Prognostic value of a mandibular canal staging system for primary lesions in patients with lower gingival squamous cell carcinoma: a multicenter, retrospective study.

BACKGROUND: The Union for International Cancer Control and American Joint Committee on Cancer tumor staging system is used globally for treatment planning. As it may be insufficient for tumor staging of lower gingival carcinomas, we proposed the mandibular canal tumor staging system. In this study, we aimed to compare the two systems for such tumor staging and to identify prognostic markers. METHODS: This multicenter, retrospective study included patients with lower gingival squamous cell carcinoma who underwent radical surgery during 2001-2018. We compared survival rates (Kaplan-Meier estimator) and patient stratification according to the two systems. RESULTS: The proposed system yielded more balanced patient stratification than the existing system. Progression in the tumor grade according to the proposed system was associated with a poorer prognosis. The 5-year overall and disease-specific survival rates for the entire cohort were 74.9% and 81.8%, respectively. Independent factors affecting overall survival were tumor stage according to the proposed system, excision margins, and number of positive nodes, whereas those affecting disease-specific survival were excision margins and number of positive nodes. CONCLUSIONS: Subsite-specific tumor classification should be used for patients with oral cancer, and our results suggest that mandibular canal tumor classification may be effective for patients with lower gingival carcinoma.

A Multicenter Study on the Effect of Margin Distance on Survival and Local Control in Stage 1-2 Squamous Cell Carcinoma of the Tongue.

BACKGROUND: Pathological close margins are considered a significant factor for local recurrence in patients with oral cancer. However, the oral cavity has complicated anatomical features, and the appropriate margin distance for each site is unknown. This multicenter, retrospective study aimed to determine the appropriate resection margin for early tongue cancer and investigate the need for additional treatment for close margins and stump dysplasia. PATIENTS AND METHODS: In total, 564 patients from ten hospitals were enrolled in this study. Sex, age, performance status, T stage, tumor length diameter, depth of invasion, elective neck dissection, iodine staining, horizontal margin distance, vertical margin distance, pathological differentiation, invasion pattern, lymphatic invasion, perineural invasion, dysplasia in the resection edge, additional treatment for close margins, local recurrence, neck metastasis, distant metastasis, and outcomes were investigated. RESULTS: Receiver operating characteristic analysis for local recurrence revealed cut-off values of 3.3 mm for horizontal distance and 3.1 mm for vertical distance. Patients with close horizontal or vertical margins showed significantly higher local recurrence rates, but these were not associated with overall or disease-specific survival. Furthermore, there was no effect of additional treatment in patients with dysplasia at the surgical margin. CONCLUSION: For early tongue cancer, a horizontal margin of 3.3 mm was defined as a close margin. Close margins were significantly correlated with local recurrence but did not affect survival. In the future, we would like to examine the concept of "quality margins," including the surrounding anatomical features.

The Impact of Pretreatment Low Body Mass Index on Cause-Specific Mortality in Patients with Squamous Cell Carcinoma of the Oral Cavity.

The association between the pretreatment body mass index (BMI) and oral squamous cell carcinoma (SCC) outcomes is controversial. We aimed to examine the association between BMI and cause-specific mortality due to cancer of the oral cavity and patterns of failure that correlate with increased mortality. We enrolled 2,023 East Asian patients in this multicenter cohort study. We used the cumulative incidence competing risks method and the Fine-Gray model to analyze factors associated with cause-specific mortality, local recurrence, regional metastasis, and distant metastasis as first events. The median follow-up period was 62 mo. The 5-year cause-specific mortality for patients with underweight was 25.7%, which was significantly higher than that for patients with normal weight (12.7%, P < 0.0001). The multivariate model revealed that underweight was an independent risk factor for cause-specific mortality and regional metastasis (P < 0.05). Moreover, patients with underweight displayed a 51% and 55% increased risk of cause-specific mortality and regional metastasis, respectively, compared with their normal weight counterparts. Local recurrence was not associated with the BMI categories; however, the incidence of distant metastasis inversely decreased with BMI value. In summary, being underweight at diagnosis should be considered a high-risk mortality factor for oral SCC.

