Extranodal Extension and Epithelial Cell Adhesion Molecule Over-expression in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Concomitant chemoradiotherapy (CCRT) with cisplatin is commonly administered after neck dissection in patients with oral squamous cell carcinoma (OSCC) showing extranodal extension (ENE). This study investigated whether the efficacy of CCRT differed depending on the degree of ENE and whether the expression of epithelial cell adhesion molecule (EpCAM) was associated with prognosis. PATIENTS AND METHODS: Patients with OSCC who underwent neck dissection and had histologically proven neck metastasis (pN+) were investigated retrospectively. ENE was divided into ENE minor (ENEmi; <2 mm) and ENE major (ENEma; ≥2 mm). The expression of EpCAM was also immunohistochemically examined using tissues obtained during neck dissection. RESULTS: One hundred and seventy pN+ cases [ENE(-), n=89; ENEmi, n=23; ENEma, n=58] were included. Multivariate analysis revealed that advanced T stage and ENEma were significantly correlated with poor prognosis. The 5-year disease-specific survival rates in ENE(-), ENEmi, and ENEma groups were 73.7%, 75.5%, and 28.0% respectively. An add-on effect of postoperative CCRT was not seen in the ENEmi group; however, postoperative CCRT improved the survival of patients in the ENEma group. In the ENEma group, the prognosis was significantly worse in EpCAM-positive patients than in EpCAM-negative patients. CONCLUSION: Postoperative CCRT may improve prognosis in ENEma cases. EpCAM expression may be a poor prognostic factor in ENEma cases. On the other hand, postoperative CCRT did not have a significant effect on prognosis in ENEmi cases. Among them, although there was no significant difference in the survival rate, postoperative CCRT could be omitted in ENEmi/EpCAM(-) cases.

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.

Complete response of recurrent oral squamous cell carcinoma treated with cetuximab in combination with radiotherapy: A case series.

Salvage surgery for recurrent oral squamous cell carcinoma (OSCC) often leads to a poor quality of life (QOL). The present study described three cases that resulted in favorable locoregional control with cetuximab in combination with radiotherapy (Cmab + RT). Case 1 had regional recurrence of OSCC at the lower right mastoid area 4 months after primary surgery. Case 2 had regional recurrence of OSCC at the parotid area 7 months after primary surgery. Case 3 had local recurrence of OSCC at the masticatory muscle and Rouviere's lymph nodes 1 year and 3 months after primary surgery. In all cases, Cmab + RT was performed, and disease-free survival was confirmed 4 months, 2 years and 6 months, and 10 months after Cmab + RT, respectively. Immunohistochemically, all resected tumors had no expression of 110-kDa catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3Kp110α). In conclusion, if salvage surgery for recurrent OSCC results in a significantly low QOL, then shifting to chemoradiotherapy may be appropriate as a treatment strategy. In addition, strong evidence indicated that PI3Kp110α expression is associated with Cmab therapy efficacy.

Clinicopathological and Prognostic Analysis of PD-L1 and PD-L2 Expression in Surgically Resected Primary Tongue Squamous Cell Carcinoma.

BACKGROUND/AIM: The expression of tumor-associated programmed death-ligand 1 (PD-L1) predicts clinical responses to PD-1-directed immunotherapy. The expression levels of PD-L2, another PD-1 ligand, and its relationship with responses to PD-1-targeting therapy in oral squamous cell carcinoma (OSCC) remain unclear. Furthermore, the clinicopathological characteristics and prognostic effects of the expression of PD-L1 and PD-L2 in OSCC have not yet been elucidated. MATERIALS AND METHODS: The expression of PD-L1 and PD-L2 was immunohistochemically examined in 98 tongue carcinomas. Furthermore, the expression levels of PD-L1 and PD-L2 in OSCC cell lines and their relationships with those of MMP2 and MMP9 were assessed. RESULTS: The expression levels of PD-L1 and PD-L2 correlated with those of MMP2 and MMP9. The expression of PD-L1 and/or PD-L2 was detected in OSCC cells, and their levels correlated with those of MMP9. The prognosis of patients with PD-L1- and PD-L2-positive tumors was significantly worse. CONCLUSION: PD-L1 and PD-L2 status is potentially a novel predictor of the prognosis of OSCC and provides a rationale for the development of novel immunotherapies.

