title: Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia.
abstract: Oral leukoplakia (OL) is a common, potentially malignant disorder of the oral cavity. SMAD4 was initially identified as a tumor suppressor and central mediator of transforming growth factor (TGF)-β signaling. In this study, we aimed to determine the expression patterns of SMAD4 in OL, its relationship with the degree of inflammation, and its clinical implications as a biomarker for OL malignant transformation. A total of 150 patients with OL were enrolled in this study. Paraffin-embedded sections obtained from biopsy or resection specimens were subjected to immunohistochemical analysis. Associations among the status of epithelial SMAD4 expression, stromal lymphocyte infiltration, and malignant transformation of OL were examined. Malignant transformation was significantly associated with the status of SMAD4 expression (P = 0.0017) and lymphocyte infiltration status (P = 0.0054). Cox regression analysis, based on the event-free survival (EFS), revealed that a low SMAD4 expression was a significant prognostic factor in OL patients (hazard ratio, 2.632; P = 0.043). In addition, a low SMAD4 expression was closely correlated with high lymphocyte infiltration (P = 0.00035), resulting in a significant correlation between the combination of low SMAD4 expression and high lymphocyte infiltration with malignant transformation of OL (P = 0.00027). The combination of the status of epithelial SMAD4 expression and stromal lymphocyte infiltration may be a useful biomarker for predicting malignant transformation in OL patients. These results suggest that not only epithelial SMAD4 loss, but also stromal features, may regulate the risk of malignant transformation of OL.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Sakata
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Hirosue
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Arita
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidenao
authors.initials: H
authors.lastname: Ogi
authors.affiliation: Section of Oral Oncology, Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Hiraki
authors.affiliation: Itoh Dent-Maxillofacial Hospital, Kumamoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007972:Leukoplakia, Oral / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D051901:Smad4 Protein / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein
keywords: Lymphocyte infiltration; SMAD4; malignant transformation; oral leukoplakia; oral squamous cell carcinoma