2N0) oral tongue squamous cell carcinoma (OTSCC) remains unclear. In this study, we aimed to evaluate the prognostic value of tertiary lymphoid structures in cT1/2N0stage OTSCC. Ninety-seven patients with cT1/2N0 stage OTSCC were enrolled in this study. Tertiary lymphoid structures were assessed in paraffin sections with H.E and immunohistochemistry staining. Overall and disease-free survivals were evaluated by the Kaplan-Meier method. Cox proportional hazards regression models were used to assess their prognostic value. Tertiary lymphoid structures can be readily identified in cT1/2N0 stage OTSCC, including early tertiary lymphoid structures, primary follicle-like tertiary lymphoid structures, and secondary follicle-like tertiary lymphoid structures. Its frequency in OTSCC was 76.3% in the cohort. The presence of tertiary lymphoid structures was associated with favorable overall survival (p=0.0176) and disease-free survival (p=0.0183) in early clinical stage OTSCC. Cox regression models showed that tertiary lymphoid structures can serve as an independent prognostic factor for overall survival (HR=0.434, 95% CI=0.212-0.886, p=0.022) and disease-free survival (HR=0.459, 95% CI=0.235-0.897, p=0.023) in early clinical stage OTSCC. The group of low maturity of TLS combined with pN positive had the lowest overall survival (p=0.0094) and disease-free survival (p=0.0028). Tertiary lymphoid structures are frequently observed in OTSCC. It is associated with a favorable prognosis for patients with cT1/2N0 stage OTSCC and may be used to predict immunotherapy sensitivity.

Improving Risk Stratification of Early Oral Tongue Cancer with TNM-Immune (TNM-I) Staging System.

Simple SummarySome patients with early-stage oral tongue cancer suffer from poor survival. The currently used classification requires further improvement to better predict the prognosis. Immune-related parameters (such as assessment of infiltrating lymphocytes) can be used as a modifier for the classification and that can aid in improving the prognostication. We included 290 cases of early-stage oral tongue cancer in this study. Lymphocytes were scored and divided as low or high and incorporated in the traditional tumor-node-metastasis (TNM) classification to form our proposed TNM-Immune staging system. The TNM-Immune staging system allowed for a significant distinction between T1 and T2. The TNM-Immune staging system showed a powerful ability to identify cases with poor survival. TNM-Immune staging forms a step towards a more personalized classification of early-stage oral tongue cancer.Although patients with early-stage oral tongue squamous cell carcinoma (OTSCC) show better survival than those with advanced disease, there is still a number of early-stage cases who will suffer from recurrence, cancer-related mortality and worse overall survival. Incorporation of an immune descriptive factor in the staging system can aid in improving risk assessment of early OTSCC. A total of 290 cases of early-stage OTSCC re-classified according to the American Joint Committee on Cancer (AJCC 8) staging were included in this study. Scores of tumor-infiltrating lymphocytes (TILs) were divided as low or high and incorporated in TNM AJCC 8 to form our proposed TNM-Immune system. Using AJCC 8, there were no significant differences in survival between T1 and T2 tumors (p > 0.05). Our proposed TNM-Immune staging system allowed for significant discrimination in risk between tumors of T1N0M0-Immune vs. T2N0M0-Immune. The latter associated with a worse overall survival with hazard ratio (HR) of 2.87 (95% CI 1.92–4.28; p < 0.001); HR of 2.41 (95% CI 1.26–4.60; p = 0.008) for disease-specific survival; and HR of 1.97 (95% CI 1.13–3.43; p = 0.017) for disease-free survival. The TNM-Immune staging system showed a powerful ability to identify cases with worse survival. The immune response is an important player which can be assessed by evaluating TILs, and it can be implemented in the staging criteria of early OTSCC. TNM-Immune staging forms a step towards a more personalized classification of early OTSCC.

