The significance of elective neck dissection for patients with T2N0M0 OSCC at different ages.

BACKGROUND: The aim of this study was to determine the significance of elective neck dissection (END) for patients of different ages with T2N0M0 oral squamous cell carcinoma (OSCC) and sought to analyze the reasons behind it and its value for clinical guidance. METHODS: This study enrolled 391 patients with T2N0M0 OSCC who were surgically treated in our hospital and were divided into young-, moderate-, and advanced-age groups according to our previous study. The Chi-square test and Kaplan-Meier analysis were performed for statistical analysis. RESULTS: Compared with moderate- and advanced-age patients, young patients with T2N0M0 OSCC had higher lymph node metastasis rates and lymph node ratios. Therefore, END significantly improved the recurrence (p = 0.001) and survival (p = 0.001) for young patients, but not for moderate-age patients. Advanced-age patients even benefit from watchful waiting. END significantly improved recurrence and survival in young patients with smoking or alcohol consumption habits. CONCLUSIONS: END improved the prognosis of young patients, and it was related to their higher metastasis rate. However, advanced-age patients benefited from the wait-and-see policy. END is essential for the young patients with smoking or drinking habit, it is also highly recommended for nonsmokers and nondrinkers.

The modified vermilion border-marionette line approach: A management for buccal cancer with wider indications and higher satisfaction.

OBJECTIVE: The purpose of this study is to explore the effects of modified vermilion border-marionette line (MVBML) approach on postoperative facial scar, nerves injury, and prognosis of patients with buccal squamous cell carcinoma (BSCC). PATIENTS AND METHODS: This is a single-center, prospective cohort study that enrolled 80 patients with BSCC from June 2015 to December 2020. According to the different surgical approaches, the patients were divided into two groups: the lower lip median (LLM) approach group and the MVBML approach group. RESULTS: The results showed that the appearance (p = 0.003), scar consciousness (p < 0.001) and satisfaction with appearance (p = 0.001) of patients in the MVBML group were significantly better than those in the LLM group, and the difference was more obvious in elderly group. Statistical analysis of postoperative nerves injury showed that the MVBML group had a lower risk of facial and mental nerves injury than the LLM group, and there was a significant statistical difference in mental nerve injury between the two groups (p < 0.001). Through Kaplan-Meier survival analysis, we found no significant difference in disease-specific survival (p = 0.47) or disease-free survival (p = 0.70) between the LLM approach group and the MVBML approach group. CONCLUSIONS: The MVBML surgical approach is worthy of advancement for the surgical treatment of BSCC.

Chemotherapy for primary cancer can reduce the risk of head and neck second primary malignancy: a propensity-matched analysis.

OBJECTIVES: To investigate the effect of chemotherapy versus no chemotherapy on the risk of second primary head and neck malignancies (SPHNMs) in patients with locally advanced oral squamous cell carcinoma (OSCC) and to assess the survival outcomes of patients with SPHNM. MATERIALS AND METHODS: A total of 937 OSCC patients were divided into chemotherapy and nonchemotherapy groups by propensity score matching (PSM). In the presence of the competing event of non-SPHNM death, the fine and gray modified Cox proportional hazard model was fitted to detect the impact of various factors, including the history of chemotherapy, on SPHNM risk. The Kaplan-Meier method was used to assess the survival outcomes of patients. RESULTS: After PSM, the 10-year cumulative probability of SPHNM was 10.7% for patients who received chemotherapy and 22.1% for patients who did not. The fine and gray regression model showed that prior chemotherapy was associated with a 51% reduced risk of SPHNM (adjusted subdistribution hazard ratio (sHR): 0.49, 95% confidence interval (CI): 0.29-0.84, P = 0.1). The disease-free survival (DFS) rates did not differ significantly between the SPHNM and non-SPHNM groups. And there were no significant differences in DFS rates between the patients with and those without prior chemotherapy in the SPHNM group. CONCLUSIONS: Chemotherapy for locally advanced primary OSCC is associated with a decreased incidence of subsequent SPHNM. However, chemotherapy for the primary cancer does not improve DFS in patients with SPHNM. CLINICAL RELEVANCE: Chemotherapy plays a positive role in preventing SPHNMs for patients with oral squamous cell carcinoma. CLINICAL TRIAL REGISTRATION: Before January 2015, the data were retrieved retrospectively, while after January 2015, the data were collected prospectively in a POROMS database (ClinicalTrials.gov ID: NCT02395367).