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab­resistant oral squamous cell carcinoma.

High expression of the 110 kDa catalytic subunit of the class IA PI3K (PI3Kp110α) may play an important role in cetuximab resistance exhibited by both colorectal cancer and head and neck squamous cell carcinoma. Therefore, the present study aimed to examine the association between the expression of proteins in the PI3Kp110α pathway and cetuximab resistance, and the antitumor effects of alpelisib (PI3K inhibitor) and cetuximab in oral squamous cell carcinoma (OSCC) cells. The association between PI3Kp110α protein expression levels and the tumor response to cetuximab was determined using immunohistochemistry. OSCC cells were treated with alpelisib, cetuximab, or in combination, and the effects were examined in vitro and in vivo. PI3Kp110α protein expression was significantly associated with the tumor response to cetuximab (P<0.05) and 1­year progression­free survival and overall survival (P<0.05). Combined treatment of alpelisib and cetuximab resulted in enhanced antitumor effects in vitro compared with either agent administered alone. In particular, the expression level of N­cadherin, an epithelial­mesenchymal transition­related protein, was decreased, suggesting that the invasion potential of cetuximab­resistant cells decreased. Furthermore, the expression of proteins in the PI3K pathway were decreased in tumors from mice with OSCC xenografts treated with alpelisib and cetuximab in combination. These results indicate that novel regimens of systemic therapy (such as chemotherapy), with combinations of cetuximab and alpelisib, may be beneficial for patients with cetuximab­resistant OSCC.

Anterior relapse or posterior drift after intraoral vertical ramus osteotomy.

This study aimed to evaluate the factors contributing to postoperative anterior relapse or posterior drift of the distal segment after intraoral vertical ramus osteotomy. A retrospective cohort study was conducted which included 31 patients who underwent setback surgery for mandibular prognathism by the intraoral vertical ramus osteotomy technique. Uni- and multivariate analyses were performed to determine the association of potential explanatory variables (sex, age, magnitude of setback, differences in setback magnitude between sides (right/left), duration of splint use, Angle's classification of malocclusion, mandibular angle, and tightness of occlusion of the molars) with positional changes in the distal segment. The setback magnitude was only significant factor affecting (P = 0.015) for posterior drift, with significant posterior in setback magnitudes of less than 7.25 mm. Posterior drift after intraoral vertical ramus osteotomy is less likely if setback magnitude exceeds 7.25 mm. For setbacks less than 7.25 mm, posterior drift should either be carefully corrected postoperatively, or an alternative surgical technique should be used. The setback magnitude showed a significant association with the risk of posterior drift following intraoral vertical ramus osteotomy, and the determined cut-off value may serve as a predictor for postoperative outcomes.

Immunohistochemical Study of PD-1/PD-L1 Axis Expression in Oral Tongue Squamous Cell Carcinomas: Effect of Neoadjuvant Chemotherapy on Local Recurrence.

While neoadjuvant chemotherapy (NAC) for patients with oral tongue squamous cell carcinoma (OTSCC) may improve tumor microenvironment, it may lead to local immune suppression caused by residual cancer cells. The efficacy of NAC is therefore controversial. In our study, we investigated tumor microenvironments after NAC using immune checkpoint molecules, and evaluated the association between tumor microenvironments, clinicopathological factors and outcomes. We reviewed the records of 121 patients who underwent radical surgery for OTSCC between April 2001 and March 2015. Patients with a positive surgical margin and a follow up period of less than 6 months were excluded. For these patients, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) expressions were immunohistochemically examined. The expression of PD-1 and PD-L1 were significantly associated with local recurrence in patients with OTSCC (P < 0.01 and P < 0.01, respectively). We found a significant decrease in 5-year disease specific survival rate for patients with combined PD-1+/PD-L1+ expressions (P < 0.05). In the subgroup analysis of local recurrence between the NAC treated group and those who received surgery alone, high levels of PD-1 and PD-L1 expressions were significantly found in the former, but not in the latter group. Local recurrence in the NAC-treated group may contribute to local immune suppression in OTSCC. NAC lead to local immune suppression and immune checkpoint molecules play an important role in local recurrence in patients with OTSCC who received NAC. NAC modality can't be recommended for patients with OTSCC at present.

