Oral Tongue Squamous Cell Carcinoma Research Articles

Depth of invasion and extranodal extension: the influential factors to predict survival rate of patients with oral tongue squamous cell carcinoma

BackgroundCancer staging is essential in determining patients’ prognoses and designing the appropriate treatment strategy. American Joint Committee on Cancer has released the latest version of the staging system for tongue SCC. However, it is interesting to know whether this change in staging and the addition of depth of invasion (DOI) and the extra-nodal extension (ENE) have any influence on patients’ prognosis.MethodsIn this retrospective cohort study, the pathology records of patients with tongue SCC who underwent surgery at the Pathology Department of Cancer Institute Hospital, 2017–2021, were collected by referring to the hospital information system. Then the rate of change of pT, pN, and overall stage were assessed based on American Joint Committee on Cancer 7th and 8th editions.ResultsThe records of 204 patients were included in the final analysis. Significant changes in the staging system 2021 resulted in upstaging 64 patients (31.4%) in the overall stage, 91 patients (44.6%) in pT, and 30 patients (14.7%) in pN. The survival of upstaged patients was inferior compared to those without upstaging. However, this was not statistically significant for tumor and overall upstaging in the univariate analysis, while those with upstaged pN had significantly shorter survival. In the multivariate analysis, pT upstage also significantly impacted survival.ConclusionThis study showed the importance of pathology reports based on the latest edition of the American Joint Committee on Cancer, the accuracy in examining factors such as depth of invasion and extra-nodal extension.

A study on direct metastasis to levels III, IV in oral tongue squamous cell carcinoma

ObjectiveThis study aimed to determine the frequency and specific metastatic patterns of direct metastasis to levels III and IV in oral tongue squamous cell carcinoma (OTSCC) among Japanese individuals. MethodsWe conducted neck dissections on 319 patients at our department from January 2001 to December 2020. Of these, 220 patients with histopathological evidence of lymph node metastasis were included in the study. Lymph node metastases were categorized by level to elucidate the metastatic patterns. Additionally, metastatic sites within level III were identified as either anterior or posterior to the internal jugular vein, and these findings were compared between the direct metastatic group and the non-direct metastatic group. ResultsAmong the patients, 13 experienced direct metastases to level III or IV. Specifically, 12 patients had metastases at level III, and one patient had metastases at both levels III and IV, constituting 5.9% (13/220) of those with cervical lymph node metastasis in OTSCC. No patients exhibited direct metastases solely to level IV. Within level III, the direct metastasis group showed a significantly higher incidence of metastasis anterior to the internal jugular vein (p = 0.03). ConclusionsDirect metastasis to levels III and/or IV occurred in 5.9% of the cases. Although elective neck dissection up to level III is generally sufficient, metastasis to level IV, while infrequent, can occur. Therefore, vigilant follow-up with attention to the lower neck regions is crucial.

Initial negative resection margin versus revised negative resection margin in patients who underwent surgery without adjuvant therapy for early-stage oral tongue squamous cell carcinoma

BackgroundIn cases of positive resection margin (RM), re-resection is generally recommended. There has been controversy about the oncologic impact of revised negative RMs after re-resection. The aim of this study was to investigate the oncologic impact of revised negative RM in patients who underwent surgery without adjuvant therapy for early-stage (pT1-2/N0) oral tongue squamous cell carcinoma (OSCC). MethodsWe retrospectively analyzed patients with pT1-2 N0 OSCC who did not receive adjuvant therapy (N=441). These patients were classified into an initial negative RM (R0, n = 380) group and a revised negative RM (R1-R0, n = 61) group. Demographic and clinical data (T stage, tumor length, depth of invasion [DOI], lymphovascular invasion [LVI], perineural invasion [PNI], and recurrence) were compared between the R0 and R1-R0 groups. ResultsAge, sex, T stage, DOI, LVI, PNI, and SUVmax were not significantly different between the two groups. Local recurrence was more frequent (P=0.045) in the R1-R0 group (13.1 %) than in the R0 group (5.5 %). Local recurrence-free survival was better in the R0 group than in the R1-R0 group (P=0.046). There was no significant difference in overall recurrence or overall survival. On multivariate analysis, initial positive RM was the independent significant risk factor (hazard ratio, 2.249; 95 % confidence interval, 1.025–4.935; P=0.043) for local recurrence. ConclusionA revised clear RM after initial cut-through margin is a risk factor for local recurrence in early-stage OSCC. Cautious should be considered in early-stage OSCC patients with revised clear RM.