Prognostic factors and related complications/sequalae of squamous cell carcinoma located in the gingivobuccal complex.

BACKGROUND: Gingivobuccal complex (GBC) was a relatively new concept of oral subsite that was comprises of the upper and/or lower gingiva, gingival buccal sulcus, and adjacent buccal mucosa. Squamous cell carcinoma (SCC) of the GBC had a poor prognosis, with few studies analyzing this particular entity. The objective of this study was to analyze the risk factors affecting the prognosis and complications/sequalae of gingivobuccal complex cancer. METHODS: Between December 2014 and August 2019, a total of 122 patients diagnosed with primary gingivobuccal complex cancer in Beijing Stomatological Hospital, Capital Medical University were enrolled in the study. Through outpatient reviewed and telephone followed-up for 2-5 years postoperatively, postoperative relapse and complications/sequalae were assessed. The primary outcome parameter was 2-year disease-free survival. RESULTS: The most common central site of the tumor was the buccal mucosa (45.1%), followed by the lower gingiva (36.9%). The most diseases were pT4a (45.1%) and there was lymph node invasion (pN+) in 41.8% of patients. Moderate differentiated squamous carcinoma (77.9%) accounted for the vast majority of the histopathological differentiation. A total of 62.3% of tumors invaded the bone, while, 5.7% invaded the skin layer. Survival analysis found that 44.3% of patients experienced relapse within two years postoperatively and the mortality rate after relapse was 75.9%. Almost 60.0% of the tumors involving the maxilla and/or mandible developed relapse. Cox proportional hazards model found that pN stage (p= 0.002) and bone invasion (p= 0.007) were significant independent predictors of 2-year disease-free survival. Importantly, 63.1% of patients had postoperative (and postradiotherapy) complications/sequalae. It was noteworthy that 18 of 43 patients (41.9%) who implanted with titanium plates had hardware-related complications/sequalae, and the most of them were titanium plate exposure (61.1%). CONCLUSIONS: Squamous cell carcinoma of the gingivobuccal complex cancer, as a new subsite worthy of attention in oral cancer, has a high complication/sequalae rate, high relapse rate and poor prognosis. TRIAL REGISTRATION: Prospective, Observational, Real-world Oral Malignant Tumors Study ( clinicaltrials.gov identifier: NCT02395367). The approval of the Institutional Review Board of the Beijing Stomatological Hospital of Capital Medical University (Approval number: CMUSH-IRB-KJPJ-2015-08).

GPD1L is negatively associated with HIF1α expression and predicts lymph node metastasis in oral and HPV- Oropharyngeal cancer.

OBJECTIVE: The study is to determine if Glycerol-3-phosphate dehydrogenase 1-like (GPD1L) and hypoxia-inducible factor-1α (HIF1α) can identify high-risk patients with delayed lymph node metastasis in early-stage head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The mRNA and protein expressions of markers were analyzed using fresh and paraffin embedded HNSCC specimens. The statistical analyses included chi-squared test, t test, correlation analysis, and univariate and multivariate analyses. RESULTS: GPD1L (downregulated) and HIF1α (upregulated) mRNA expression had a negative correlation (r = -.496, p = .001) in cT1-2N0 HNSCC. The low GPD1L + high HIF1α expression group (22.6%) showed a significant decrease in disease-free survival compared with the high GPD1L + low HIF1α expression group (71.4%) in the neck dissection group. The low GPD1L + high HIF1α expression (39.4%) resulted in a significantly higher delayed metastasis rate than the high GPD1L + low HIF1α expression (5.6%) for cT1-2N0 HNSCC in the neck observation group. GPD1L and HIF1α protein expression more accurately predicted lymph node metastasis than the WINTER hypoxia gene panel (false-negative rate in predicting metastasis: 8.1% versus 26.4%). Cox regression analyses found that the combined protein expression of GPD1L and HIF1α could predict delayed metastasis (HR:0.118, 95% CI:0.027-0.525). CONCLUSIONS: Low GPD1L + high HIF1α expression can serve as candidate biomarkers for high-risk populations with lymph node metastases in early-stage HNSCC.