Importance and implications of neurovascular bundle involvement and other MRI findings of oral tongue squamous cell carcinoma (OTSCC) on prognosis

BackgroundThe description for T4a oral tongue cancer in the 8th edition AJCC staging can be improved further. In this article we attempted to identify the important radiological (MRI) findings that could possibly be included in the staging eventually. MethodsWe included all oral tongue squamous cell carcinoma patients who underwent surgery at TMH between Jan 2012 to Dec 2018 and whose MRIs were available for review. The relation of the tumor to the neurovascular bundle (NVB) on MRI was classified as Type I to IV. The association of the type of NVB involvement with DFS and the presence of PNI in the final HPR was analyzed. ResultsTwo-hundred and fifty-nine patients satisfied the eligibility criteria. The majority of them were men (82.6%), with a median age of 49 Yrs. Sixty-nine percent of patients had either abutment (Type III) or encasement (Type IV) of the NVB. The presence of Abutment/encasement of the NVB was significantly associated with the presence of PNI in the final HPR (p < 0.001). This abutment/encasement was seen in clinically advanced T-stage tumors. However, the presence of abutment/encasement of the NVB influenced the DFS in the univariate analysis only. ConclusionAbutment/encasement of the NVB in patients with carcinoma oral tongue is often seen in advanced-stage tumors and is significantly associated with the presence of PNI in the final HPR. Hence, the relation of the tumor with the NVB should be further assessed to understand its importance and its possible inclusion in the AJCC T-staging.

NOVEL ADVANCES IN STAGING AND GRADING OF EARLY ORAL TONGUE CANCER: A MULTICENTER STUDY

<h3>Background</h3> Recent research has proposed modifications for the TNM staging and the World Health Organization (WHO) histopathologic grading system of oral cancer. <h3>Objective</h3> (1) To study the significance of different cutoff points of depth of invasion (DOI) in T classification. (2) To study the incorporation of tumor budding to modify the WHO grading system. <h3>Methods</h3> In this multi-institutional study, we included 311 cases treated for early (cT1-2N0M0) oral tongue squamous cell carcinoma at the 5 university hospitals in Finland or at the A.C. Camargo Cancer Centre, São Paulo, Brazil. We suggest using 2 mm DOI to upstage to T2 and 4 mm DOI to upstage to T3. For histopathologic grading, our proposal incorporates tumor budding and defines Grade I as a "well-differentiated cohesive tumor"; grade II as a "moderately differentiated and/or slightly dissociated tumor"; and grade III as a "poorly differentiated and/or dissociated tumor." <h3>Results</h3> There was a significantly improved performance in identification of the high-risk cases for recurrence (hazard ratio [HR] = 2.08; 95% confidence interval [CI], 1.07-4.01; <i>P</i> = .03) and cancer-related mortality (HR = 2.21; 95% CI, 1.05-4.64; <i>P</i> = .036) based on our proposed adjustment of the T stage. Similarly, the proposed histopathologic grade showed worse survival (HR = 3.42; 95% CI, 1.23-9.56; <i>P</i> = .001) and a high rate of recurrence (HR = 1.85; 95% CI, 0.91-3.76; <i>P</i> = .024) for cases having poorly differentiated and/or dissociated tumors. <h3>Conclusions</h3> Our proposed adjustments for staging and grading criteria could improve the risk stratification in early oral tongue squamous cell carcinoma.

OBJECTIVE MEASUREMENT OF TUMOR FRONTS IN EARLY ORAL CANCER

<h3>Introduction</h3> Oral cancer, one of the 10 most common cancers worldwide, has a high mortality rate, and the level of disfigurement that survivors experience gives rise to a considerable global public health burden. Some early-stage oral tongue squamous cell carcinomas (OTSCCs) show aggressive behavior and poor prognosis even in cN0 patients. This motivates the search for prognostically relevant features to tailor individual management. Histopathologic reporting of oral cancer is limited by some elements of subjectivity. This study aimed to identify quantitative histologic features that allow objective stratification of patients into treatment categories and improve overall patient outcome. <h3>Methods</h3> We conducted a retrospective study of 50 cases of early stage T1/T2 OTSCC. Sections immunostained with anti–pan-cytokeratin antibodies were scanned into digital images to assess the global complexity (fractal dimension) of the tumor epithelial–connective tissue interface (ECTI). The results were related to information from the Royal College of Pathology Dataset for mucosal malignancies of the oral cavity. <h3>Results</h3> At tumor depths over 5.5 mm, there was a positive correlation between tumor invasion depth and ECTI complexity. There were also significant differences in ECTI complexity between tumors graded as well, moderately, and poorly differentiated (1.24 ± 0.10, 1.32 ± 0.06, and 1.39 ± 0.07, respectively). The ECTI complexity in poorly differentiated tumors was significantly lower in the patients with a positive 5-year survival status. <h3>Conclusions</h3> Fractal analysis of the ECTI provided an unbiased descriptor of neoplasm dissociation and invasion pattern modality with potentially useful prognostic value.

