Expanding the cytological and architectural spectrum of mucoepidermoid carcinoma: The key to solving diagnostic problems in morphological variants.

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Varying sized cysts and sheets composed of three cell types (epidermoid, intermediate, and mucous cells) with varying degrees of atypia form the characteristic histological appearance of MEC. MEC frequently contains a wide variety of modified tumor cells and can be entirely cystic or completely solid. Under these circumstances, MEC requires critical differentiation from many mimickers, ranging from simple cysts and benign tumors to high-grade carcinomas. Tumor-associated lymphoid proliferation and sclerotic changes in the stroma also contribute to diagnostic difficulties. Several well-known diagnostically challenging variants (oncocytic, clear cell, spindle cell, and sclerosing) exist in MEC. With the advent of studies on specific CRTC1/3::MAML2 fusion genes in MEC, newly proposed subtypes have emerged, including Warthin-like and non-sebaceous lymphadenoma-like MECs. In addition to the recently defined mucoacinar variant with a serous cell phenotype, MEC devoid of squamous differentiation has also been reported, implying the need to reconsider this basic concept. In this article, we outline the general clinical features and MAML2 status of conventional MEC and review the cytoarchitectural subtypes, with an emphasis on a pitfall in the interpretation of this histologically diverse single entity.

Ghost cell odontogenic carcinoma arising in dentinogenic ghost cell tumor, peripheral: A case report.

Ghost cell odontogenic carcinoma (GCOC) is an extremely rare intraosseous malignant odontogenic tumor with prominent ghost cell keratinization and dentinoid formation. Here, we present the first case of GCOC arising in dentinogenic ghost cell tumor (DGCT), peripheral. The patient was a man in his 60s with an exophytic mass in the anterior part of lower gingiva. The resected tumor measured 4.5 cm in maximum diameter. Histologically, the nonencapsulated tumor proliferated in the gingiva without bone invasion. It was predominantly composed of ameloblastoma-like nests and islands of basaloid cells with ghost cells and dentinoid in the mature connective tissue, suggesting DGCT, peripheral. As minor components, sheets of atypical basaloid cells and ameloblastic carcinoma-like nests with pleomorphism and high proliferative activity (Ki-67 labeling index up to 40%) consistent with malignancy were identified. CTNNB1 mutation and ß-catenin nuclear translocation were observed in both benign and malignant components. Final diagnosis was GCOC arising in DGCT, peripheral. GCOC shows similar histological features to DGCT. In this unique case without invasion, the cytological atypia and high proliferative activity supports the diagnosis of malignant transformation from DGCT.

Non-sebaceous lymphadenoma-like mucoepidermoid carcinoma: A case report.

Non-sebaceous lymphadenoma is a rare benign salivary gland tumor comprised of non-sebaceous epithelial cells and lymphoid tissue. Although its clinicopathological features have been described, its histogenesis and genetic background have not yet been elucidated. MAML2 rearrangement and the resultant CRTC1/3-MAML2 fusion gene are well-known specific genetic changes in mucoepidermoid carcinoma. Here, we present a case of lymphoepithelial tumor characterized by histomorphology of the non-sebaceous lymphadenoma and CRTC1-MAML2 fusion gene. The patient was an 83-year-old woman with an 8-year history of a solid, well-circumscribed tumor in the parotid gland. Histologically, the tumor was surrounded by thin fibrous connective tissue and was composed of tubular-cystic and solid nests of epithelial cells equally distributed in the lymphoid tissue. The histological features were suggestive of non-sebaceous lymphadenoma. Although the histomorphology was not consistent with mucoepidermoid carcinoma, a diagnosis of non-sebaceous lymphadenoma-like mucoepidermoid carcinoma was made based on the presence of the CRTC1-MAML2 fusion gene. The histological features alone could not establish the diagnosis, and ancillary molecular analysis was required.

Elimination of Porphyromonas gingivalis inhibits liver fibrosis and inflammation in NASH.