Is Perineural Invasion a Reasonable Indicator for Neck Dissection in cT1N0M0 Squamous Cell Carcinoma of the Oral Cavity?

PURPOSE: Perineural invasion (PNI) is considered an adverse histological feature in oral squamous cell carcinoma (OSCC). Controversy exists regarding elective neck dissection (END) in cT1N0M0 OSCC with PNI as the only risk factor. The purpose of this study was to evaluate PNI as an indicator for END, as well as its utility when combined with the depth of invasion (DOI) as a second indicator. PATIENTS AND METHODS: cT1N0M0 (AJCC8) OSCC patients treated from August 1998 to July 2017 in the Department of Oral and Maxillofacial Surgery, University of Michigan (MI), and Beijing Stomatological Hospital, Capital Medical University (BSH) were reviewed. Data from these sites included both prospectively captured data housed in a database and retrospective data. RESULTS: 283 cT1N0M0 OSCC patients were analyzed. The tongue was the most common subsite (56.2%). Ninety-nine (99) patients received END and 184 neck observation. PNI was found in only 8 patients (2.83%) all in the tongue or inferior gingiva. END was performed in 7 of the PNI patients. The mean depth of invasion for tumors with PNI was 3.97 mm, compared to 2.54 mm in tumors without PNI. PNI was statistically correlated with nodal disease (pN+) and extranodal extension (ENE+). After using DOI as a primary indicator for END, no additional PNI patients benefited from END. In addition, only 2 patients had PNI identified preoperatively both with 5 mm DOI, and therefore, already indicated for END on the basis of DOI status. CONCLUSIONS: PNI status is statistically correlated with pN+ and ENE + pathology in cT1N0M0 OSCC. After using DOI as a primary indicator for END, PNI status had no added value in decision making. Even surgeons who do not use DOI will find very limited value in PNI status with less than 1% preoperative prevalence (0.71%) in this patient population.

Is it necessary to receive radiation for pT3-4N0 oral cancer without other adverse risk features?

OBJECTIVE: The purpose of this study was to explore the necessity of adjuvant radiotherapy for well-differentiated pT3-4aN0M0 OSCC without other negative features histologically. PATIENTS AND METHODS: This is a double-center, ambispective cohort study enrolling 250 patients with well-differentiated pT3-4aN0M0 OSCC. RESULTS: A total of 250 patients were enrolled in the double-center study, 155(62.0%) men and 95 (38.0%) women, and the mean age was 60.1 ± 11.1 years. T staging was classified as follows: T3 (n = 99, 39.6%) and T4a (n = 151, 60.4%). Kaplan-Meier analysis showed that there was no significant difference in the DSS between patients who received adjuvant radiotherapy (72.2%) and those who did not (77.4%) (p = .615). Specifically, no significant difference was found in the DSS of pT3N0M0 or pT4aN0M0 patients who received adjuvant radiotherapy compared with those who did not (pT3N0M0: 71.9% vs. 75.8%, p = .993; pT4aN0M0: 72.4% vs. 78.5%, p = .491). The Cox proportional hazards regression models showed that no factor was independent prognostic factor for pT3-4aN0M0 patients, or pT3N0M0 subgroup or pT4aN0M0 subgroup in DSS. And no independent prognostic factor was found for the surgery-alone subgroup and adjuvant radiotherapy subgroup. CONCLUSIONS: The results showed that adjuvant radiotherapy did not obviously improve the prognosis of pT3-4aN0M0 well-differentiated OSCC without other negative features.

Clinical Manifestations, Diagnosis, and Management of First Branchial Cleft Fistula/Sinus: A Case Series and Literature Review.