Oral melanoma: a multicenter study of 69 patients from Japan.

OBJECTIVES: The purpose of this multicenter retrospective study was to investigate the demographic characteristics and treatment outcomes of patients with mucosal malignant melanoma (MM) of the oral cavity. MATERIALS AND METHODS: This was a multicenter study involving 8 Japanese universities. The medical records of 69 patients who were diagnosed with primary oral MM between January 2000 and December 2020 were retrospectively analyzed. Overall survival (OS) and prognostic factors for OS were analyzed statistically. RESULTS: There were 40 (58.0%) males and 29 (42.0%) females, and their mean (range) age was 69.8 ± 14.6 (22-96) years old. The most common primary site was the palate (30 patients, 43.5%). Stage IVA was the most common disease stage (36 patients, 52.2%). Radical therapy was performed in 55 patients (79.7%). The 2-year and 5-year OS rates of the 69 patients were 64.6% and 42.5%, respectively. The 2-year and 5-year OS rates of the stage III patients were 85.9% and 72.5%, respectively, and those of the stage IVA patients were 56.3% and 26.0%, respectively. The 1-year OS rate of the stage IVB/IVC patients was 26.7%. The 2-year and 5-year OS rates of the radical therapy group were 74.1% and 50.5%, respectively, whereas the 2-year OS rate of the non-radical therapy group was 26.0%. An advanced T classification was the only identified prognostic factor for OS (hazard ratio: 6.312, 95% confidence interval: 1.133-38.522, p < 0.05). CONCLUSIONS: Early detection and radical treatment are essential for improving the prognosis of oral MM patients. CLINICAL RELEVANCE: Early detection and adequate radical therapy leads to the better prognosis of oral MM patients.

General rules for clinical and pathological studies on oral cancer (2nd edition): a synopsis.

For doctors and other medical staff treating oral cancer, it is necessary to standardize the basic concepts and rules for oral cancer to achieve progress in its treatment, research, and diagnosis. Oral cancer is an integral part of head and neck cancer and is treated in accordance with the general rules for head and neck cancer. However, detailed rules based on the specific characteristics of oral cancer are essential. The objective of this article was to contribute to the development of the diagnosis, treatment, and research of oral cancer, based on the correct and useful medical information of clinical, surgical, pathological, and imaging findings accumulated from individual patients at various institutions. Our general rules were revised as the UICC was revised for the 8th edition and were published as the Japanese second edition in 2019. In this paper, the English edition of the "Rules" section is primarily presented.

Clinical significance of the G8 screening tool in elderly patients with oral squamous cell carcinoma.

OBJECTIVES: The present study investigated the clinical significance of the G8 screening tool in elderly oral squamous cell carcinoma (OSCC) patients using a multicenter analysis. MATERIALS AND METHODS: The medical records of 438 primary OSCC patients aged 75 years and older were retrospectively reviewed. To examine the clinical significance of the G8 screening tool in elderly OSCC patients, self-reliance (SR) rates and prognostic factors were statistically analyzed. RESULTS: The mean score of the G8 screening tool was 10.9 ± 2.93. The SR cut-off value of the G8 score was 9.5 in a receiver operating characteristic curve analysis. Five-year overall survival rates were 40.1% in patients with a G8 score < 9.5 and 58.4% in those with a G8 score ≥ 9.5 (p < 0.01). Five-year cancer-specific rates were 34.3% in patients with a G8 score < 9.5 and 55.7% in those with a G8 score ≥ 9.5 (p < 0.01). Five-year SR rates were 40.7% in patients with a G8 score < 9.5 and 55.3% in those with a G8 score ≥ 9.5 (p < 0.05). A multivariate analysis identified an advanced age (≥ 80 vs < 80; HR, 1.437; 95%CI, 1.181-1.843; p < 0.01), poorer ECOG-PS (2-4 vs 0-1; HR, 1.560; 95%CI, 1.14-2.106; p < 0.01), and standard treatment (non-standard therapy vs standard therapy; HR, 0.598; 95%CI, 0.405-0.910; p < 0.05) as significant independent prognostic factors for SR. A lower G8 score was associated with poorer SR (≥ 9.5 vs < 9.5; HR, 0.765; 95%CI, 0.575-1.034; p = 0.081). CONCLUSION: The clinical significance of the G8 score for elderly OSCC patients was demonstrated and its combination with ECOG-PS may be useful for assessing their prognoses.