The incidence and risk factors for early death among patients with oral tongue squamous cell carcinomas.

The objective of this study is to evaluate the early mortality rate and associated factors for early death in oral tongue squamous cell carcinomas (OTSCC) patients. Patients with OTSCC were extracted from the SEER database between 2004 and 2014. The early death (survival time≤3months) rate was calculated, and associated risk factors were evaluated by the logistic regression models. A total of 7756 patients were analysed and 282 (3.6%) patients died within 3months after cancer diagnosis, among whom 214 (2.8%) patients died from cancer-specific cause. In univariate analyses, advanced age, divorced/single/widowed (DSW), higher histological grades, black, advanced T stage, advanced N stage, distant metastasis and no surgery were significantly associated with all-causes and cancer-specific early death. Multivariate analyses showed that advanced age, DSW, advanced T stage, advanced N stage, distant metastasis, and no surgery were significantly associated with all-cause and cancer-specific early death. Our results showed that a total of 3.6% patients with OTSCC suffered early death. Predictors of early death are primarily related to age older than 60years, advanced T stage, advanced N stage, distant metastasis and no surgery but also include unmarried status, but better prognostic and predictive tools in larger sample to select early death patients are needed.

The prognostic role of the pre-treatment neutrophil to lymphocyte ratio (NLR) and tumor depth of invasion (DOI) in early-stage squamous cell carcinomas of the oral tongue.

The appropriate surgical management of early-stage oral tongue squamous cell carcinoma (OTSCC) remains a debated topic. The aim of this study is to investigate the role of the pre-treatment neutrophil to lymphocyte ratio (NLR) and tumor depth of invasion (DOI) in predicting the presence of occult neck metastases in early-stage OTSCC. A retrospective analysis of patients affected by early-stage (cT1-T2 cN0) OTSCC who were submitted to elective neck dissection (END) was performed. Tumors were classified retrospectively according to the 8th TNM classification, the DOI was assessed on the pre-operative magnetic resonance imaging, and the pre-treatment NLR was calculated for each patient. A logistic regression model to estimate the probability π (x) of cervical metastases by studying the NLR and DOI was carried out. Next, the correlation between the two variables, the NLR and DOI, was preliminarily studied. A cohort of 110 patients was analyzed (mean age, 62years old; male to female ratio 1.2:1). The patients were staged as cT1 in 53 cases and cT2 in 57 cases. A DOI greater than 5.4mm and a NLR greater than 2.93 are associated with an increased risk of presenting occult cervical metastases. Furthermore, the variables NLR and DOI are linearly associated with a positive correlation, proved by Spearman's rank correlation coefficient rho of 0.64, with a unitary increase in the DOI of 1mm directly associated with an increase of 0.47 in the NLR. The DOI and NLR can be effectively used to predict the occurrence of occult neck metastasis and therefore to plan an END in early-stage OTSCC.