PURPOSE: First branchial cleft fistula/sinus is a rare congenital developmental deformity that can sometimes be acquired from incision and drainage of a branchial cleft cyst. The aim of the present study was to explore the clinical manifestations, diagnosis, and surgical management of first branchial cleft fistula/sinus in both a large patient series and a review of the pertinent literature. MATERIALS AND METHODS: The data from 31 cases diagnosed from February 2004 to April 2019 as first branchial cleft fistula/sinus were retrospectively reviewed. The patient demographic data and outcomes were explored. In addition, we performed a literature review of studies reported from 1923 to 2018 for first branchial cleft fistula/sinus and summarized those results. RESULTS: The present study included 31 patients (15 males, 16 females) with a median age of 4 years. All the patients reviewed had presented with a unilateral first branchial cleft fistula/sinus. The parotid region was the most frequent site of presentation (41.9%) in these cases. The fistula/sinus had occurred on the left side in 13 patients (41.9%) and on the right side in 18 patients (58.1%). Of the 31 patients, 24 (77.4%) had acquired the disease from infection of an existing brachial cleft cyst or incomplete previous excision. Of the 31 cases, 28 (90%) had an intimate relationship between the tract and the facial nerve. Despite this close association, no patient developed postoperative facial nerve palsy. Of the 31 operations, 30 (97%) successfully accomplished complete resection with no recurrence postoperatively. Only 1 patient with a history of multiple recurrences experienced a subsequent recurrence, which was successfully treated with a second surgery. CONCLUSIONS: First branchial cleft fistula/sinus is a frequently misdiagnosed and, therefore, undertreated entity, which leads to recurrence. It is closely associated with the facial nerve and extra auditory canal. The correct diagnosis and meticulous removal can be effectively achieved with minimal risk to the facial nerve.

Elective Neck Dissection in T1N0M0 Oral Squamous Cell Carcinoma: When Is It Necessary?

PURPOSE: Elective neck dissection (END) versus observation remains controversial for cT1N0M0 oral cavity squamous cell carcinoma (OSCC). The aim of this study was to determine whether neck dissection is indicated for cT1N0M0 OSCC versus observation when considering oral cavity subsites and depth of invasion (DOI) as predictors. PATIENTS AND METHODS: A multicenter, ambispective cohort study of patients with cT1N0M0 OSCC treated at the University of Michigan and Beijing Stomatological Hospital from August 1998 to July 2017 with a follow-up end date of July 2019 was performed. Patients were excluded if follow-up was less than 2 years and no neck disease had occurred or if the final pathologic analysis resulted in upstaging to T2 using American Joint Committee on Cancer criteria, eighth edition. A total of 283 patients met the criteria. The main outcome parameter was the 2-year neck metastatic rate. RESULTS: The total 2-year lymph node metastatic rate was 11.3%. Overall neck metastatic rates escalated consistently according to DOI: less than 2 mm, 2.1%; 2 to 3 mm, 9.4%; 3 to 4 mm, 15.2%; and 4 to 5 mm, 24.6%. On univariate Cox regression analysis, DOI greater than 3 mm, tumor grade, and perineural invasion were statistically significant indicators of 2-year neck metastasis. On multivariate analysis, only DOI and tumor grade remained. On multivariate analysis of 2-year survival, no factors were independent predictors. Our proposed treatment strategy for END based both on statistically significant results for DOI and on review of the raw data using a 20% cutoff analysis showed cutoffs of 2 mm for the tongue (18.2%), 3 mm for the floor of the mouth (40.0%) and upper gingiva (20%), and 4 mm for the lower gingiva (33.3%) and no cutoff for the hard palate (0.0%). CONCLUSIONS: The watch-and-wait approach remains a reasonable approach in selected patients with cT1N0M0 OSCC. Decision making for END in T1N0M0 patients should minimally consider tumor grade, DOI, and oral cavity subsite.

Surgical Management of Giant Cell Tumor Involving the Lateral Skull Base.

