Kazunari Oobu

Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma

Recent studies have revealed that cancer cells are exacerbated by chronic inflammation. The present study examined the immunohistochemical expression for interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, in oral squamous cell carcinoma (OSCC) to elucidate the association of IL-6 expression with tumor progression, chemoresistance and prognosis. Seventy-eight patients with primary OSCC were analyzed by immunohistochemical staining for IL-6. These labeling indexes (LIs) were calculated and evaluated in association with the clinicopathologic characteristics and prognosis in the OSCC patients. The patients were divided into three groups as follows: negative group = LI <5%; low IL-6 group = 5% ≤ LI <30%; high IL-6 group = LI ≥30%. The patient numbers of the negative, low and high expression groups were 24, 22 and 32, respectively. In the high IL-6 expression group, IL-6 receptor (IL-6R), phospho-signal tranducer and activator of transcription 3 (p-STAT3) were also detected in almost all the cancer cells. The prevalence of the cervical lymph node or the distant metastasis in the high expression group was significantly higher than those in the negative and low expression groups. Furthermore, the high expression group had a significantly poorer tumor response to the preoperative chemoradiotherapy and a more unfavourable prognosis than the negative and the low expression groups. Interestingly, IL-6, IL-6R and p-STAT3 were expressed in the residual cancer cells of all the patients in the high expression group with poor response to chemoradiotherapy. These results suggested that IL-6 signaling possibly is involved in the progression and treatment-resistance of OSCC and IL-6 expression in cancer cells could be a useful predictive factor of poor response to chemoradiotherapy and unfavorable prognosis.

Clinical Significance of Combined Assessment of the Maximum Standardized Uptake Value of F-18 FDG PET with Nodal Size in the Diagnosis of Cervical Lymph Node Metastasis of Oral Squamous Cell Carcinoma

RATIONALE AND OBJECTIVES This study aimed to elucidate the diagnostic accuracy of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for nodal involvement in oral squamous cell carcinoma (OSCC), and to reveal clinically useful factors to distinguish between true-positive (TP) and false-positive (FP) nodes. MATERIALS AND METHODS Thirty-eight patients with primary OSCC who underwent neck dissection were assessed. The diagnostic accuracy of F-18 FDG PET/CT was evaluated, and then compared with that of CT/ultrasonography (US). Furthermore, the association of the maximum standardized uptake value (SUVmax) and nodal size with the histopathologic findings was examined. RESULTS Sensitivity and specificity using F-18 FDG PET/CT were 77.1% and 97.3%, and those using CT/US were 72.9% and 98.9%, respectively. The SUVmax of TP nodes was significantly higher than that of FP nodes. Nodes with SUVmax >4.5 were pathologically confirmed as metastasis. Nodes with SUVmax ≤4.5 were further discriminated between TP and FP nodes by using the long axis diameters or the ratios of long to short axis diameter as clinical parameters. Positive correlation between the SUVmax and the short-axis diameter was found in TP nodes. The AUC obtained from the ROC curves of the SUVmax alone (AUC, 0.804) was improved by combination with the long-axis diameter (AUC, 0.867) or the short-axis diameter (AUC, 0.846), although no significant difference was found. CONCLUSIONS These results indicated that F-18 FDG PET/CT was potentially useful in diagnosing preoperative nodal state. Furthermore, combined assessment of SUVmax with nodal size could be significant in the identification of metastatic lymph nodes in OSCC patients.

Imaging findings of neurogenic tumours in the head and neck region

OBJECTIVE The aim of this study was to describe the CT, MRI and ultrasonography findings of five cases of neurogenic tumours in the head and neck region. METHODS Five neurogenic tumours were analysed with respect to their CT value, the presence of cystic change, target sign, lobulation, connection to the nerve and vascularity. RESULTS The contrast-enhanced CT (ECT) of the schwannomas demonstrated either a mass with low enhancement (two out of three cases), which reflected the predominant Antoni B components, or a mass with cystic changes, which was an Antoni A-based schwannoma displaying cystic changes (one out of three cases). On MRI, all tumours showed homogeneous and isointense signals for muscle on T₁ weighted images (T₁ WIs). T₂ weighted images (T₂ WIs) and gadolinium (Gd)-enhanced T₁ WIs demonstrated target sign in both schwannomas. Ultrasound examination showed a well-defined, ovoid or round hypoechoic mass. The direct connection to the nerve was demonstrated in two of the five cases. Lobulation was observed in only one of the five cases and cystic changes were observed in one of the five cases. In all of the cases, no vascularity was seen in power Doppler images (PDIs) obtained percutaneously. CONCLUSIONS Low-enhanced areas on ECTs can be specific for schwannomas, which suggests the predominance of Antoni B components. The target sign on T₂ WIs and Gd-enhanced T₁ WIs can be specific, which can be used to differentiate the two different components (Antoni A and Antoni B). The direct connection to the nerve can be a specific finding for neurogenic tumours; however, at present the sensitivity is 40%.

Acute gingival necrosis caused by drug-induced agranulocytosis

A case of acute gingival necrosis, which was caused by drug-induced agranulocytosis, is reported. The patient had classic signs and symptoms, and the treatment of oral lesions was symptomatic. Regeneration of the gingival mucosa was almost complete 20 days after the onset of the disease.