AIM: Non-alcoholic steatohepatitis (NASH) is a critical liver disease showing potential progression to liver cirrhosis/cancer. Previously, we had reported that odontogenic infection of Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, exacerbates fibrosis in NASH through the production of fibrosis mediators such as transforming growth factor-ß1 (TGF-ß1) and galectin-3. In this study, we determined the effects of therapeutic interventions using antibiotics on NASH progression induced by P. gingivalis odontogenic infection. MATERIALS AND METHODS: To eliminate P. gingivalis infection, the macrolide antibiotic [azithromycin (AZM)] was applied locally and/or systemically to a high-fat-diet-induced NASH mouse model with P. gingivalis odontogenic infection. After treatment with AZM, liver and periodontal tissues were analysed with focus on inflammation markers such as tumour necrosis factor-α (TNF-α)/Tnf-α and interleukin-1ß (IL-1ß)/Il-1ß, and fibrosis markers such as galectin-3, phosphorylated Smad2 (pSmad2; key signalling molecule of TGF-ß1), and the number of hepatic crown-like structures (hCLSs). Further, Non-alcoholic Fatty Liver Disease Activity Score (NAS), a common histological scoring system, and fibrosis area were evaluated. RESULTS: P. gingivalis odontogenic infection significantly increased the expression of Tnf-α, Il-1ß, galectin-3, and pSmad2, the number of hCLSs, and NAS score, whereas the elimination of P. gingivalis odontogenic infection, especially local with or without systemic application, significantly inhibited them. CONCLUSION: This study suggests that elimination of P. gingivalis odontogenic infection inhibited NASH progression induced by the infection.

The transition of tissue inhibitor of metalloproteinases from -4 to -1 induces aggressive behavior and poor patient survival in dedifferentiated liposarcoma via YAP/TAZ activation.

Liposarcoma (LS) is the most common soft-tissue sarcoma. Dedifferentiated liposarcoma (DDLS) shows more aggressive biological behavior than that of well-differentiated liposarcoma (WDLS), so advanced therapeutic agents based on molecular mechanism are urgently needed. Here we show that tissue inhibitors of metalloproteinases (TIMPs) from TIMP-1 to TIMP-4 are differently expressed and regulate yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) in LS. Database analysis showed high TIMP-1 expression in DDLS patients correlating with poor prognosis, but high TIMP-4 expression in WDLS patients with better prognosis. Stable TIMP-1 knockdown inactivated YAP/TAZ and inhibited proliferation, colony formation and migration in DDLS cells, which was rescued by a constitutive active YAP. However, stable overexpression of TIMP-1 showed the opposite in WDLS cells. Stable TIMP-4 knockdown activated YAP/TAZ and promoted proliferation and migration in WDLS cells, which was suppressed by YAP/TAZ inhibitor (verteporfin) or knockdown of YAP/TAZ. Recombinant TIMP-4 showed opposite results in DDLS cells. These results indicate that dedifferentiation in LS shifts the expression of TIMPs from type 4 to type 1, inducing more aggressive behavior and poor prognosis through YAP/TAZ activation, which can be prognostic markers and therapeutic targets for LS patients.

Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report.

Central mucoepidermoid carcinoma (MEC) poses a diagnostic challenge because of its rarity and histological overlap with glandular odontogenic cyst (GOC). In MEC of both salivary glands and jaws, MAML2 arrangement has been well known as the specific gene alteration. We report a case of central MEC arising from GOC diagnosed by MAML2 fusion gene. A 57-year-old male presented a multilocular cystic lesion in left molar region of the mandible. Histopathologically, multiple cysts lined by thin cuboidal or non-keratinized squamous epithelium with small duct-like structures, mucous cells and ciliated cells were present. It was diagnosed as GOC. The recurrent lesion after nine years showed the proliferation of many cystic and solid nests composed of epidermoid, mucous and intermediated cells. Nested PCR revealed CRTC3-MAML2 fusion gene in the recurrent lesion, but not in the primary one. Similarly, MAML-2 rearrangement by FISH analysis was positive in the recurrent lesion, while negative for the primary one, thus confirming the diagnosis of central MEC arising from GOC. Analysis of MAML2 rearrangement can be used as a supportive evidence to distinguish central MEC from GOC.