Contralateral submental artery island flap for oral tongue reconstruction — a retrospective study in patients with oral tongue squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related death in developing countries. The oral tongue is the most common site involved by OSCC. About a third of the patients have neck nodal metastasis at presentation. Reconstruction of the oral tongue after resection for cancer is necessary for proper rehabilitation. For patients who are medically unfit for prolonged surgery like a free tissue transfer, local flaps are employed for tongue reconstruction. The submental flap is a popular option. However, when there is extensive floor of mouth involvement or bulky nodal disease in ipsilateral level 1, harvesting the submental flap based on contralateral facial vessels is possible, without compromising oncological safety. We discuss the feasibility and outcomes of contralateral submental artery island flap for reconstruction after resection of oral tongue carcinoma in a retrospective series of 34 patients followed up for a median of 8.5 months. ResultsOf the 34 oral tongue cancer patients in the study, 16 had neoadjuvant chemotherapy prior to surgery. 33 underwent bilateral neck dissection. Two patients had partial flap loss which was managed conservatively. There were five patients who had either locoregional or distant recurrence, none in the flap site. Three had pathological positive nodes at contralateral level 1b and two had pathologically positive nodes in contralateral level 1b. Tongue motility and speech intelligibility were satisfactory on follow-up. ConclusionIn the properly selected patient, the contralateral submental artery island flap offers an oncologically safe and technically simpler alternative for free flap reconstruction.

Role of midline raphe in compartmental surgery for squamous cell carcinoma of the tongue.

In the present study, we investigated how tumor distance from midline (TDFM) and depth of invasion (DOI) may affect survival outcomes after compartmental tongue surgery (CTS) for oral tongue squamous cell carcinoma (OTSCC). A retrospective series of cT2-T3 OTSCC treated with upfront CTS at our Department from 2010 to 2021 was evaluated. Radiological and pathological DOI and TDFM were correlated. The main outcomes were overall (OS) and loco-regional recurrence free survival (LRRFS). The linear relationship between DOI and TDFM with 2-year OS and LRRFS was tested. Survival estimates were obtained by the Kaplan-Meier method. Univariate analysis was performed for variables of interest, and results expressed in terms of hazard ratios and 95% confidence intervals. A total of 64 patients underwent CTS and neck dissection. No significant difference was found between pathological (pDOI) and radiological DOI (rDOI) (p = 0.321) or between pathological (pTDFM) and radiological TDFM (p = 0.435). Two- and 5-year OS and LRRFS were 85.7% and 70.4%, 84.3% and 76.1%, respectively. A linear and significant relationship with OS (p = 0.020) and LRRFS (p = 0.013) was found for pDOI; although linear, the relationship between pTDFM was not statistically significant for either survival outcomes. Once categorized, the ideal cut-off for pDOI according to OS was set at 10mm (p = 0.023). In patients undergoing CTS for primary OTSCC, magnetic resonance-derived rDOI represents an accurate estimate of pDOI, In contrast, TDFM was not associated with OS suggesting that the median raphe is a safe deep margin for CTS. BS/231,009 retrospectively registered.

Risk factors and impact of occult and skip metastasis in early-stage oral tongue squamous cell carcinoma.