A Multicenter Retrospective Study of Elective Neck Dissection for T1-2N0M0 Tongue Squamous Cell Carcinoma: Analysis Using Propensity Score-Matching.

BACKGROUND: This multicenter retrospective study aimed to determine whether elective neck dissection (END) can be performed for T1-2N0M0 tongue cancer. METHODS: Patients with T1-2N0M0 tongue squamous cell carcinoma who received treatment between January 2000 and December 2012 were enrolled at 14 multicenter study sites. The 5-year overall survival (OS) and 5-year disease-specific survival (DSS) were compared between the propensity score-matched END and observation (OBS) groups. RESULTS: The results showed that the OS rates among the 1234 enrolled patients were 85.5% in the END group and 90.2% in the OBS group (P = 0.182). The DSS rates were 87.0% in the END group and 94.3% in the OBS group (P = 0.003). Among the matched patients, the OS rates were 87.1% in the END group and 76.2% in the OBS group (P = 0.0051), and the respective DSS rates were 89.2% and 82.2% (P = 0.0335). CONCLUSION: This study showed that END is beneficial for T1-2N0M0 tongue cancer. However, END should be performed for patients with a tumor depth of 4-5 mm or more, which is the depth associated with a high rate of lymph node metastasis. The use of END should be carefully considered for both elderly and young patients.

Tumor budding and adjacent tissue at the invasive front correlate with delayed neck metastasis in clinical early-stage tongue squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: Some patients with early-stage oral cancer have a poor prognosis owing to the delayed neck metastasis (DNM). Tumor budding is reportedly a promising prognostic marker in many cancers. Moreover, the tissue surrounding a tumor is also considered to play a prognostic role. In this study, we evaluated whether tumor budding and adjacent tissue at the invasive front can be potential novel predictors of DNM in early tongue cancer. METHODS: In total, 337 patients with early-stage tongue squamous cell carcinoma were retrospectively reviewed. The patient characteristics and histopathological factors were evaluated for association with DNM. DNM rates were calculated; items which were significant in the univariate analysis were used as explanatory variables, and independent factors for DNM were identified by the multivariate analysis. RESULTS: The univariate analysis identified T classification, depth of invasion, tumor budding, vascular invasion, and adjacent tissue at the invasive front as significant predictors of DNM; the multivariate analysis using these factors revealed all the above variables except vascular invasion, which are independent predictors of DNM. CONCLUSION: In addition to conventional predictors, high grade tumor budding and adjacent tissue at the invasive front can serve as useful predictors of DNM in early tongue cancer.

Performance status scale for head and neck scores for oral cancer survivors: predictors and factors for improving quality of life.

OBJECTIVES: This study aimed to determine the factors associated with long-term quality of life of oral cancer survivors. MATERIALS AND METHODS: A total of 508 survivors were assessed using the performance status scale for head and neck (PSS-HN), which comprises Eating in Public (E-Public), Normalcy of Diet (N-Diet), and Understandability of Speech (U-Speech). Stepwise multiple linear regression analysis was performed. RESULTS: The median time between the end of treatment and participating in the survey was 38 months (range, 6-250). Overall, 57-60% of survivors achieved full performance (100 score) of each PSS-HN score, whereas 15% had moderate or severe impairment (≤ 50 score) in E-Public and N-Diet, and 4% had impairment in U-Speech. These three scores deteriorated with increasing T-stage. Age, soft tissue reconstruction, trismus, and missing occlusal contacts on the contralateral side were significantly associated with E-Public and N-Diet. Neck dissection, hard tissue reconstruction, and missing occlusal contacts bilaterally were associated with U-Speech score. CONCLUSION: Older age, T4 tumor, and soft tissue reconstruction were predictors of low E-Public and N-Diet performance scores. Increasing mouth opening and maintaining optimal occlusal contacts on the contralateral side may be effective ways to improve N-Diet and E-Public performance. Maintaining optimal occlusal contacts bilaterally may be effective for improving speech performance. CLINICAL RELEVANCE: Oral health care to increase optimal occlusal contacts and rehabilitation of trismus may be promising factors to improve the functional performance of oral cancer survivors.