Revisiting the History of Odontoma, with Special Reference to Its Original Illustration.

BACKGROUND: Practically every facet of the most common odontogenic tumor, odontoma, has been covered by an extensive volume of literature. However, uncertainty about its precise history has persisted. MATERIALS AND METHODS: The historical evolution of odontoma was traced with reference to the original illustrations that accompanied European and American reports published at the beginning of the 19th century and also at the turn of the century. RESULTS: The prevailing views regarding the first description of odontoma by Oudet of Paris in 1809 and the original designation "odontome" by Broca of Paris in 1867 are not entirely accurate. Before Broca's suggested term, "exostose dentaire" (dental exostosis) and "tumeur dentaire" (dental tumor) proposed by Oudet and Forget of Paris, respectively, were popular terms adopted in France, while in Briatin the terms "warty tooth" and "supernumerary teeth" proposed by Salter and Tomes of London, respectively, were widely coined. The original illustrations of complex odontoma were published by Wedl of Vienna in 1851, and in 1862 Tomes published the first drawing of compound odontoma denticles. Before the advent of diagnostic radiography in the early 1900s, spontaneous exposure or eruption of odontoma followed by secondary infection was very common. In 1887-1888, Bland Sutton of London criticized Broca's monumental research and formulated the first modern classification which, in essence, remains valid today. At that time, large osteomas of the maxilla were inappropriately classified as odontomas by many pathologists because of Bland Sutton's influential view. Interestingly, the first radiographic evidence of odontoma was published by the American oral surgeon Gilmer in 1899. CONCLUSION: In view of their fundamental achievements, the names of Wedl, Salter, Broca and Bland Sutton have been closely associated with the true history of odontoma.

Warthin Tumor of the Parotid Gland: The History of an Eponym.

The eponymous history of Warthin tumor (WT) is a fascinating issue in the field of salivary gland pathology. The late decades of the nineteenth century and the turn of the century saw notable German and French contributions on WT. Especially, the seminal 1910 paper of Albrecht and Arzt of Vienna is the foundation for the current knowledge of WT. It is generally believed that prior to this pioneering study, Hildebrand of Göttingen accurately described the lesion of WT in 1895. However, the historical origins of WT appear to be unsettled, and only a few German pathologists and surgeons are aware that dating back to 1885, the first recognizable reference to WT was that by the renowned German-Swiss pathologist Zahn, whose name is eponymously associated with "Zahn infarct" and "lines of Zahn". Two noted French surgeons with a major interest in pathology, Albarrán in 1885 and Lecéne in 1908, did not contribute to the topic. Since the 1950s, a mostly American group of pathologists and surgeons gradually adopted the term WT to replace the very accurate histologic descriptor "papillary cystadenoma lymphomatosum" coined by Warthin himself in 1929. It is our opinion that from a historical viewpoint, there is no particular reason why this tumor should have been named WT.

The True History of Cementoblastoma.

REVIEW OF THE LITERATURE: Cementoblastoma (CB) is unique among odontogenic tumors because its gross pathological anatomy is pathognomonic in most cases, i.e., a rounded calcified growth that is fused to the root of a tooth and completely encapsulated by fibrous tissue. The resulting radiographic appearance is a well-defined, globular mixed radiopaque/lucent or completely radiopaque mass obliterating some details of the root, with a thin radiolucent zone surrounding the central opacity. Although hundreds of publications have covered the clinicopathologic features of CB, almost nothing is known about its true history. Also it seems there is little understanding about how the term "CB" was originally introduced as a pathologic entity. This report covers some overlooked papers on CB dating back to the 19th century, including the first complete description in 1888 and the first radiographic presentation in 1906.