To investigate risk factors associated with occult lymph node metastases (ONM) and skip metastasis in early-stage oral tongue squamous cell carcinoma (OTSCC) patients. Meanwhile, to analyze the contribution of metastatic nodes to survival outcomes. 544 OTSCC patients who were clinically staged T1-T2N0 with pathologic results from May 2018 to January 2024 were enrolled. Those with ONM were divided into subgroups with or without skip metastasis. Clinical, laboratorial, radiological and pathological factors between groups were analyzed by using univariate analysis and multivariate logistic analysis. The association of tumor growth behavior with the metastatic pattern of lymph nodes was summarized. Additionally, disease free survival (DFS) among different groups were compared using Kaplan-Meier analysis. Tumor growth behavior was associated with ONM. Tumor thickness with a threshold of 6.4mm was not inferior to histological depth of invasion in predicting ONM. Only 1.3% of patients had nodal involvement of neck level IV or V. The DFS of patients with ONM were significantly reduced than those without ONM (P<0.001). The DFS between patients with and without skip metastasis exhibited no statistical significance(P = 0.246). The 1-year, 2-year recurrence rates of patients with or without ONM were 31.9%, 37.5%, 10.1% and 14.0%, correspondingly. Tumor thickness with a threshold of 6.4mm could be used as a preoperative predictor for ONM. Elective neck dissection of level I - III might be sufficient for early stage OTSCC patients. OTSCC patients with ONM should be closely observed during the first 2 years after surgery. The risk of ONM in early stage OTSCC patients might be predicted by tumor thickness calculated on MR imaging. Elective neck dissection of level I - III could remove micrometastases timely and effectively.

Evaluation of prognostic factors for oral tongue squamous cell carcinoma: Significance of intratumoral tumor-infiltrating lymphocytes, lymph node ratio, and depth of invasion.

132 Background: Oral tongue squamous cell carcinoma (SCC) is an aggressive malignancy with a variable prognosis. Identifying reliable prognostic factors is crucial for developing personalized treatment strategies and improving patient outcomes. This study examined the prognostic significance of clinicopathological factors in oral tongue SCC. Methods: A retrospective cohort study was conducted on 192 patients who underwent surgical resection at Asan Medical Center between 2010 and 2017. Clinicopathological data, including age at diagnosis, American Joint Committee of Cancer (AJCC) 8th edition stages, depth of invasion (DOI), extranodal extension (ENE), intratumoral and stromal (invasive front) tumor-infiltrating lymphocytes (TILs), lymphovascular invasion (LVI), margin status, metastatic-to-examined lymph nodes ratio (LNR), number of metastatic lymph nodes, perineural invasion (PNI), sex, size, tumor budding, tumor differentiation, tumor-to-stromal ratio (TSR), and worst pattern of invasion (WPOI) were analyzed. The total cohort, early-stage group, and late-stage group were analyzed separately. Results: Most variables showed significant associations with the survival rate. The multivariate Cox proportional hazard models for the total cohort showed significant results for intratumoral TILs, DOI grade, and LNR. However, other factors failed to show statistical significance. Intratumoral TIL was the only consistently potent factor for survival in all study groups. Conclusions: Our findings highlight the need for increased focus on the prognostic significance of intratumoral TILs. The DOI grade and LNR were also powerful prognostic factors, especially in late-stage tongue SCCs. Our data suggest that the prognostic significance of certain variables, such as the WPOI, may have been overestimated in the literature, thereby warranting a reassessment of the currently utilized prognostic markers in oral tongue SCC.

Pathological examination of factors involved in PD-L1 expression in patients with oral tongue squamous cell carcinoma