Multi-center retrospective study of the prognosis and treatment outcomes of Japanese oral squamous cell carcinoma patients with single lymph node metastasis and extra nodal extension.

BACKGROUND: Oral squamous cell carcinoma (OSCC) containing single lymph node metastasis (pN1) with extra nodal extension (ENE) is a rare clinical situation. Therefore, it is unclear whether pN1 with ENE is at high risk of recurrence among the OSCC population, or whether postoperative radiotherapy (RT)/concomitant chemoradiotherapy (CCRT) is effective in these cases. OBJECTIVES: The purpose of this retrospective study was to investigate the prognosis and compare between no postoperative therapy and postoperative RT/CCRT in pN1 with ENE OSCC patients. METHODS: Clinicopathological data and treatment modalities were investigated. The evaluated endpoints were overall survival (OS) and type of recurrence. RESULTS: The 3-year cumulative OS rates for the pN1 only, multiple lymph node metastasis (MLM) only, ENE + MLM, and ENE + pN1 groups were 77.2%, 66.8%, 43.3%, and 66.6%, respectively. In the ENE + pN1 group, the most common cause of death in the surgery only group was from regional failure. The surgery + RT/CCRT group was associated with better disease-specific survival and OS rates than the surgery only groups (P < 0.05). CONCLUSIONS: The prognosis of ENE + pN1 was not as poor as that of ENE + MLM, although both these groups feature ENE. Adjuvant therapy (RT/CCRT) after surgery is recommend for cases of ENE + pN1.

Progression level of extracapsular spread and tumor budding for cervical lymph node metastasis of OSCC.

OBJECTIVES: The progression level of extracapsular spread (ECS) for cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) was previously divided into three types, and their relationships with the prognosis of patients were re-examined. PATIENTS AND METHODS: The Kaplan-Meier method was used to examine overall survival (OS) and relapse-free survival (RFS) curves. Prognosis factor for recurrence was analyzed with univariate and multivariate analysis. RESULTS: ECS was detected in 216 cases of OSCC and analyzed. The 5-year overall survival and RFS rates of patients with type C, which was microscopically defined as tumor invasion to perinodal fat or muscle tissue, were significantly poor at 40.6 and 37.8%, respectively. The results of a univariate analysis suggested that the prognosis of ECS in OSCC patients is associated with its progression level, particularly type C. The 5-year RFS rate of type C with tumor budding was significantly poor at 31.5%. Type C with tumor budding correlated with local and regional recurrence as well as distant metastasis. In a multivariate analysis, tumor budding was identified as an independent prognostic factor. CONCLUSIONS: These results suggest that the progression level of ECS and tumor budding are useful prognostic factors in OSCC patients. CLINICAL RELEVANCE: This study indicated that the progression level and tumor budding of ECS for cervical lymph node metastasis were useful prognostic factors in OSCC patients.

Significant prognostic factors affecting treatment outcomes of salivary gland carcinoma: a multicenter retrospective analysis.

The purpose of this study was to investigate the prognostic factor in salivary gland carcinoma patients. Clinical and pathological data of 211 consecutive patients who treated with curative intent were analyzed. The overall survival (OS) rate, local control rate, and distant metastasis rate were calculated. To examine a prognostic factor in salivary gland carcinoma patients, a multivariate analysis was performed. The 5-year-OS rate was 84.0%, and 10-year was 69.2%. The 5-year-local control rate was 84.6%, and 10-year was 70.1%. The 5-year-distant metastasis rate was 16.9%, and 10-year was 21.1%. In a multivariate analysis, the OS rate was affected by pN(+), high-grade malignancy, and primary tumor size. The local control was affected by the primary tumor size, high-grade malignancy, and the status of the surgical margin. The primary tumor size and pN(+) were associated with the distant metastasis. The results of this study suggested that pN(+), malignancy grade, primary tumor size, and the margin status might affect the prognosis of salivary gland carcinoma patients. Postoperative radiotherapy and adjuvant chemotherapy were suggested the possibility of contribution to the good prognosis of salivary gland carcinoma patients.