Bcl-xL expression and regulation in the progression, recurrence, and cisplatin resistance of oral cancer

BackgroundBcl-xL is an anti-apoptotic molecule, but its role in the progression and recurrent/ drug-resistant oral squamous cell carcinoma (OSCC) is poorly understood. Materials and methodsA total of one hundred twenty-five human OSCC tissue specimens including twenty-nine adjacent normals (AN), sixty-nine primary tumors (PT), twenty-seven recurrent chemoradiation resistance (RCRT) samples, and oral tongue SCC derived cisplatin-resistant (CisR SCC-4/-9) cells were used, for this study. Protein/mRNA expression levels of Bcl-xL and its regulation by ERK1/2, Stat-3, p53, NFκB, AP-1 (components: c-Jun, c-Fos, and Fra-2) molecules, and cell viability were measured by immunohistochemistry, Western blot, RT-PCR, and MTT analysis. Further, the individual and synergistic effects of Fra-2 (siRNA) and nimbolide were tested in CisR SCC-4/-9 cells. ResultsProgressive increase of Bcl-xL expression and its transcriptional-deregulation was observed with OSCC progression and resistance. Among all the possible upstream regulators of Bcl-xL, such as ERK1/2, Stat-3, p53, AP-1, and NFκB, the TF AP-1 (r = 0.644, p = 0.0001) showed maximum association with Bcl-xL mRNA expression. Though differential expression of AP-1 components were detected in OSCC specimens, with more striking positive-correction of c-Jun (r = 0.381, p = 0.049), c-Fos (r = 0.139, p = 0.488, ns) and Fra-2 (r = 0.664, p = 0.0001) with Bcl-xL expression observed stronger in RCRT tumor subgroup. Further, knockdown of Fra-2 and the application of plant-based phytochemical nimbolide decreased Bcl-xL expression and induced apoptosis in CisR SCC-4/-9 cells. ConclusionCollectively, we have demonstrated the role of Bcl-xL and AP-1 (Fra-2), causing OSCC progression and cisplatin resistance. Targeting Bcl-xL upstream pathway along with the application of nimbolide might be beneficial in eliminating drug-resistant OSCC.

Pattern and localization of perineural invasion predict poor survival in oral tongue carcinoma.

Survival rate for oral tongue squamous cell carcinoma (OTSCC) is still poor and, despite Tumor-Node-Metastasis staging system has been recently updated, patients included under the same stage still show difference in prognosis. Perineural invasion (PNI) emerged to be an indicator of tumor aggressive behavior and unfortunate events. In this study, we investigate the clinic and prognostic value of PNI in a cohort of OTSCC patients. About 200 patients with OTSCC were retrospectively evaluated the presence of PNI. PNI was furtherly descripted as uni-/multifocal and as intra-/peritumoral. Disease-Specific and Relapse-Free Survival (DSS; RFS) were estimated; moreover, we included PNI in the current AJCC 8th Staging System, improving the prognostication model. Perineural invasion was found in 40.5% of patients. Intratumoral PNI predicted patients at high risk of being diagnosed with lymph-node metastasis. Tumors with positive PNI reported a worse DSS (Hazard Ratio=1.878, p-value=0.008). Moreover, patients exhibiting both multifocal intra- and peritumoral PNI reported poorest DSS (Hazard Ratio=2.409, p-value=0.010). Patients were reclassified in a new staging system in case of multifocal PNI, providing better stratification capacity. Perineural invasion might serve as an additional prognostic factor in OTSCC, and by integrating PNI in the staging system, further improvements in prognostication might be reached.

Comparison between computed tomography and ultrasound for presurgical evaluation of oral tongue squamous cell carcinoma tumor thickness

PurposeTo compare the accuracy of oral tongue squamous cell carcinoma (OTSCC) tumor thickness (TT) measured on CT to intraoperative ultrasound (US) and histopathology. Methods and materialsTwenty-six patients with OTSCC who underwent tumor resection by a single surgeon with simultaneous intraoperative US between 3/2016 and 4/2019 were prospectively identified, and their data reviewed. TT was independently measured in 19 patients who underwent preoperative CT (cTT) by two neuroradiologists blinded to US and histological results. The confidence level of interpretation of cTT was recorded by each reader using a 5-point Likert scale. The degree of dental artifact on CT was also scored. cTT was compared to TT measured on intraoperative US (uTT) and histopathologic assessment of TT (hTT). ResultsOTSCC was visualized on CT in 52% (10/19) and 63% (12/19) of cases for readers 1 and 2, respectively. Mean Likert score was 0.42 for reader 1 and 0.73 for reader 2. Mean cTT of OTSCCs was 5.8 mm +/− 1.7 mm (n = 11). In comparison, mean uTT and hTT were 7.6 mm±3.5 mm and 7.1 +/− 4.2 mm, respectively. The Pearson coefficient (95% confidence interval) was 0.10 (−0.53–0.66) between cTT and hTT (n = 11) and 0.93 (0.74–0.98) between uTT and hTT. ConclusionsPreoperative CT is not reliable for assessment of TT in OTSCC compared to US and histopathology, particularly for OTSCC under 10 mm. US offers a practical complementary imaging tool with a unique role for primary tumor assessment that can aid in pre-operative planning, especially for small tumors.

Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma.

The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.

Comparison of diagnostic characteristics between sentinel lymph node biopsy (SLNB) and radio-guide elective neck dissection (RGEND) in patients with T1-2N0 oral tongue cancer.

e18037 Background: Elective neck dissection remains the standard treatment for cN0 oral cancer due to the high incidence of occult lymph node (LN) metastases. Sentinel lymph node biopsy (SNB) might be a less morbid alternative to neck dissection. Diagnostic value of SLNB depends on the number of sampled LNs. We aimed to compare the diagnostic features of SNB and RGEND in patients with T1-2N0 oral tongue cancer. Methods: A prospective study was conducted in patients with cT1-2N0M0 oral tongue squamous cell carcinoma treated between January 2016 and December 2020. The procedure included SLNB ollowed by immediate extent ipsilateral neck dissection. SLNB included accumulated radiotracer LNs, which located close to the primary tumor. RGEND included LNs accumulated radiotracer with all LNs located at the same level. Pathology assessment was performed and diagnostic characteristics were compared between SLNB and RGEND. Results: A total of 38 patients were enrolled. The mean age was 55.7±13,1. Twenty-four patients had unilateral lymph flow and 14 had bilateral. Sentinel LNs were located at levels IIa-III. Occult metastases were found in 15,8% (n = 6) of patients. The median number of LNs in the sample was 3 (IQR: 1-5). The sensitivities of SLNB and RGEND were 50% (95%CI: 15.7 - 84.3) and 100% (95%CI: 54.7-100), respectively, p-value = 0.001. Specificity was similar among groups: 100% (95%CI: 88-100) and 100% (95%CI: 89.1-100. SLNB had accuracy of 89.5% (95%CI: 77.2 - 97), and RGEND 100% (95% CI: 90.7-100), p-value = 0.001. Positive predictive value (PPV) was similar among groups. Negative predictive value (NPV) was 88.2% (95% CI: 78.9 - 93.7) in SLNB and 100% (95%CI: 91-100) in RGEND groups. p-value = 0.001. Conclusions: SLNB and RGEND have high rates of specificity, accuracy, PPV, and NPV, regardless of sampling size. RGEND has the highest sensitivity in patients with cT1-2N0 oral tongue cancer.

Validation of Selected Head and Neck Cancer Prognostic Markers from the Pathology Atlas in an Oral Tongue Cancer Cohort.

Simple SummaryPrognostic markers are used to predict the aggressiveness of a cancer and to help decide the best treatment for individual patients. Despite intense research, reliable prognostic markers for oral cancer are still few. The aim of the present study was to validate selected prognostic markers for head and neck cancer identified by unbiased approaches in oral tongue cancer, a specific subsite of head and neck cancer. From a list of 790 markers, we selected three based on reported prognostic value as well as expression pattern and availability of validated antibodies. These were analyzed on transcriptional and protein level in a cohort of 121 oral tongue cancers. Only one of the markers showed significant prognostic value when controlling for established prognostic parameters. Our study highlights the need to evaluate prognostic markers in homogeneous groups of cancers and to control for established prognostic parameters.The Pathology Atlas is an open-access database that reports the prognostic value of protein-coding transcripts in 17 cancers, including head and neck cancer. However, cancers of the various head and neck anatomical sites are specific biological entities. Thus, the aim of the present study was to validate promising prognostic markers for head and neck cancer reported in the Pathology Atlas in oral tongue squamous cell carcinoma (OTSCC). We selected three promising markers from the Pathology Atlas (CALML5, CD59, LIMA1), and analyzed their prognostic value in a Norwegian OTSCC cohort comprising 121 patients. We correlated target protein and mRNA expression in formalin-fixed, paraffin-embedded cancer tissue to five-year disease-specific survival (DSS) in univariate and multivariate analyses. Protein expression of CALML5 and LIMA1 were significantly associated with five-year DSS in the OTSCC cohort in univariate analyses (p = 0.016 and p = 0.043, respectively). In multivariate analyses, lymph node metastases, tumor differentiation, and CALML5 were independent prognosticators. The prognostic role of the other selected markers for head and neck cancer patients identified through unbiased approaches could not be validated in our OTSCC cohort. This underlines the need for subsite-specific analyses for head and neck cancer.