BackgroundTumor tissues comprise cancer cells and stromal cells, and their interactions form the cancer microenvironment. Therefore, treatments targeting cells other than cancer cells are also actively being developed, and among them, treatment targeting PD-1, an immune checkpoint molecule that is important in tumor immune evasion, has also been indicated for head and neck cancer. PD-L1, a ligand of PD-1, is expressed in both tumor cells and stromal cells, and the scoring system based on the combined positivity rates of both types of cells, the combined positive score (CPS), is used for predicting treatment effect. However, much is unknown regarding the expression of PD-L1. In this study, we histopathologically examined factors controlling the expression of PD-1/PD-L1. This study included 37 patients who underwent resection surgery for tongue squamous cell carcinoma in the Department of Oral and Maxillofacial Surgery at Tokyo Dental College Suidobashi Hospital. The expression levels of PD-L1, α-SMA, and p53 were assessed by immunohistochemical staining.ResultsSeven participants had CPS ≥ 20, twenty-four participants had 1 ≤ CPS < 20, and six participants had CPS < 1. The overall positivity rate of α-SMA, a marker for cancer-associated fibroblasts (CAFs), was 27% (10/37 participants), and the positivity rates of α-SMA for the three CPS groups were 85.7% (6/7 participants), 16.7% (4/24 participants), and 0% (0/6 participants), respectively. In addition, the overall positivity rate of p53 was 37.8% (14/37 participants), and the positivity rates of p53 for the three CPS groups were 71.4% (5/7 participants), 37.5% (9/24 participants), and 0% (0/6 participants), respectively.ConclusionsThe expression of PD-L1 demonstrated an association with α-SMA and p53 positivity. In addition, compared with the expression of p53, the expression of α-SMA demonstrated a higher association with PD-L1 expression in patients with a high CPS. The abovementioned findings suggest that the interactions between CAFs, cancer cells, and immunocompetent cells may regulate the expression of PD-L1.

Histopathologic predictors of recurrence and survival in early T stage oral tongue squamous cell carcinoma.

Recurrence and survival in early T-stage oral tongue squamous cell carcinoma (OTSCC) may be impacted by histopathologic risk factors. This study aims to examine which of these factors predict long-term outcomes of T1 and T2 OTSCC. A retrospective review of T1 and T2 OTSCC patients treated with surgery at a single tertiary care center was conducted. Multivariate regression and Kaplan-Meier survival plots were used to identify predictors of recurrence and compare disease-free survival respectively. 100 consecutive patients were studied. Of these, 51 were staged pT1, 49 pT2, 69 pN0, 10 pN1, and 21 pN2. Multivariate regression analysis revealed that >4 nodes was the strongest predictor of overall recurrence [odds ratio 1.68 (1.23-2.28), p = 0.001], while >4 nodes [odds ratio 1.14 (1.09-1.85), p = 0.008] and pT2 [odds ratio 1.15 (1.01-1.30), p = 0.033] were predictors of local recurrence (R2 = 0.112). Five-year disease-free survival was not significantly impacted by any risk factors except for the number of positive nodes-86% for ≤4 nodes vs. 20% for >4 nodes (p < 0.001)-and pathologic T-stage-90% for pT1 vs. 75% for pT2 (p = 0.035) regardless of adjuvant radiation and/or chemotherapy use. Patients who underwent adjuvant radiation and/or chemotherapy had similar survival to those who did not despite having worse overall tumor prognostic factors. Adding adjuvant therapy may equalize some high-risk histopathologic factors. In the highest risk patients-specifically those with pathologic >4 nodes and pT2 staging-adjuvant therapy should be considered.

The prognostic role of MRI-based radiomics in tongue carcinoma: a multicentric validation study

PurposeRadiomics is an emerging field that utilizes quantitative features extracted from medical images to predict clinically meaningful outcomes. Validating findings is crucial to assess radiomics applicability. We aimed to validate previously published magnetic resonance imaging (MRI) radiomics models to predict oncological outcomes in oral tongue squamous cell carcinoma (OTSCC).Materials and methodsRetrospective multicentric study on OTSCC surgically treated from 2010 to 2019. All patients performed preoperative MRI, including contrast-enhanced T1-weighted (CE-T1), diffusion-weighted sequences and apparent diffusion coefficient map. We evaluated overall survival (OS), locoregional recurrence-free survival (LRRFS), cause-specific mortality (CSM). We elaborated different models based on clinical and radiomic data. C-indexes assessed the prediction accuracy of the models.ResultsWe collected 112 consecutive independent patients from three Italian Institutions to validate the previously published MRI radiomic models based on 79 different patients. The C-indexes for the hybrid clinical-radiomic models in the validation cohort were lower than those in the training cohort but remained > 0.5 in most cases. CE-T1 sequence provided the best fit to the models: the C-indexes obtained were 0.61, 0.59, 0.64 (pretreatment model) and 0.65, 0.69, 0.70 (posttreatment model) for OS, LRRFS and CSM, respectively.ConclusionOur clinical-radiomic models retain a potential to predict OS, LRRFS and CSM in heterogeneous cohorts across different centers. These findings encourage further research, aimed at overcoming current limitations, due to the variability of imaging acquisition, processing and tumor volume delineation.