A Third Supernumerary Tooth Occurring in the Same Region: A Case Report.

The presence of a supernumerary tooth is one of the most common dental anomalies, and surgical treatment is often required to address this anomaly. Moreover, it may lead to malocclusion, and long-term follow-up is important to monitor its status. A 4-year-and-11-month-old boy was referred to our hospital for dental caries treatment. At 5 years and 5 months of age, a radiographic examination showed a supernumerary tooth (first supernumerary tooth) near the permanent maxillary left central incisor, and it was extracted 6 months later. Eighteen months after the extraction of the first supernumerary tooth, a new supernumerary tooth (second supernumerary tooth) was detected in the same region, which was extracted when the patient was aged seven years and seven months. Seven months later, another supernumerary tooth (third supernumerary tooth) was detected and extracted immediately. However, the permanent maxillary left central incisor did not erupt spontaneously even after 6 months. Therefore, surgical exposure was performed, and the central incisor erupted into the oral cavity. This report describes our experience with this patient with three metachronous supernumerary teeth and their management until the eruption of the permanent tooth. This report highlights the importance of long-term follow-up after supernumerary tooth extraction until the permanent teeth in that region have erupted completely.

Porphyromonas gingivalis-odontogenic infection is the potential risk for progression of nonalcoholic steatohepatitis-related neoplastic nodule formation.

Porphyromonas gingivalis (P.g.), a major periodontal pathogen is a known risk factor for various systemic diseases. However, the relationship between P.g. and nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is unclear. Thus, we aimed to elucidate whether P.g.-odontogenic infection promotes NASH-related HCC development/progression and to clarify its mechanism. Using high-fat diet (HFD)-induced NASH mouse model, P.g. was infected odontogenically. After 60 weeks of infection, tumor profiles were examined. Chow diet (CD) groups were also prepared at 60 weeks. Nodule formation was only seen in HFD-mice. P.g.-odontogenic infection significantly increased the mean nodule area (P = 0.0188) and tended to promote histological progression score after 60 weeks (P = 0.0956). Interestingly, P.g. was detected in the liver. HFD-P.g. (+) showed numerous TNF-α positive hepatic crown-like structures and 8-OHdG expression in the non-neoplastic liver. In P.g.-infected hepatocytes, phosphorylation of integrin ß1 signaling molecules (FAK/ERK/AKT) was upregulated in vitro. In fact, total AKT in the liver of HFD-P.g. (+) was higher than that of HFD-P.g. (-). P.g.-infected hepatocytes showed increased cell proliferation and migration, and decreased doxorubicin-mediated apoptosis. Integrin ß1 knockdown inhibited these phenotypic changes. P.g.-odontogenic infection may promote the progression of neoplastic nodule formation in an HFD-induced NASH mouse model via integrin signaling and TNF-α induced oxidative DNA damage.

A multi-institutional study of salivary gland cytopathology: Application of the Milan System for Reporting Salivary Gland Cytopathology in Japan.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a risk-stratification reporting system that was introduced in 2018. The objective of this multi-institutional study was to evaluate the utility of the MSRSGC in Japan. METHODS: In total, 1608 fine-needle aspiration samples with matching histologic diagnoses were retrieved from 12 large institutions in Japan. The diagnostic categories of the MSRSGC were assigned prospectively or retrospectively, and the results were compared with the histologic diagnoses. RESULTS: The cases were classified as follows: nondiagnostic, 18.1%; non-neoplastic, 4.1%; atypia of undetermined significance, 11.5%; neoplasm-benign, 43.7%; salivary gland neoplasm of uncertain malignant potential, 9.6%; suspicious for malignancy, 3.6%; and malignant, 9.4%. The risk of neoplasm and the risk of malignancy in each MSRSGC category were as follows: nondiagnostic, 72.9% and 13.4%, respectively; non-neoplastic, 15.2% and 9.1%, respectively; atypia of undetermined significance, 77.9% and 24.9%, respectively; neoplasm-benign, 99% and 1.8%, respectively; salivary gland neoplasm of uncertain malignant potential, 94.8% and 37%, respectively; suspicious for malignancy, 100% and 89.7%, respectively; and malignant, 100% and 99.3%, respectively. The accuracy of the MSRSGC for diagnosing neoplasms was 97.8%, and its accuracy for diagnosing malignancy was 97.3%. Institutions that used Romanowsky-stained preparations had lower nondiagnostic rates and lower risks of neoplasm and malignancy in the non-neoplastic category. CONCLUSIONS: The MSRSGC is useful for risk stratification and quality control. Widespread use of the MSRSGC would improve the accuracy of salivary gland cytology and lead to better patient care in Japan.