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)

BackgroundHost 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. MethodsThe 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. ResultsHigh 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. ConclusionssTIL 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.

Prognostic Role of Tumor-Infiltrating Lymphocytes and Tumor Budding in Early Oral Tongue Carcinoma.

Objectives/HypothesisOccult lymph metastasis is an important prognosticator for the treatment of early oral tongue squamous cell carcinoma (SCC). The objective of this study was to evaluate the prognostic significance of tumor‐infiltrating lymphocytes (TILs) in early oral tongue SCC. The combination of the TIL subtype and intermediate‐ or high‐grade budding scores was investigated as a prognostic marker for occult neck metastases.Study DesignRetrospective study.MethodsSpecimens from 62 patients with early oral tongue SCC treated with only primary surgery were analyzed by immunohistochemistry for CD4+, CD8+, FoxP3+, and CD45RO+ T cells and CD163+ macrophages. The highest number of each TIL subtype was counted in two areas of parenchyma and stroma in the tumor (Tumor) and peripheral stroma of the invasion margin.ResultsBased on multivariate analysis, a high density of Tumor CD163+ macrophages served as the poorest prognostic factor for regional control (RC) and disease‐free survival (DFS). Patients with both a high density of Tumor CD163+ macrophages and an intermediate‐ or a high‐grade budding score had a poor prognosis for RC according to the log‐rank test.ConclusionsIn summary, each TIL subtype may use different mechanisms during early and advanced stages of oral tongue SCC. A high density of Tumor CD163+ macrophages was determined to be a risk factor for RC and DFS as well as an additional stratification factor for RC in patients with intermediate‐ or high‐grade budding scores. Therefore, identifying TIL subtypes in daily clinical practice can help determine a more successful and individualized therapeutic approach for early oral tongue SCC.Level of EvidenceStep 4 (Level 4) Laryngoscope, 131:2512–2518, 2021

Prediction of lymph node metastasis in oral tongue squamous cell carcinoma using the neutrophil-to-lymphocyte ratio and platelet-to-neutrophil ratio.

BackgroundLymph node metastasis in a variety of tumors is associated with systemic inflammatory markers. However, this association has not been reported in oral tongue squamous cell carcinoma (OTSCC). This study aimed to investigate how the preoperative neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐neutrophil ratio (PNR) in OTSCC patients correlated with the occurrence of OTSCC and lymph node metastasis.MethodsThe data of 73 patients with primary OTSCC who underwent surgical resection were retrospectively analyzed. Patients with other malignant tumors, patients who had received radiotherapy or chemotherapy before surgery, and patients with active inflammation were excluded. The enrolled patients were divided into groups N0 (no early‐stage lymph node metastasis) and N1 (early‐stage lymph node metastasis). Venous blood samples were collected before surgery and at the third week after surgery and subjected to complete blood counting in a blood analyzer. Eighty‐seven healthy people were included as a control group. In addition, the NLR and PNR in OTSCC patients were compared with those in the controls, and the postoperative NLR and PNR of group N0 were compared with those of group N1.ResultsThe NLR was significantly higher in the OTSCC patients than the controls (p < 0.05). The area under the receiver operating characteristic curve was 0.595. Further comparison of the NLR and PLR between group N0 and group N1 showed that when NLR was ≤1.622, and the probability of early‐stage lymph node metastasis in OTSCC patients was 73.3%, and when PNR was >60.889, the probability was 86.7%. In re‐examination 3 weeks postoperatively, the NLR and PNR were not significantly different between groups.ConclusionThe NLR has certain reference value for the diagnosis of OTSCC. The preoperative NLR and PNR can be used to predict early‐stage lymph node metastasis in patients with histopathologically confirmed OTSCC.