Outcome of Upfront Surgically Resected Patients of Oral Tongue Squamous Cell Carcinoma and Factors Affecting it: Experience from Tertiary Care Facility in North India.

Oral tongue squamous cell carcinoma (OTSCC) is the most aggressive subsite among oral cancers. The poor survival rate has been primarily attributed to high loco-regional recurrence. Two recent developments viz. incorporation depth of invasion (DOI) in American Joint Committee on Cancer (AJCC) TNM 8th edition and elective neck dissection in clinically negative neck have potential to improve survival. We in our study have tried to look at overall survival and factors affecting patients of only OTSCC. 144 patients of OTSCC operated upfront between July 2017 and December 2023 were included in our study. Selective neck dissection was done in all patients with clinically negative neck. T staging was done using both AJCC TNM 7th and 8th edition. Primary objective of the study was to determine the overall survival and factors affecting it. The secondary objectives were to determine the disease-free survival and to look at the effect of forementioned new developments in patients in OTSCC. Mean overall survival and disease-free survival in our study cohort was 48.8 months and 48.3 months respectively in follow up period ranging from 2 months to 75 months. DOI > 10 millimetres and involved margins were factors significantly associated with survival on multivariate analysis. Lymph node metastasis was detected in 32(35.2%) patients out of 91 patients with clinically negative neck and 31(21.6%) of patients were upstaged from T1/T2 in AJCC TNM 7th to T3/T4 according to AJCC TNM 8th edition. The 5-years overall survival of our patients was about 54% with nearly half of our patients presenting in stage III and stage IV. There is need to create awareness in general population as the impact of the new changes will only be seen if patients present at an early stage.

Association between the Worst Pattern of Tumor Invasion and Epithelial-mesenchymal Transition and their Prognostic Impact on Early-stage Oral Tongue Squamous Cell Carcinoma.

We aimed to determine the association between the worst pattern of tumor invasion (WPOI) and epithelial-mesenchymal transition (EMT) in early-stage oral tongue squamous cell carcinoma (OTSCC) with no adverse features and their impact on 2-year disease-free survival (DFS) and overall survival (OS) rates. This prospective observational study included treatment-naive 50 patients who underwent primary surgery for OTSCC (pT1T2N0M0; AJCC 8th edition, with no adverse features) from June 1, 2020, to March 31, 2021 (minimum follow-up period, 2 years). WPOI (low- or high-invasive) and EMT (E-cadherin, N-cadherin, and vimentin expression at the tumor invasive front) were assessed. High invasive WPOI was seen in 66% and low invasive in 34%. 80% of the patients had EMT. No statistically significant association was found between WPOI and EMT. The OS and DFS at 2 years were 90% and 80% respectively. WPOI had statistically significant impact on 2-year DFS (100% for low & 69.7% for high, p-value 0.014). EMT did not significantly affect DFS or OS rates. In early stage OTSCC with no adverse features, WPOI can be a promising predictor for disease recurrence. However, this should be validated for modifying treatment guidelines.

Web-based prognostic tools for oral tongue cancer: An analysis of online predictors.