Relationships between intraoral ultrasonographic and histopathological findings in patients with tongue cancer.

BACKGROUND: In this study, we aimed to investigate the relationships between histopathological and intraoral ultrasonographic (IUS) findings in patients with tongue cancer. METHODS: IUS and histopathological findings in 46 patients with tongue cancer were considered for this study. We assessed the relationships between IUS findings regarding tumor thickness, margin type, border type, and internal echo intensity; internal/peripheral Doppler findings; and muscle invasion and histopathological findings regarding tumor thickness, differentiation, Yamamoto-Kohama (YK)-classification grade, blood vessel invasion, lymphatic invasion, perineural invasion, and muscle invasion. RESULTS: Statistical associations were found between the following findings: between thickness determined through IUS measurement and that determined through histopathological measurement, between the IUS findings regarding tumor margin and border types and the histopathologically determined YK-classifications grades, and between a Doppler image of the internal area of tongue lesions and lymphatic invasion. CONCLUSIONS: IUS findings may be used to predict histopathological findings about tumor thickness and YK-classification grades.

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation.

Odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-ß1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-ß1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFß-receptor II resulting in increasing sensitivity for TGF-ß1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-ß1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-ß1 and Gal-3 production from HSCs and hepatocytes.

Porphyromonas gingivalis, a cause of preterm birth in mice, induces an inflammatory response in human amnion mesenchymal cells but not epithelial cells.

INTRODUCTION: Inflammation and infection, including dental infectious diseases, are factors that can induce preterm birth. We previously reported that mice with dental Porphyromonas gingivalis infection could be used as a model of preterm birth. In this model, cyclooxygenase (COX)-2 and interleukin (IL)-1ß levels are increased, and P. gingivalis colonies are observed in the fetal membrane. However, the mechanism underlying fetal membrane inflammation remains unknown. Therefore, we investigated the immune responses of human amnion to P. gingivalis in vitro. METHODS: Epithelial and mesenchymal cells were isolated from human amnion using trypsin and collagenase, and primary cell cultures were obtained. Confluent cells were stimulated with P. gingivalis lipopolysaccharide (P.g-LPS) or P. gingivalis. mRNA expressions of IL-1ß, IL-8, IL-6 and COX-2, protein expressions of nuclear factor (NF)-κB pathway components and culture medium levels of prostaglandin E2 were evaluated. RESULTS: Following stimulation with 1 µg/mL P.g-LPS, the mRNA expression levels of IL-1ß, IL-8, IL-6 and COX-2 in mesenchymal cells were increased 5.9-, 3.3-, 4.2- and 3.1-fold, respectively. Similarly, the expression levels of IL-1ß, IL-8, IL-6 and COX-2 in mesenchymal cells were increased by 7.6-, 8.2-, 13.4- and 9.3-fold, respectively, after coculture with P. gingivalis. Additionally, stimulation with P.g-LPS or P. gingivalis resulted in the activation of NF-κB signaling and increased production of IL-1ß and prostaglandin E2. In contrast, no significant changes were observed in epithelial cells. DISCUSSION: Our findings suggest that mesenchymal cells might mediate the inflammatory responses to P. gingivalis and P.g-LPS, thereby producing inflammation that contributes to the induction of preterm birth.