MMP8 increases tongue carcinoma cell\u2013cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5

Matrix metalloproteinases (MMPs) modify bioactive factors via selective processing or degradation resulting in tumour-promoting or tumour-suppressive effects, such as those by MMP8 in various cancers. We mapped the substrates of MMP8 to elucidate its previously shown tumour-protective role in oral tongue squamous cell carcinoma (OTSCC). MMP8 overexpressing (+) HSC-3 cells, previously demonstrated to have reduced migration and invasion, showed enhanced cell-cell adhesion. By analysing the secretomes of MMP8 + and control cells with terminal amine isotopic labelling of substrates (TAILS) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS), we identified 36 potential substrates of MMP8, including FXYD domain-containing ion transport regulator 5 (FXYD5). An anti-adhesive glycoprotein FXYD5 has been previously shown to predict poor survival in OTSCC. Cleavage of FXYD5 by MMP8 was confirmed using recombinant proteins. Furthermore, we detected a loss of FXYD5 levels on cell membrane of MMP8 + cells, which was rescued by inhibition of the proteolytic activity of MMP8. Silencing (si) FXYD5 increased the cell-cell adhesion of control but not that of MMP8 + cells. siFXYD5 diminished the viability and motility of HSC-3 cells independent of MMP8 and similar effects were seen in another tongue cancer cell line, SCC-25. FXYD5 is a novel substrate of MMP8 and reducing FXYD5 levels either with siRNA or cleavage by MMP8 increases cell adhesion leading to reduced motility. FXYD5 being a known prognostic factor in OTSCC, our findings strengthen its potential as a therapeutic target.

The Potential of MET Immunoreactivity for Prediction of Lymph Node Metastasis in Early Oral Tongue Squamous Cell Carcinoma.

ObjectiveMET positivity is independently associated with survival in oral squamous cell carcinoma (OSCC). Since MET is a known orchestrator of invasive tumor growth, we investigated its association with LNM in early oral tongue squamous cell carcinoma (OTSCC). As it is recommended by the NCCN to use tumor depth of invasion (DOI) in making decisions on elective neck dissection (END), the results obtained for MET positivity were aligned with those for DOI > 4 mm. The cutoff value used in our institution.MethodsTumor samples from patients who underwent primary tumor resection and neck dissection between 1995 and 2013, were collected from the archives of the Leiden and Erasmus University Medical Center. Immunohistochemistry with D1C2 was performed to identify MET negative (< 10% uniform positivity) and MET positive (≥ 10% uniform positivity) cancers. ROC curve analysis and the Chi-squared test were used to investigate the association of MET positivity with LNM (pN+ and occult). Binary logistic regression was used to investigate the association of MET positivity with LNM.ResultsForty-five (44.1%) of the 102 cancers were MET positive. Ninety were cN0 of which 20 were pN+ (occult metastasis). The remaining 12 cancers were cN+, of which 10 were proven pN+ and 2 were pN0. MET positivity was associated with LNM with a positive predictive value (PPV) of 44.4% and a negative predictive value (NPV) of 82.5% for pN+. For the occult group, the PPV was 36.8% and the NPV was 88.5%. Regression analysis showed that MET positivity is associated with pN+ and occult LNM (p-value < 0.05).ConclusionMET positivity is significantly associated with LNM in early OTSCC, outperforming DOI. The added value of MET positivity could be in the preoperative setting when END is being considered during the initial surgery. For cases with DOI ≤ 4 mm, MET positivity could aid in the clinical decision whether regular follow-up, watchful waiting, or END is more appropriate. Realizing that these preliminary results need to be independently validated in a larger patient cohort, we believe that MET positivity could be of added value in the decision making on END in early OTSCC.