Oral tongue squamous cell carcinoma (OTSCC) often presents with aggressive clinical behaviour that may require multimodality treatment based on reliable prognostication. We aimed to evaluate the prognostic ability of five online web-based tools to predict the clinical behaviour of OTSCC resection and biopsy samples. A total of 135 OTSCC resection cases and 33 OTSCC biopsies were included to predict recurrence and survival. Area under the receiver operating characteristic curves (AUC), χ2 tests, and calibration plots constructed to estimate the prognostic power of each tool. The tool entitled 'Prediction of risk of Locoregional Recurrences in Early OTSCC' presented an accuracy of 82%. The tool, 'Head & Neck Cancer Outcome Calculator' for 10-year cancer-related mortality had an accuracy 77% and AUC 0.858. The other tool entitled 'Cancer Survival Rates' for 5-year mortality showed an accuracy of 74% and AUC of 0.723. For biopsy samples, 'Cancer Survival Prediction Calculators' predicted the recurrence free survival with an accuracy of 70%. Web-based tools can aid in clinical decision making of OTSCC. Three of five online web-based tools could predict recurrence risk and cancer-related mortality in resected OTSCC and one tool could help in clinical decision making for biopsy samples.

Subtotal glossectomy with conservation of the hyo-styloglossus unit (HSU): a new pivotal concept for preserving tongue function in extended glossectomy.

The local spread of oral tongue squamous cell carcinoma (OTSCC) follows pathways of dissemination along areas of lesser resistance. In more advanced scenarios, the tumor can extend beyond the hemi-tongue of origin, by passing through the lingual septum and following the fibers of the transverse muscle. This can lead to the invasion of the contralateral extrinsic muscles, the first being the genioglossus and more laterally the hyoglossus. An anatomically guided surgical resection of the tumor can be planned to ensure both oncological safety and an acceptable functional outcome. This approach aims to preserve the hyo-styloglossus unit (HSU) whenever feasible. Between January 2019 and November 2022, six patients received extended glossectomy Type B (EG Type B), with preservation of the HSU. Preliminary oncological results and functional results in terms of swallowing (FOIS score) and quality of life (MDADI) are presented. Five out of the six patients are alive and disease-free, while one patient died due to other causes. All patients who were candidates for an EG Type B underwent a swallowing assessment prior to surgery and followed daily postoperative swallowing training. At discharge, the patients continued swallowing training in an outpatient clinic. Five out of the six patients reached a full oral diet within 1 year of follow-up. The oncological results confirm the safety of this technique. The importance of preserving the HSU, the minimal functional unit, shows very encouraging results in terms of swallowing rehabilitation.

Role of Computed Tomography in Prediction of Depth of Invasion and Cervical Lymph Node Metastasis in Oral Cancer.

The primary aim is to determine the accuracy of contrast-enhanced computed tomography (CT) in evaluation of depth of invasion (DOI) and detection of cervical node metastasis. We also analysed the relation between radiographic DOI (rDOI) and cervical lymph node metastasis. We have retrospectively reviewed 201 oral squamous cell carcinoma (SCC) patients. The rDOI was compared with histological DOI. Sensitivity, specificity, accuracy, and negative (NPV) and positive (PPV) predictive values were evaluated for CT scan in predicting nodal metastasis. The relation between rDOI and lymph node metastasis was analysed using ROC curve. rDOI correlated significantly with histologic DOI for oral tongue, buccal mucosa, gingiva, and mucosal lip SCC (P < 0.05) and for tumours with rDOI > 5mm. The sensitivity, specificity, PPV, NPV and accuracy rate of CT scan were found to be 84.71%, 50.86%, 55.81%, 81.94% and 65.17%, respectively. Tumours with rDOI > 16mm had significant (P < 0.001) chance of having neck node metastasis. CT-derived DOI correlates significantly with pathological DOI although both are not similar. CT scan can predict nodal metastasis in fairly accurate manner using the four radiographic criteria used in this study. Radiographic depth of invasion can be used as predictor of cervical node metastasis.

Prognostic implications of mucosal and deep margin distances according to T-status in oral tongue squamous cell carcinoma: A single-center retrospective study.