Possible involvement of ΔNp63 downregulation in the invasion and metastasis of oral squamous cell carcinoma via induction of a mesenchymal phenotype

Epithelial-to-mesenchymal transition (EMT), an essential developmental program, is involved in tumor progression. ΔNp63, a homolog of p53, is associated with the EMT program, but the detailed mechanism remains to be elucidated. In this study, we investigated the role of ΔNp63 in EMT during progression of oral squamous cell carcinoma (OSCC). Five OSCC cell lines and specimens from 78 patients with OSCC were used. The expressions of ΔNp63, p63α, p63β and epithelial markers (cytokeratins 5 and 14) was detected in the OSCC cells, but not in SQUU-B cells (high metastatic potential). E-cadherin was expressed in all OSCC cells. Mesenchymal markers were strongly expressed in the SQUU-B cells. Knockdown of endogenous ΔNp63 in HSC-2 cells induced morphological changes to the spindle shape, decreased the expression of epithelial markers, increased the expression of mesenchymal markers, increased migration and reduced proliferation. By contrast, SQUU-B cells overexpressing ΔNp63β showed changed their morphology from stromal cell-like to epithelial cells. However, E-cadherin expression was not affected by ΔNp63 knockdown or overexpression. Immunohistochemical staining revealed that cancer cells expressing vimentin were found at the invasive front in the OSCC specimens. The intensity of ΔNp63 expression was also decreased in these cells. Interestingly, the vimentin positivity or decreased intensity of ΔNp63 was positively associated with metastases and poor prognosis in the OSCC patients. These results indicated that ΔNp63 downregulation in cancer cells induces a mesenchymal phenotype that is related to tumor progression of OSCC.

Significant association of increased PD-L1 and PD-1 expression with nodal metastasis and a poor prognosis in oral squamous cell carcinoma

Programmed cell death ligand 1 (PD-L1) and its receptor PD-1 are immune checkpoint molecules that attenuate the immune response. Blockade of PD-L1 enhances the immune response in a variety of tumours and thus serves as an effective anti-cancer treatment. However, the biological and prognostic roles of PD-L1/PD-1 signalling in oral squamous cell carcinoma (OSCC) remain to be elucidated. The purpose of this study was to examine the correlation of PD-L1/PD-1 signalling with the prognosis of OSCC patients to assess its potential therapeutic relevance. The expression of PD-L1 and of PD-1 was determined immunohistochemically in 97 patients with OSCC and the association of this expression with clinicopathological characteristics was examined. Increased expression of PD-L1 was found in 64.9% of OSCC cases and increased expression of PD-1 was found in 61.9%. Univariate and multivariate analysis revealed that increased expression of PD-L1 and PD-1 positively correlated with cervical lymph node metastasis. The expression of CD25, an activated T-cell marker, was negatively correlated with the labelling index of PD-L1 and PD-1. Moreover, the patient group with PD-L1-positive and PD-1-positive expression showed a more unfavourable prognosis than the group with PD-L1-negative and PD-1-negative expression. These data suggest that increased PD-L1 and PD-1 expression is predictive of nodal metastasis and a poor prognosis and is possibly involved in cancer progression via attenuating the immune response.

Secondary Squamous Cell Carcinoma of the Oral Cavity in Young Adults after Hematopoietic Stem Cell Transplantation for Leukemia: Report of Two Cases with Human Papillomavirus Infection

Abstract Two cases of secondary oral squamous cell carcinoma (SCC), which developed in recipients of hematopoietic stem cell transplantation (HSCT) for leukemia, are reported. The first patient underwent allogeneic HSCT for chronic myelogenous leukemia at 32 years of age. He suffered from chronic graft-versus-host-disease (GVHD) of the oral mucosa after HSCT, and has subsequently received immunosuppressive therapy. He experienced metachronous multiple SCCs in the maxillary gingiva and the dorsum of the tongue at 36 years and 40 years of age, respectively. The second patient received autologous HSCT for acute myelogenous leukemia at 22 years of age, and she did not experience GVHD after transplantation. SCC developed in the lateral border of the tongue at 27 years of age. PCR analysis detected both HPV16 and HPV18 in the tongue tumor of the first patient, and only HPV18 in that of the second patient, suggesting that the infection of highrisk HPVs was possibly involved in the development of post-HSCT oral cancers in these patients. Since risk factors for post-HSCT oral SCC are not yet well recognized, long-term close follow-up is necessary for the early detection of secondary oral cancers in all transplant recipients.

Oral methotrexate-related lymphoproliferative disease presenting with severe osteonecrosis of the Jaw: A case report and literature review

Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control.

Cytokeratin 17 mRNA as a prognostic marker of oral squamous cell carcinoma

Despite diagnostic and therapeutic advances, the 5-year survival rate of oral squamous cell carcinoma (OSCC) remains between 70–80% due to recurrences and secondary metastases to cervical lymph nodes. It is difficult to find these recurrences and metastases postoperatively, thus, careful follow-up is recommended. Cytokeratins (CKs) are intermediate filaments of the cytoskeleton and candidate prognostic biomarkers for OSCC, as they are overexpressed in OSCC compared with normal mucosa. The aim of the present study was to determine the relative levels of occurrence of 3 CK mRNA (CK17, CK19, CK20) transcripts in peripheral blood mononuclear cells (PBMC) using reverse transcription-quantitative polymerase chain reaction. The study comprised pre- and post-operative PBMC samples from 19 OSCC patients. In the good-prognosis group, 10 of 13 patients demonstrated reduced CK17 mRNA expression post-operatively, compared with pre-operative samples, conversely, only 3 of 6 patients in the poor-prognosis group had reduced post-operative CK17 mRNA expression. This difference was statistically significant (P<0.01). The disease-free survival rate of the group with reduced post-operative CK17 mRNA expression was significantly increased compared with the elevated CK17 mRNA group (P<0.01); however, the overall survival rates of the two groups were not significantly different. Neither CK19 mRNA nor CK20 mRNA were significantly expressed in the PBMC of OSCC patients. Overall, CK17 mRNA expression may be a useful prognostic biomarker for OSCC.