Clinical investigation of 38 cases of oral mucosal melanoma: A multicentre retrospective analysis in Japan.

BACKGROUND/OBJECTIVES: The aim of the present study was to investigate treatment modalities and outcomes in oral mucosal melanoma. METHODS: The clinical and pathological data of 38 consecutive patients with oral mucosal melanoma were retrospectively analyzed. Patients' characteristics were analyzed and overall survival (OS) rates were calculated. RESULTS: Sixteen patients had stage III (42%), 19 IVA (50%), and three had stage IVC (8%) disease. Among the therapeutic approaches used, 31 patients (82%) received radical therapy (surgery +/- chemotherapy). The 5-year OS rate was 40%. Five-year OS rates according to the clinical stage were 71% for stage III, 24% for stage IVA, and 0% for stage IVC. Five-year OS rates according to therapeutic approaches were 52% in the radical therapy group and 0% in the palliative therapy and best supportive care groups. CONCLUSIONS: The results of this multicentre retrospective analysis of patients with oral mucosal melanoma suggest that radical therapy based on surgical treatments with complete surgical excision with clear margins leads to a better prognosis.

Multicenter Retrospective Study of Adjuvant Therapy for Patients with Pathologically Lymph Node-Positive Oral Squamous Cell Carcinoma: Analysis of Covariance Using Propensity Score.

BACKGROUND: The presence of pathologically positive lymph nodes (pN+) is a well-known prognostic factor in oral squamous cell carcinoma (OSCC). The aims of this retrospective multicenter study were to assess the prognosis of OSCC patients with pN+ disease; to compare the prognosis of patients with pN+ disease who underwent surgery plus radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) with that of patients who underwent surgery only; and to account for biases associated with treatment selection of adjuvant RT or CCRT. METHODS: The records of 313 OSCC patients with pN+ disease were retrospectively reviewed. The main outcome measures were 5-year disease-specific survival (DSS) and overall survival (OS) rates. To reduce selection biases associated with retrospective data, the treatment groups were evaluated by Cox proportional hazard analysis with propensity score as a covariate. RESULTS: The 5-year OS and DSS survival rates for the entire patient cohort were 51.8 and 59.2 %, respectively. T3-4 stage, closed (<5 mm) margin distance, ≥4 involved nodes, and extracapsular spread were significant poor prognostic factors for OS and DSS. In the propensity score analysis, postoperative RT/CCRT significantly improved OS and DSS compared to surgery only. However, OS and DSS were not significantly different between patients who received postoperative RT and CCRT. CONCLUSION: The addition of cytotoxic chemotherapy to RT does not provide additional survival benefit in OSCC patients with pN+ disease. Alternative strategies, such as molecular targeted therapies, are needed to further improve the survival of high-risk OSCC patients with pN+ disease.

Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion.

Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein in the immunoglobulin superfamily, which plays an important role in cell adhesion and signal transduction. Although ICAM-1 is believed to play a role in several malignancies, it is still uncertain whether or not ICAM-1 expression contributes to cancer progression. In this study, we performed clinicopathological and cell biological analyses of ICAM-1 expression in oral squamous cell carcinoma (SCC). First, we examined the ICAM-1 expression in tongue SCC immunohistochemically, and revealed that ICAM-1 was expressed predominantly at the invasive front area of tongue SCC. ICAM-1 expression at the invasive front area was correlated with invasion, lymph node metastasis and increased blood and lymphatic vessel density of the tongue SCC. The relationship between ICAM-1 expression and clinicopathological factors were consistent with the increased proliferation, invasion and cytokine-production activities of ICAM-1-transfected SCC cells. Second, we analyzed the relationship between macrophages and ICAM-1-expressing tongue SCC cells because ICAM-1 is known to act as a ligand for adhesion of immune cells. Increased ICAM-1 expression in tongue SCC was correlated with increased macrophage infiltration within SCC nests. Moreover, macrophage/SCC-cell adhesion through ICAM-1 molecule was revealed using an in vitro cell adhesion and blockade assay. These findings indicate that ICAM-1 plays an important role in tongue SCC progression, which may result from the SCC-cell activity, angiogenic activity, lymphangiogenic activity and macrophage/SCC-cell adhesion.

