Stiffness as measured with strain elastography is a prognostic factor for pT1/T2 tongue squamous cell carcinoma with muscle-layer invasion.

OBJECTIVE: The objective was to evaluate stiffness as a prognostic factor for tongue squamous cell carcinoma (TSCC). STUDY DESIGN: This retrospective study included 55 patients with pathologic stage pT1 or T2 TSCC with muscle-layer invasion who underwent preoperative strain elastography of the tongue, followed by surgery, as the primary treatment modality at our cancer center. The stiffness of TSCC was semi-quantified as the ratio of the strain value of a non-tumor site to the strain value of the tumor site (strain ratio [SR]) using ultrasound strain elastography findings. RESULTS: SR cutoff values that maximized the significance of the difference for prognosis of delayed cervical lymph node metastasis (DCLNM) and overall survival (OS) were 7.10 and 7.49, respectively. In univariate analysis, SR, age, depth of invasion, pT stage, and perineural invasion were significant risk factors for DCLNM, whereas SR, sex, and DCLNM were identified as having an association with OS. In multivariate analysis, SR was a significant risk factor for DCLNM (hazard ratio [HR] = 3.102; P = .021) and a non-significant but relevant risk factor for OS (HR = 8.774; P = .073). Age also had an association with OS (HR = 0.382; 95% CI 0.127-1.152; P = .088). CONCLUSION: Tongue stiffness is a prognostic factor in patients with pT1/T2 TSCC with muscle-layer invasion. SR values >7.10 indicate a poor prognosis, thereby warranting a strict follow-up regimen in these cases.

Stiffness of tongue squamous cell carcinoma measured using strain elastography correlates with the amount of collagen fibers in the tumor.

OBJECTIVES: To evaluate the stiffness of tongue squamous cell carcinoma (TSCC) using ultrasound strain elastography, a relatively new sonographic imaging technique, and to identify the factors that affect this stiffness. METHODS: We treated 62 patients diagnosed with muscle invasive TSCC, who were treated at the department of oral surgery of our institution. Each patient's tumor stiffness was semi-quantified according to the ratio of cancer to tongue muscle strain measured using ultrasound strain elastography (the strain ratio). Histopathological diagnosis was made on the same section as the ultrasound strain elastography. We set the following histopathological parameters: cancer cell content in the tumor area (%CCC), collagen fiber content in the tumor area (%CFC), and tumor-infiltrating inflammatory cell content in the stromal compartment (%TIIC). Spearman's rank correlation (rs) was used to assess correlations, and P values < 0.05 were considered significant. RESULTS: The mean strain ratio was 9.7 ± 9.8. The mean %CCC was 38.4 ± 11.3%, and % CFC was 31.1 ± 7.8%, % TIICs was 19.9 ± 8.9%. Log (strain ratio) by ultrasound strain elastography was positively correlated with %CFC (rs = 0.379, P = 0.024). %CFC was negatively correlated with %TIICs (rs = - 0.318, P = 0.012). No correlations were observed between other clinico-histopathological factors and either strain ratio, or %CFC. CONCLUSION: The strain ratio of the cancer to the strain of the tongue muscle measured through ultrasound strain elastography positively correlates with the collagen fiber content of the tumor area.

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.

Minimal essential region for krüppel-like factor 5 expression and the regulation by specificity protein 3-GC box binding.

Krüppel-like factor 5 (KLF5) transcriptionally controls the proliferation-differentiation balance of epithelium and is overexpressed in carcinomas. Although genomic region modifying KLF5 expression is widespread in different types of cells, the region that commonly regulates basal expression of the genes across cell-types is uncertain. In this study we determined the minimal essential region for the expression and its regulatory transcription factors using oral carcinoma cells. A reporter assay defined a 186bp region downstream of the transcription start site and a cluster of six GC boxes (GC1-GC6) as the minimal essential region. Mutation in the GC1 or GC6 regions but not other GC boxes significantly decreased the reporter expression. The decrease by the GC1 mutation was reproduced in the 2kbp full-length promoter, but not by the GC6 mutation. Additionally, specificity proteins (Sp) that can be expressed in epithelial cells and bind GC box, Sp3 co-localized with KLF5 in oral epithelium and carcinomas and chromatin immunoprecipitation analyses showed Sp3 as the prime GC1-binding protein. Inhibition of Sp-GC box binding by mithramycin A and knockdown of Sp3 by the short interfering RNA decreased expression of the reporter gene and endogenous KLF5. These data demonstrate that a 186bp region is the minimal essential region and that Sp3-GC1 binding is essential to the basal expression of KLF5.

The onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus: a case report.

Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.

Disordered arrangements of basal cells as a prognostic factor for oral epithelial dysplasia: a morphometric study of 96 cases.

OBJECTIVE: The aim of this study was to assess objectively the predictive value of the atypical appearance of the basal layer of oral epithelial dysplasia (OED) for development into invasive carcinoma. STUDY DESIGN: Ninety-six OED cases were examined. These cases were divided into 2 groups: 38 cases that developed into invasive carcinoma and 58 cases that did not. Furthermore, 12 histopathological factors were quantified morphometrically in each case and assessed by Cox's proportional hazards model. RESULTS: The standard deviation of the length between the apical membrane of the basal cells and the basement membrane was significantly associated with development of OED into invasive carcinoma (P < .001; hazard ratio, 3.124). CONCLUSION: We provided novel, objective data demonstrating that an atypical appearance, especially the disordered arrangement of the basal cells representing loss of polarity, may be useful for predicting the development of OED into invasive carcinoma of the tongue.