The aim of the study is to discuss the current management options for intra- and extra-cranial communication giant cell tumor of the lateral skull base and perform a review of the literature. A total of 6 patients with giant cell tumor of the lateral skull base were retrospectively enrolled in the study. The principal complaints, imaging manifestations, surgical resection and reconstruction of intra- and extra-cranial communication defects for the diseases were discussed. There were 2 males and 4 females. The most of principal complaints were discomfort or pain in the temporomandibular joint in 5 cases (83.3%). Imaging examination showed invasion of the temporal bone alone in 3 cases (50.0%) and both temporal bone and sphenoid bone involvement in 3 cases (50.0%). C-shaped preauricular infratemporal fossa approach was used for tumour removal and gross total resection was done in all 6 cases. The pedicled temporal muscle fascial flap was used to reconstruct the intra- and extra-cranial communication defect of the lateral skull base. The conclusion is that giant cell tumor is a benign tumor but is also locally aggressive. Gross total resection is the most commonly recommended treatment choice for giant cell tumor of the skull and can achieve good treatment outcomes. The temporalis muscle flap is a good alternative choice for reconstruction of the defect.

The small extracellular vesicle-mediated intercellular transformation of CXCR1Low to CXCR1High tumour cells promotes the progression of head and neck squamous cell carcinoma.

The heterogeneity of tumour cells enables cancers to dynamically adapt to microenvironmental stresses during progression. However, the mechanism underlying the transformation and intercellular communication between heterogeneous tumour cells has remained elusive. Here, we report a "contagion model" that mediates intercellular transformation between heterogeneous tumour cells which facilitates tumour progression. Initially identifying heterogeneous expression of CXCR1, a receptor for interleukin-8, in head and neck squamous cell carcinoma (HNSCC) tumour cells, we found that CXCR1High tumour cells had higher abilities for migration and invasion. Following interleukin-8-mediated activation, CXCR1High cells transformed CXCR1Low cells into CXCR1High cells through the secretion of small extracellular vesicles (sEVs), which increased the proportion of CXCR1High cells and facilitated tumour progression. Mechanistically, we demonstrate that sEVs derived from interleukin-8-activated CXCR1High cells contain high levels of ATP citrate lyase (ACLY), which acetylates NF-κB p65 and facilitates its nuclear translocation to transcribe CXCR1 in CXCR1Low cells. That process could be inhibited by Bempedoic acid, an FDA-approved ACLY-targeted drug. Taken together, our study reveals an sEV-mediated transformation of CXCR1Low to CXCR1High cells that promotes HNSCC progression. This provides a new paradigm to explain the dynamic changes of heterogeneous tumour cells, and identifies Bempedoic acid as a potential drug for HNSCC treatment.

The enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of oral squamous cell carcinoma.

The tumor margin as the invasive front has been proven to be closely related to the progression and metastasis of oral squamous cell carcinoma (OSCC). However, how tumor cells in the marginal region obtain the extra energy needed for tumor progression is still unknown. Here, we used spatial metabolomics and the spatial transcriptome to identify enhanced energy metabolism in the tumor margin of OSCC and identified that the downregulation of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD) in tumor cells mediated this process. The absence of RRAD enhanced the ingestion of glucose and malignant behaviors of tumor cells both in vivo and in vitro. Mechanically, the downregulation of RRAD promoted the internal flow of Ca2+ and elevated its concentration in the nucleus, which resulted in the activation of the CAMKIV-CREB1 axis to induce the transcription of the glucose transporter GLUT3. GLUT inhibitor-1, as an inhibitor of GLUT3, could suppress this vigorous energy metabolism and malignant behaviors caused by the downregulation of RRAD. Taken together, our study revealed that enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of OSCC and proved that GLUT3 is a potential target for future treatment of OSCC.

Development and validation of a nomogram for the prediction of lymph node metastasis within 2-year postoperatively in cT1-T2N0 oral squamous cell carcinoma.

BACKGROUND: The current neck management for early oral squamous cell carcinoma (OSCC) has always been a controversial issue. A comprehensive model is necessary for predicting an individual's metastasis risk and appropriate patient counseling. METHODS: A nomogram for predicting 2-year LNM in patients with cT1-2N0 OSCC was developed and validated using clinicopathological data from 642 patients from 2000 to 2018 in four hospitals, China. RESULTS: Three variables (pathology grade, depth of invasion, tumor-infiltrating lymphocytes) were included in nomogram. C-indices were 0.826 (95% CI: 0.786-0.866) and 0.726 (95% CI: 0.653-0.780) in the internal and external validation. Kaplan-Meier method found the 2-year LNM rate of high-risk group (35.8%) was much higher than that of the low-risk group (14.5%). The nomogram model has an advantage over the 8th AJCC TNM stage in predicting the individual 2-year LNM probability for early OSCC. CONCLUSION: Patients with low-risk nomogram score may receive neck observation; those with high-risk score should receive END.