To elucidate the prognostic implications of mucosal and deep margin distances in oral tongue squamous cell carcinoma (OTSCC), and to assess a different margin cut-off value in T1-T2 versus T3-T4 tumors. This single-center retrospective study included 223 patients who received surgery for a primary OTSCC between January 2017 and December 2021. Multivariable analysis showed that deep margin distance ≥3 mm in T1-T2 tumors and ≥5 mm in T3-T4 tumors was significantly associated with better RFS and OS. Mucosal and deep margin distances were globally clinically useful for 2-year RFS prediction of T1-T2 tumors, for which deep margins seemed to have more clinical utility than mucosal margins. The influence of margin distances on 2-year RFS seemed greater for T1-T2 tumors than T3-T4 tumors. Mucosal and deep margin distances were associated with OS and RFS in OTSCC. Shorter deep margin distances may be aimed for in T1-T2 versus T3-T4 tumors.

Biomolecular alterations temporally anticipate microarchitectural modifications of collagen in oral tongue squamous cell carcinoma

High resolution analysis of collagen bundles could provide information on tumor onset and evolution. This study was focused on the microarchitecture and biomolecular organization of collagen bundles in oral tongue squamous cell carcinoma (OTSCC). Thirty-five OTSCC biopsy samples were analyzed by synchrotron-based phase-contrast microcomputed tomography and Fourier transform infrared imaging (FTIRI) spectroscopy. PhC-microCT evidenced the presence of reduced and disorganized collagen in the tumor area compared to the extratumoral (ExtraT) one. FTIRI also revealed a reduction of folded secondary structures in the tumor area, and highlighted differences in the peritumoral (PeriT) areas in relation with the OTSCC stage, whereby a significantly lower amount of collagen with less organized fibers was found in the PeriT stroma of advanced-OTSCC stages. Interestingly, no significant morphometrical mismatches were detected in the same region by PhC-microCT analysis. These results suggest that biomolecular alterations in the OTSCC stroma temporally anticipate structural modifications of collagen bundle microarchitecture.

Predicting nodal metastasis progression of oral tongue cancer using a hidden Markov model in MRI.

The presence of occult nodal metastases in patients with oral tongue squamous cell carcinomas (OTSCCs) has implications for treatment. More than 30% of patients will have occult nodal metastases, yet a considerable number of patients undergo unnecessary invasive neck dissection to confirm nodal status. In this work, we propose a probabilistic model for lymphatic metastatic spread that can quantify the risk of microscopic involvement at the lymph node level (LNL) given the location of macroscopic metastases and the tumor stage using the MRI method. A total of 108 patients of OTSCCs were included in the study. A hidden Markov model (HMM) was used to compute the probabilities of transitions between states over time based on MRI. Learning of the transition probabilities was performed via Markov chain Monte Carlo sampling and was based on a dataset of OTSCC patients for whom involvement of individual LNLs was reported. Our model found that the most common involvement was that of level I and level II, corresponding to a high probability of 𝑝b1 = 0.39 ± 0.05, 𝑝b2 = 0.53 ± 0.09; lymph node level I had metastasis, and the probability of metastasis in lymph node II was high (93.79%); lymph node level II had metastasis, and the probability of metastasis in lymph node III was small (7.88%). Lymph nodes progress faster in the early stage and slower in the late stage. An HMM can produce an algorithm that is able to predict nodal metastasis evolution in patients with OTSCCs by analyzing the macroscopic metastases observed in the upstream levels, and tumor category.

Obesity enhances the response to neoadjuvant anti-PD1 therapy in oral tongue squamous cell carcinoma.