Undifferentiated carcinoma of the oral tongue treated with cetuximab: A case report.

Undifferentiated carcinoma of the oral cavity is a rare and possibly fatal malignant neoplasm. We present here a case of undifferentiated carcinoma of the oral tongue, which responded well to chemotherapy with cisplatin, 5-fluorouracil, and cetuximab. A 59-year-old man was referred to our hospital for a large tumor of the tongue. Physical examination revealed an ulcerative tumor, approximately 50 mm in diameter, on the right edge of the tongue and swelling of multiple cervical lymph nodes; therefore, the clinical diagnosis was tongue cancer (T4aN2bM0). The histological diagnosis from a biopsy specimen was undifferentiated carcinoma; we tested the sample for human papilloma virus immunoreactivity, which was positive. The patient then underwent chemotherapy with cisplatin, 5-fluorouracil and cetuximab. The tumor's size decreased markedly after two courses of chemotherapy, but the treatment was stopped due to the patient' various mental problems and pneumonia; he died 6 months after the initial visit. Our encounter with this patient suggests that cetuximab treatment is a good option for HPV-positive undifferentiated carcinoma of the oral tongue.

The Effect of Improving Oral Hygiene through Professional Oral Care to Reduce the Incidence of Pneumonia Post-esophagectomy in Esophageal Cancer.

Radical esophagectomy for thoracic esophageal cancer is invasive and frequently results in postoperative pulmonary complications. Postoperative pneumonia is the most common such complication and affects hospital mortality and survival rates. Oral care has been very effective in reducing pneumonia. In Japan, preoperative professional oral care is highly recommended. However, there are few studies on the effect of preoperative improvements in oral hygiene as a result of intervention on the incidence of postoperative pneumonia. The primary end-point of this retrospective study was the incidence of postoperative pneumonia after radical esophagectomy. The oral health levels of 46 patients were individually categorized, and then patients were grouped according to whether they maintained or improved their oral hygiene. At the first dental examination, oral health levels were classified as good in 22 patients and bad in 24. Of the 46 patients studied, 39 patients maintained or improved their oral hygiene (good control group), whereas 7 showed no improvement (bad control group). Postoperative pneumonia occurred in eight patients: four in the good control group and four in the bad control group. Statistical analysis with postoperative pneumonia as a dependent variable showed a significant effect of oral hygiene improvement on the incidence of pneumonia. Logistic regression analysis with this factor as an independent variable demonstrated that the risk of postoperative pneumonia was reduced in the good control group (OR 0.086, 95% CI 0.014-0.529). Therefore, preoperative professional oral care may improve oral hygiene and oral health, which may in turn reduce the incidence of postoperative pneumonia.

Prognostic Significance of Pretreatment Lymphocyte-to-Monocyte Ratio in Patients with Tongue Cancer.

BACKGROUND/AIM: Low pre-operative lymphocyte-to-monocyte ratio (LMR) is associated with worse outcomes in several malignancies. The aim of this study was to determine the prognostic value of LMR in tongue cancer. MATERIALS AND METHODS: A total of 103 patients with pathologically-proven tongue cancer were retrospectively analyzed. The peripheral LMR and the ratio of CD8-positive to CD14-positive (CD8+/CD14+) tumor-infiltrating cells were determined by immunohistochemical staining. Receiver operating characteristic curve analysis, log-rank test, and Cox proportional hazards regression models were used for statistical analysis. RESULTS: There was a significant difference in overall survival (OS) between low LMR and high LMR, and low CD8+/CD14+ tumor-infiltrating cells and high CD8+/CD14+ tumor infiltrating cells. For the clinical analysis, multivariate analysis showed that clinical ocular inspection type and low LMR were independent predictors for poor OS. Concerning the immunohistochemical analysis, monocyte count was independent predictor of poor OS. CONCLUSION: Pre-operative LMR and CD8+/CD14+ tumor-infiltrating cells serve as independent prognostic biomarkers.

