Harumi Inoue

Podoplanin expression during dysplasia–carcinoma sequence in the oral cavity

Human podoplanin, a type-1 transmembrane sialomucin-like glycoprotein, is involved in cell migration, tumor cell invasion, and metastasis. However, the role of the protein in squamous cell carcinoma (SCC) has been unclear and immunohistochemical reactivity for podoplanin differs from organ-to-organ. In the present study, immunohistochemical and molecular biological analyses were performed to examine the importance of podoplanin expression in oral precancerous and cancerous lesions and metastases. We immunohistochemically investigated the expression of podoplanin in 103 precancerous lesions, 69 primary oral squamous cell carcinomas (OSCCs), and 32 metastases, and that of E-cadherin and vimentin in primary OSCCs with metastasis. Furthermore, human OSCC-derived cell lines preincubated with fibrous growth factor-basic, epidermal growth factor (EGF), and tumor growth factor-β1 were subjected to real-time reverse transcription polymerase chain reaction. Immunoreactivity for podoplanin was detected in 89 (86.4%) of the precancerous lesions and the intensity was correlated with the degree of epithelial dysplasia (P = 0.016). Enhanced podoplanin expression was observed in 66 (95.7%) of the OSCCs and was significantly associated with a poor pathologic grade of differentiation (P = 0.020). Epithelial–mesenchymal transition was observed in 18 (58.1%) of the primary OSCCs with metastasis to regional lymph nodes. Messenger RNA for podoplanin was markedly increased after treatment with EGF in three OSCC cell lines. The present findings suggest that podoplanin is associated with tumor development via the oral dysplasia–carcinoma sequence and could be involved in a signaling pathway governing tumor growth and invasion in OSCC.

Overexpression of Activation-Induced Cytidine Deaminase in MTX- and Age-Related Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders of the Head and Neck

Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated with c-myc translocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age-related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs.

Apocrine Hidrocystoma of the Lower Lip: A Case Report and Literature Review

The hidrocystomas (HCs) are cystic forms of sweat gland resulting from proliferation of the apocrine secretory coil or eccrine duct. Apocrine -HCs are cystic lesions that arise from the apocrine secretory coil, while eccrine -HCs represent retention cysts of the eccrine duct. The commonest site for such lesions is around the eye, and they may also occur on the ears, scalp, chest, shoulders, or feet. However, HCs of the perioral region are uncommon. The differential diagnosis with minor salivary gland cyst or cystic neoplasms often poses a problem in this site. Here we report a rare case of apocrine -HC of the right lower lip for which excisional biopsy of the lesion was performed. Histopathologically, the lesion was a unilocular cyst lined by a double-layered epithelium of the apocrine secretory type. Immunohistochemically, the secretory epithelium was positive for mammaglobin, gross cystic disease fluid protein 15 (GCDFP-15), cytokeratin 7 (CK 7) and CK18, and the myoepithelium was positive for alpha-smooth muscle actin (α-SMA) and weakly positive for S100 protein. Here we present this very rare case of apocrine -HC of the lower lip, and discussed regarding differential diagnosis with minor salivary gland cystic lesion in the lip.

Comparative study of cytokeratin and langerin expression in keratinized cystic lesions of the oral and maxillofacial regions.

Dermoid cysts (DMCs) and epidermoid cysts (EDMCs) usually arise in soft tissues, whereas orthokeratinized odontogenic cysts (OOCs) and keratocystic odontogenic tumors (KCOTs) develop in the jaw. In this study, we performed immunohistochemical analysis of cytokeratins (CKs) to examine differences in the lining epithelium of DMCs, EDMCs, OOCs, and KCOTs. In addition, we carried out immunohistochemical examination of langerin to clarify the biological characteristics of the orthokeratinized lining epithelium of DMCs, EDMCs, and OOCs. Seven DMCs, 30 EDMCs, 11 OOCs, and 28 KCOTs were examined immunohistochemically using antibodies against CK10, 13, 14, 16, 17, 19, and langerin. Immunoreactivities for CKs and langerin in oral DMCs and EDMCs were similar to those of lesions affecting the skin. Positive reactivity for CK13 and 17 was evident in OOCs, but not in DMCs/EDMCs. CK10 was significantly positive in all layers except for the basal layer in OOCs, but was negative in KCOTs. CK17 was positive in all layers in KCOTs, and in all layers except for the basal layer in both OOCs and dentigerous cysts. CK19 was negative in OOCs. Langerhans cells were found mainly in OOCs, but were hardly evident in KCOTs. These results suggest that DMCs/EDMCs, OOCs and KCOTs are independent diseases.

Telomerase activity in the occurrence and progression of oral squamous cell carcinoma.

Chronic inflammation is considered to be one of the risk factors for carcinogenesis. It was recently reported that telomerase plays an important role in inducing such chronic inflammation. Although high telomerase activity is detected in cancer tissues, the activator of telomerase is still unknown. In this study, we used an immunohistochemical method to examine the expression of human telomerase reverse transcriptase (hTERT) in the dysplasia-carcinoma sequence in the oral cavity. Furthermore, the effects of inflammatory cytokines on the telomerase activity and migration of oral cancer cell lines (Ca9-22, HSC-3, and HSC-4) were examined. Immunoreactivity for hTERT was observed in squamous intraepithelial neoplasia 3 and squamous cell carcinoma. Telomerase activity in Ca9-22 cells was increased by treatment with TNF-α and INF-γ, while its activity in HSC-4 cells was decreased by IL-1β. Although inflammatory cytokines did not affect the proliferative activity of any of the oral cancer cell lines, cytokines and hTERT siRNA promoted the migration of HSC-3 cells. These results suggest that the presence of long-term chronic inflammation may increase telomerase activity and therefore contribute to malignant transformation of the oral mucosal epithelium. Furthermore, inhibition of telomerase activity by inflammatory stimuli increases the invasion of certain types of oral squamous cell carcinomas.