Previous studies have demonstrated that obesity may impact the efficacy of anti-PD1 therapy, but the underlying mechanism remains unclear. In this study, our objective was to determine the prognostic value of obesity in patients with oral tongue squamous cell carcinoma (OTSCC) treated with pembrolizumab and establish a subtype based on fatty acid metabolism-related genes (FAMRGs) for immunotherapy. We enrolled a total of 56 patients with OTSCC who underwent neoadjuvant anti-PD1 therapy. Univariate and multivariate Cox regression analyses, Kaplan-Meier survival analysis, and immunohistochemistry staining were performed. Additionally, we acquired the gene expression profiles of pan-cancer samples and conducted GSEA and KEGG pathway analysis. Moreover, data from TCGA, MSigDB, UALCAN, GEPIA and TIMER were utilized to construct the FAMRGs subtype. Our findings indicate that high Body Mass Index (BMI) was significantly associated with improved PFS (HR = 0.015; 95% CI, 0.001 to 0.477; p = 0.015), potentially attributed to increased infiltration of PD1 + T cells. A total of 91 differentially expressed FAMRGs were identified between the response and non-response groups in pan-cancer patients treated with immunotherapy. Of these, 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) were found to affect PD-1 expression and T cell infiltration in HNSCC, which may impact the efficacy of anti-PD1 therapy. This study demonstrates that obesity serves as a robust prognostic predictor for patients with OTSCC undergoing neoadjuvant anti-PD1 therapy. Furthermore, the expression of 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) plays a pivotal role in the context of anti-PD1 therapy and deserves further investigation.

Effect of CBD on anti-tumor immune response and interaction with GPR55 on MAPK signaling in head and neck squamous cell carcinoma.

6060 Background: Head and neck squamous cell carcinoma (HNSCC) is a lethal malignancy and comprises two distinct etiology: human papillomavirus (HPV)+ve and -ve. Marijuana use is associated with HPV+ oropharyngeal infection and conflicting data show positive and negative associations of daily marijuana use with HPV+ and tobacco-associated HPV- HNSCC. However, cannabinoid use continues to increase in the US general population for recreational purposes as well as in cancer patients for palliative care. G-protein coupled receptors (GPCRs), including cannabinoid GPCRs, stimulated by specific ligands interact with multiple G proteins creating diversity and complexity of signaling. In this study, we aimed to investigate the CBD-induced GPCR coupling and its effect on anti-tumor activity by modulating immune response in HNSCC by using pre-clinical models. Methods: The anti-cancer effect of CBD was measured by cell proliferation, apoptosis and migration analysis. Next, TGF-α shedding assay was performed to identify the CBD-induced GPCR coupling with different cannabinoid receptors. The cannabinoid receptor GPR55 was subjected to silencing by siRNA and western blot analysis was performed to evaluate its role in activation of p38 MPAK pathway. Next, the anti-tumor immune response of CBD was evaluated by using an immunocompetent syngeneic C57BL/6 mEER RasG12D+/- HPV E6/E7 transformed tongue epithelial cell model that serves as a model for HPV+ HNSCC and the 4MOSC1 orthotopic, syngeneic, 4NQO (4-nitroquinoline-1 oxide)-induced murine oral tongue squamous cell carcinoma C57BL/6 mouse model that serve as HPV- HNSCC model as well as in immune-deficient Rag1 -/- and athymic nude mouse followed by measurement of immune cell infiltration by IHC analysis. Results: We found that 10μM of CBD treatment inhibited cell proliferation and migration in HNSCC cells by promoting apoptosis. Interestingly, we observed that CBD resulted in GPCR coupling for Gαi with GPR55 and Gαq/o and Gαq/s for CNR1, CNR2 and GPR55. Furthermore, we silenced GPR55 and observed that 10μM of CBD treatment inhibits the activation of p38 MAPK pathway whereas it promotes activation in non-silenced HNSCC cells. Next, we observed that treatment with 10μM of CBD significantly inhibited tumor growth compared to control in both HPV- and HPV+ models in immune-intact animals whereas, no significant difference in the tumor growth was observed in immune-deficient (Rag1 -/- and athymic nude) mouse, indicating role of CBD in modulating tumor immune microenvironment. We also observed CBD treatment enhanced CD4+ and CD8+ T cell infiltration into the primary tumors of HPV+ and HPV- mice models, implicating a downstream cytotoxic T cell response. Conclusions: Our study suggests that CBD promotes anti-tumor activity by modulating the immune microenvironment and interacts with GPR55 to activate intrinsic MAPK signaling pathway.