Risk factors for distant metastasis in squamous cell carcinoma of the oral cavity.

PURPOSE: This study aimed to identify risk factors for distant metastasis (DM) in patients with squamous cell carcinoma of the oral cavity. MATERIALS AND METHODS: A retrospective analysis of 516 patients with squamous cell carcinoma of the oral cavity from 1986 through 2009 was performed. DM was classified as 2 types based on whether patients had locoregional failure (LRF). The frequency and clinicopathologic risk factors for the 2 types of DM were evaluated separately using univariate χ(2) tests and multivariate logistic regression models. Overall survival was evaluated with the Kaplan-Meier method and compared by the log-rank test. RESULTS: Fifty-four patients (10%) developed DM, 16 with isolated DM and 38 with DM with LRF. The 5-year survival rate from a DM diagnosis in patients with isolated DM was 13%, significantly higher than the rate of those with DM with LRF (0%; log-rank test, P < .05). Multivariate analysis indicated unique risk factors and common risk factors for the 2 types of DM. The common factors were nonsurgical treatment and the presence of pathologic positive nodes. The unique factors for isolated DM were histologic grade G3 and the later treatment period (after 1998). Conversely, the unique factor for DM with LRF was extracapsular spread. CONCLUSION: The risk of isolated DM development after 1998 was 2.6 times higher than that before 1997. Histologic grade G3 and the presence of pathologic positive nodes may play a causative role in isolated DM.

Multicenter retrospective study of the prognosis and the effect of postoperative adjuvant therapy in Japanese oral squamous cell carcinoma patients with close margin.

BACKGROUND: The purpose of this retrospective study was to investigate the prognosis of patients with oral cavity cancer with positive margin (PM) or close margin (CM) divided into pN- and pN+ groups. METHODS: The evaluated endpoints were local control and disease-specific survival (DSS) rates. RESULTS: Higher T classification, lymphovascular space invasion (LVSI), and older age were significant risk factors for DSS in the pN- groups. On the other hand, extranodal extension, multiple lymph node metastases, and LVSI were significant risk factors for DSS in the pN+ groups. Among the CM pN+ patients, no significant differences in the 3-year DSS were observed between the only surgery (51.9%) and adjuvant groups (53.2%). CONCLUSIONS: Higher T classification and LVSI are high-risk features more than PM or CM in the pN- groups for DSS. However, further prospective studies are needed to demonstrate the usefulness of adjuvant treatment in patients with PM or CM.

Comparison of the 8th edition of TNM staging of oral cancer with the 7th edition and its prognostic significance using clinical depth of invasion and extranodal extension.

OBJECTIVES: The 8th edition of the International Union Against Cancer Control/American Joint Committee on Cancer Staging System introduced depth of invasion (DOI) and extranodal extension (ENE) into the staging of oral cavity cancer. We evaluated the prognostic ability of this new staging system compared with the 7th edition using clinical DOI (cDOI) and clinical ENE (cENE). MATERIALS AND METHODS: We retrospectively reviewed and restaged 2,118 patients with oral squamous cell carcinoma treated between 2001 and 2018 using cDOI and cENE. Overall and disease-specific survival were used as endpoints to compare the prognostic outcomes of the 7th and 8th editions using Harrell's concordance index (C-index). RESULTS: In total, 305 (14.4 %) cases were upstaged in the T category, 85 (4.0 %) cases were upstaged in the N category, and 280 (13.2 %) cases were upstaged in the overall TNM stage. The introduction of the cDOI increased the C-index and hazard ratio (HR) for each T category. The introduction of cENE increased the N3b category of 85 cases, bringing the total to 94 cases, thereby widening the differences between each N category. In the 8th edition, the C-index and HR for overall TNM stage increased, and the discrimination between stage groups improved. CONCLUSIONS: The 8th edition of the TNM clinical staging system using cDOI and cENE predominantly identified patients with a high mortality rate, thus improving the ability to discriminate and prognosticate oral cancer.