Primary intestinal-type adenocarcinoma of the buccal mucosa: A case report and literature review

Intestinal-type adenocarcinoma of the primary salivary glands is extremely rare. So far, only 11 cases of primary intestinal-type adenocarcinoma of the oral cavity and major salivary glands have been reported. Two of those tumors arose in the floor of mouth, 7 in the tongue, and 2 in the major salivary glands. However, it has remained unclear whether these tumors are derived from mature salivary glands, and primary intestinal-type adenocarcinoma of the buccal mucosa has not been reported previously. Here, we present the first documented case of primary intestinal-type adenocarcinoma arising in a minor salivary gland of the buccal mucosa. Histopathologically, the tumor resembled a well-differentiated or mucinous colonic adenocarcinoma. Immunohistochemically, the tumor cells were diffusely positive for AE1/AE3, CAM5.2, CK7, SATB2, β-catenin, p53, Ki-67, MUC2, and MUC5 AC. CK14 and CK20 were positive in some of the tumor cells. CDX2, CA19-9, SP-A, TTF-1, PSA, SMA, p63, and cyclin D1 were negative in the tumor cells. The tumor in the present case may have originated from salivary gland duct epithelium that underwent transformation to phenotypic intestinal-type epithelium. In this very rare case of primary intestinal-type adenocarcinoma of the buccal mucosa, we considered diagnostic markers that could be indicative of mature salivary gland origin.

Epstein–Barr virus (EBV)-associated epithelial and non-epithelial lesions of the oral cavity

Summary Epstein–Barr virus (EBV) is known to be associated with the development of malignant lymphoma and lymphoproliferative disorders (LPDs) in immunocompromised patients. EBV, a B-lymphotropic gamma-herpesvirus, causes infectious mononucleosis and oral hairy leukoplakia, as well as various pathological types of lymphoid malignancy. Furthermore, EBV is associated with epithelial malignancies such as nasopharyngeal carcinoma (NPC), salivary gland tumor, gastric carcinoma and breast carcinoma. In terms of oral disease, there have been several reports of EBV-related oral squamous cell carcinoma (OSCC) worldwide. However, the role of EBV in tumorigenesis of human oral epithelial or lymphoid tissue is unclear. This review summarizes EBV-related epithelial and non-epithelial tumors or tumor-like lesions of the oral cavity. In addition, we describe EBV latent genes and their expression in normal epithelium, inflamed gingiva, epithelial dysplasia and SCC, as well as considering LPDs (MTX- and age-related) and DLBCLs of the oral cavity.

Microorganisms and cancer of the oral cavity

Numerous microorganisms, such as bacteria, viruses and fungi, inhabit the oral cavity, and it has been pointed out that poor oral hygiene and chronic periodontitis increase the risk of oral squamous cell carcinoma (OSCC). However, the molecular mechanism whereby the risk of OSCC is increased under such conditions has not yet been clarified. Microbes in the oral cavity may elicit both innate and acquired immune responses, resulting in the establishment of uncontrolled inflammation such as chronic periodontitis. Further microbial attack and various host-derived factors may subsequently contribute to events such as genetic and epigenetic alterations, inhibition of apoptosis, increased cell growth, promotion of invasion and metastasis, and lymphangiogenesis, thus linking the chronic inflammation to OSCC. Here we review the various factors involved in promoting the development and progression of OSCC. The facts suggest the importance of early prevention and treatment of chronic periodontitis to maintain oral health and prevent serious diseases such as OSCC. Introduction Most malignant neoplasms of the oral cavity are squamous cell carcinomas (SCCs) [1], and many factors are involved in the development of oral squamous cell carcinoma (OSCC) [2]. Although the primary causes of OSCC are tobacco and alcohol [1], the malignancy can occur even in individuals who do not smoke and drink [3], suggesting that other factors may also play a role. It has been pointed out that poor oral hygiene [4-8] and chronic periodontitis [9-12] may increase the risk of oral cancer. Numerous microorganisms, inhabiting in the oral region, such as bacteria, viruses and fungi, may affect the development and progression of OSCC. In this article, we describe the association of oral microorganisms and host-derived factors with OSCC, and also emphasize the importance of early prevention and treatment of chronic periodontitis for maintaining oral health and preventing lethal diseases such as OSCC. Dental caries and cancer Dental caries, one of the two major common diseases of the oral cavity, is characterized by destruction of enamel, dentin and cementum by commensal gram-positive bacteria. As the condition progresses, pulpitis and apical periodontitis develop jointly as sequelae. In extreme cases, patients may develop osteomyelitis and periostitis of the jaw, maxillary sinusitis, or Ludwig’s angina, leading to potentially fatal sepsis or systemic inflammatory response syndrome (SIRS) (Figure 1). Therefore, early prevention and treatment of dental caries are clearly very important. Tezal et al. [13] have reported an inverse association between dental caries and head and neck squamous cell carcinoma (HNSCC) and showed an inverse association, although the reason for this remains unknown and further studies are needed. Association between periodontal diseases and cancer Periodontal disease is the other major common disease of the Correspondence to: Kaoru Kusama, DDS, PhD, Division of Pathology, Department of Diagnostic & Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan, E-mail: kusama@dent.meikai.ac.jp