Three-dimensional reconstruction of oral tongue squamous cell carcinoma at invasion front.

We conducted three-dimensional (3D) reconstruction of oral tongue squamous cell carcinoma (OTSCC) using serial histological sections to visualize the architecture of invasive tumors. Fourteen OTSCC cases were collected from archival paraffin-embedded specimens. Based on a pathodiagnostic survey of whole cancer lesions, a core tissue specimen (3 mm in diameter) was dissected out from the deep invasion front using a paraffin tissue microarray. Serial sections (4 µ m thick) were double immunostained with pan-cytokeratin and Ki67 antibodies and digitized images were acquired using virtual microscopy. For 3D reconstruction, image registration and RGB color segmentation were automated using ImageJ software to avoid operator-dependent subjective errors. Based on the 3D tumor architecture, we classified the mode of invasion into four types: pushing and bulky architecture; trabecular architecture; diffuse spreading; and special forms. Direct visualization and quantitative assessment of the parenchymal-stromal border provide a new dimension in our understanding of OTSCC architecture. These 3D morphometric analyses also ascertained that cell invasion (individually and collectively) occurs at the deep invasive front of the OTSCC. These results demonstrate the advantages of histology-based 3D reconstruction for evaluating tumor architecture and its potential for a wide range of applications.

Proteomic identification of keratin alterations with enhanced proliferation of oral carcinoma cells by loss of mucosa-associated lymphoid tissue 1 expression.

Progression of oral carcinomas associates with aberrant activation and inactivation of molecules that work in established or unknown pathways. Although mucosa­associated lymphoid tissue 1 (MALT1) expressed in normal oral epithelium is inactivated in the aggressive subset of carcinomas with worse prognosis, phenotypic changes of carcinoma cells upon the loss of expression is unknown. We performed a proteomic analysis to identify MALT1­regulated proteins in oral carcinoma cells. Four different keratins were included in the ten most abundantly changed proteins. K8/18 were upregulated in MALT1 stably­expressing carcinoma cells and K5/14 in MALT1­marginal control cells. K8/18 upregulation and K5/14 downregulation were MALT1 dose­dependent and observed in a series of oral carcinoma cells. MALT1 suppressed cell proliferation (0.52-fold, P<0.01) and its dominant-negative form stimulated it (1.33-fold, P<0.01). The decreased proliferation associated with reduction of cyclin D1, which was recovered by the short interfering RNA against MALT1. Taken together, loss of MALT1 expression alters keratin expression and enhances proliferation of carcinoma cells, and may progress oral carcinomas into the advanced state.

General rules for clinical and pathological studies on oral cancer: a synopsis.

For the doctors and other medical staff treating oral cancers, it is necessary to standardize basic concepts and rules on oral cancers to progress in the treatment, research and diagnosis. Oral cancers are integrated in head and neck cancers and are applied to the general rules on head and neck cancer, but it is considered that more detailed rules based on the characteristics of oral cancers are essential. The objectives of this 'General Rules for Clinical and Pathological Studies on Oral Cancer' are to contribute to the development of the diagnosis, treatment and research of oral cancers based on the correct and useful medical information of clinical, surgical, pathological and image findings accumulated from individual patients at various institutions.

Contribution of sialic acid-binding adhesin to pathogenesis of experimental endocarditis caused by Streptococcus gordonii DL1.

An insertional mutation in hsa, the gene encoding the sialic acid-binding adhesin of Streptococcus gordonii DL1, resulted in a significant reduction of the infection rate of the organism and an inflammatory reaction in the rat aortic valve with experimental endocarditis, suggesting that the adhesin contributes to the infectivity of the organism for heart valves.

Molecular mechanism for connective tissue destruction by dipeptidyl aminopeptidase IV produced by the periodontal pathogen Porphyromonas gingivalis.

Porphyromonas gingivalis is a pathogen associated with adult periodontitis. It produces dipeptidyl aminopeptidase IV (DPPIV), which may act as a virulence factor by contributing to the degradation of connective tissue. We investigated the molecular mechanism by which DPPIV contributes to the destruction of connective tissue. DPPIV itself did not show gelatinase or collagenase activity toward human type I collagen, but it promoted the activity of the host-derived matrix metalloproteinase 2 (MMP-2) (gelatinase) and MMP-1 (collagenase). DPPIV bound to fibronectin and mediated the adhesion of P. gingivalis to fibronectin. Mutant DPPIV with catalytic Ser mutagenized to Ala (DPPSA) did not accelerate the degradation of collagen and gelatin by MMPs but retained fibronectin-binding activity. The adhesion of human gingival fibroblasts and NIH 3T3 cells to fibronectin was inhibited by DPPIV. Strain 4351ADPPSA exhibited an intermediate level of virulence in mice, between that of the strain expressing wild-type DPPIV (4351ADPP) and that of the strain harboring only the plasmid vector (4351AVEC). It is suggested that both activity promoting the degradation of collagen and gelatin and binding to fibronectin are required for full virulence. These results reveal novel biological functions of DPPIV and suggest a pathological role in the progression of periodontitis.