Postoperative Complications of Free Flap Reconstruction in Moderate-Advanced Head and Neck Squamous Cell Carcinoma: A Prospective Cohort Study Based on Real-World Data.

Background: Postoperative complications (POCs) of moderate-advanced head and neck squamous cell carcinoma (HNSCC) after free flap reconstruction have received little attention. We investigated the risk factors that lead to POCs and their impact on management and prognosis. Patients and Methods: A single-center, prospective cohort study was conducted at Beijing Stomatological Hospital on primary HNSCC patients treated between 2015 and 2020. Results: In total, 399 consecutive HNSCC patients who underwent radical resection of the primary tumor and free flap reconstruction were enrolled in this study, 155(38.8%) experienced POCs. The occurrence of POCs directly led to worse short-term outcomes and poorer long-term overall survival (P=0.0056). Weight loss before the operation (P=0.097), Tumor site (P=0.002), stage T4b (P=0.016), an ACE-27 index of 2-3 (P=0.040), operation time≥8h (P=0.001) and Clindamycin as antibiotic prophylaxis (P=0.001) were significantly associated with POCs. Conclusions: The occurrence of POCs significantly leads to worse short-term outcomes and increases the patients' burden.

Primary intraosseous malignancies: A 10-year retrospective cohort study.

OBJECTIVE: This study aimed to explore the characteristics and prognoses of primary jaw malignancies and identify valuable prognostic factors. STUDY DESIGN: Patients who were primarily diagnosed with jaw malignancies at Beijing Stomatological Hospital between 2006 and 2016 were retrospectively reviewed. RESULTS: Eighty patients with malignant jaw tumors were enrolled in the study. Squamous cell carcinoma was the most common type (56.2%). The age range of patients varied from 11 to 92 years old (mean age = 51.5 years), and the male-to-female ratio was 2.1:1. Anatomically, the mandible was involved in 82.5% of cases. The estimated disease-free survival and overall survival (OS) rates were 60.6% and 73.2%, respectively. Cox multivariate analysis showed that a smoking history (hazard ratio = 5.015, 95% confidence interval, 1.900-13.235, P = .001) and advanced age (≥60 years; hazard ratio = 2.464, 95% confidence interval, 0.987-6.155, P = .046) were independent prognostic factors for poor OS. CONCLUSION: Primary jaw malignancies were more prevalent in the mandible and among males and middle-aged patients. Radical resection of the primary surgery was the basis of a good prognosis, and the choice of postoperative adjuvant therapy may not ultimately affect OS. Patients with a history of smoking and advanced age were at high risk for poor prognosis.

Modified in-continuity resection is advantageous for prognosis and as a new surgical strategy for management of oral tongue cancer.

OBJECTIVE: The aim of this study was to explore the application value of modified in-continuity resection compared with traditional in-continuity resection and discontinuous resection for patients with cT2 N0 M0 oral tongue squamous cell carcinoma. STUDY DESIGN: This was a retrospective cohort study. The predictor was surgical management. The main outcome assessment parameters were the 5-year intervening regional (submandibular area and floor of mouth) recurrence rate and the 5-year disease-specific survival rate. Descriptive and bivariate statistics were computed, and the P value was .05. RESULTS: We reviewed 406 patients: 212 in the discontinuous resection group, 101 in the in-continuity resection group, and 93 in the modified in-continuity resection group. Kaplan-Meier analysis showed that modified in-continuity resection was better than discontinuous resection with regard to both 5-year intervening regional recurrence (6.3% vs 18.8%; P = .004) and 5-year disease-specific survival (88.6% vs 75.1%; P = .003). Additionally, modified in-continuity resection had a lower postoperative complication rate compared with in-continuity resection (3.8% vs 13.2%; P = .044). CONCLUSIONS: The modified in-continuity resection is valuable for application in clinical practice for cT2 N0 M0 oral tongue squamous cell carcinoma.