Clinical Study of Reconstruction Plates Used in the Surgery for Mandibular Discontinuity Defect.

BACKGROUND/AIM: Postresective mandibular reconstruction is common in cases of oral and mandibular tumors. However, complications such as plate fracture and/or plate exposure can occur. The purpose of this study was to analyze complications and survival of reconstructive plates used to correct mandibular defects caused by oral cancer. PATIENTS AND METHODS: Clinical and radiological data from 34 patients were analyzed. Only discontinuous mandibular defect cases were included in this study. All cases were classified using the Hashikawa's CAT and Eichner's classification methods. Then, we determined whether these classifications and clinical treatment methods were significantly related to complications. RESULTS: Complications after mandibular reconstruction occurred in 10 of 34 patients, specifically, two plate fractures, one screw fracture, and seven plate exposures occurred. The plate fractures occurred 5 and 6 months after operation, and the screw fracture occurred 39 months after operation. Using the Hashikawa's CAT classification, the two cases of plate fracture were one of AT type and the other of T type, and the screw fracture was AT type. Using Eichner's classification, all three cases of plate and screw fractures were B2 type. CONCLUSION: We suggest that plate and screw fractures were caused by the type of mandibular defect and bite force.

mTORC1 and mTORC2 Expression Levels in Oral Squamous Cell Carcinoma: An Immunohistochemical and Clinicopathological Study.

BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays a critical role in the regulation of tumor cell motility, invasion and cancer cell metastasis. mTOR consists of two separate multi-protein complexes, mTOR complex (mTORC) 1 and mTORC2. MATERIALS AND METHODS: We investigated the expression levels of mTORC1 and mTORC2 immunohistochemically in oral squamous cell carcinoma (OSCC). RESULTS: mTORC1 and mTORC2 were more highly expressed in tumors than in normal oral mucosa. mTORC1 expression was correlated with T classification, N classification, and survival rate (p<0.05), whereas mTORC2 expression was only correlated with T classification (p<0.05). Histologically, the expression levels of mTORC1 and mTORC2 correlated with cancer cell invasion and the expression of proliferating cell nuclear antigen (p<0.05), respectively. Expression levels of vascular endothelial growth factors and hypoxia-inducible factor 1 in the mTORC1 (-)/ mTORC2 (+) group were significantly lower than those in other groups. CONCLUSION: These findings suggested that mTORC1 and mTORC2 could be promising anti-tumor targets in OSCC, and mTORC1 (-)/mTORC2 (+) may have a correlation with the malignant potential of OSCC.

Intraoral extraction of an ectopic mandibular third molar detected in the subcondylar region without a pathological cause: A case report and literature review.

PURPOSE: To present a case report on the presence of an ectopic mandibular third molar (EMTM), the surgical treatment, and outcome. CASE REPORT: A 63-year-old woman presented with right preauricular facial swelling, limited jaw function, and pain. Radiographic assessment demonstrated an EMTM positioned in the superoposterior aspect of the ramus. Radiographically, there was a bony tunnel extending from the third molar to distal of the second molar. The patient was treated by an intraoral approach on the medial aspect of the ramus for removal of the ectopic third molar, as well as the tissue in the bony tunnel. RESULTS: The patient healed uneventfully. The soft tissue in the bony canal was granulation tissue, and nerve function was preserved. A literature search of EMTMs was conducted identifying 17 reported cases. CONCLUSION: Three-dimensional imaging in the management of EMTM can be beneficial in identifying position of the tooth, associated pathology, and identifying the position of neurovascular structures to aid in removal of the ectopic tooth.