Frequency of pain and correlation with clinical and histologic parameters in T1 squamous cell carcinoma of the tongue: a retrospective pilot study.

AIMS: To conduct a pilot retrospective study to investigate the frequency of pain among patients with early-stage oral squamous cell carcinoma (OSCC) of the tongue and to correlate the pain with clinical and histopathologic parameters. METHODS: Twenty-four archival cases of T1 OSCC of the tongue were reviewed. No power analysis was conducted due to the pilot nature of the study. Tumors were classified into two groups according to the presence or not of pain (P+ and P- groups). Clinical and histopathologic parameters, such as grade of differentiation, depth of invasion, and presence of vascular, muscular, and perineural invasion were recorded. Statistical analyses included parametric (Student t) and nonparametric (chi-square) tests. RESULTS: Pain was reported by 13 of the 24 patients. In the P+ group, 11 of the 13 had moderately differentiated and 2 well-differentiated tumors; in contrast, P- patients had moderately differentiated tumors in 5 of the cases and well-differentiated tumors in 6 cases (P = .082). Vascular invasion was observed in 5 of the 13 P+ and 5 of the 11 P- patients, muscular invasion in 5 P+ and 2 P- patients, and perineural invasion in 4 P+ and 1 P- patients, respectively. The mean depth of invasion was 1.51 mm for P+ patients and 1.25 mm for P- patients. Only lymphoplasmocytic infiltration differed significantly, with P+ tumors exhibiting more intense inflammation (P = .041). CONCLUSION: Despite the limited number of cases, the results of this study suggest that painful OSCCs of the tongue may be associated with more intense inflammation.

Endometrial carcinoma metastatic to the retromolar pad.

Metastatic carcinoma from the female genitalia to the oral mucosa is exceptionally rare, with only 11 such cases having been previously reported in the English-language literature. We describe a new case in a 65-year-old woman with a history of endometrial carcinoma who presented with swelling of the retromolar pad. Radiographic examination showed slight opacities and irregular trabecular bone in the left posterior mandible. Following an incisional biopsy, histologic examination and immunohistochemical studies revealed glandular adenocarcinoma with positivity for progesterone receptor, estrogen receptor, and cytokeratin 7. The patient was referred to her primary care physician for comprehensive treatment. This case illustrates the value of considering cancer metastasis in the differential diagnosis of an oral swelling, particularly in a patient with a history of cancer.

Expression of midkine in ameloblastomas and its correlation with clinicopathologic parameters.

OBJECTIVE: Midkine (MK) is a heparin-binding growth factor that is overexpressed in various human cancers. The aim of this study was to investigate the expression of MK in ameloblastomas and correlate the results with clinicopathologic parameters. STUDY DESIGN: Cases of ameloblastoma seen between 1999 and 2010 were identified. Clinical information was collected regarding age, gender, race, and location of tumor. Cases were classified as solid/multicystic, unicystic, and peripheral. The expression of midkine was assessed using immunohistochemistry. A significant difference was considered present at P < 0.05. RESULTS: A total of 34 cases of ameloblastoma and 4 cases of ameloblastic carcinomas were identified. MK was expressed in 67% of lesions (23.5% weak expression; 14.7% moderate expression; 29.4% strong expression). A significant difference was seen between solid/multicystic and unicystic lesions. CONCLUSIONS: MK is expressed in the majority of ameloblastomas, suggesting a role of the protein in the tumor's development, progression, and behavior.

A clinicopathological study of malignant odontogenic tumours.

AIMS: Malignant odontogenic tumours (MOTs) are rare neoplasms occurring primarily within the jaw. The objective of this study was to determine the incidence, demographics and clinicopathological features of the MOTs from two institutions. METHODS AND RESULTS: The records of the Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand and the Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, USA were searched from 1991 to 2010; we identified 17 cases of previously diagnosed MOTs. All cases were reviewed independently of the previous diagnosis by two blinded oral pathologists and reclassified based on the 2005 World Health Organization classification of head and neck tumours. In this study we describe in detail these 17 cases which presented with an average age of 50.29 years and a male to female ratio of 2.4:1. These cases included five ameloblastic carcinomas, four atypical ameloblastomas, three primary intraosseous squamous cell carcinomas, three intraosseous mucoepidermoid carcinomas and two clear cell odontogenic carcinomas. All cases were treated by surgical resection and one patient with ameloblastic carcinoma received postoperative radiotherapy. CONCLUSIONS: Malignant odontogenic tumours are considered rare central odontogenic lesions. Awareness of their existence, rapid diagnosis and successful treatment using surgery, radiation and/or chemotherapy is critical to patient survival.

Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers.

BACKGROUND: Bisphosphonates (BPs) were designed for the prevention of skeletal-related events secondary to bone metastases. The purpose of this study was to show that zoledronic acid (ZA) directly eradicates highly tumorigenic and potentially metastatic cancer cells. MATERIALS AND METHODS: Human prostate and breast highly tumorigenic (PC3, MCF 7) and low- or non-tumorigenic (LNCaP, MCF 10a) cell lines, respectively, were exposed to different concentrations of ZA (0-10 µM). Reverse transcriptase double quantitative polymerase chain reaction was used for quantitative gene expression analysis. Apoptosis and cell proliferation were determined using microscopic observation and MTS assays. Western blot was used to confirm the translational effects of apoptotic genes on protein expression. RESULTS: Human prostate and breast highly tumorigenic (PC3, MCF 7) and low- or non-tumorigenic (LNCaP, MCF 10a) cell lines, respectively, showed multiple genes demonstrating differential expressions, including TRAF, TRADD, BCL2, CASPASES and IAP families. Increasing ZA concentrations showed a greater concentration-time response on cell proliferation and apoptosis in the highly tumorigenic cells. These results were confirmed by both reversing and enhancing the effect of ZA on cell proliferation with caspase 3, 7 or survivin siRNA, respectively. Pro-apoptotic proteins bax and caspase 2, 3, 7 and 9 were up-regulated, while the anti-apoptotic proteins bcl2, birc3 and survivin were down-regulated only in the highly tumorigenic cells. CONCLUSIONS: This explains the ability of ZA to inhibit bony metastasis in highly tumorigenic cells compared with the low- or non-tumorigenic cells through a significant decrease in cell proliferation and increase in apoptosis through gene-regulated and translational-mediated down-regulation of survivin coupled with the inhibition of caspase 3 or 7. This has significant implications toward understanding the pharmacophysiology of BPs in metastasis and supports the clinically observed effect of BPs when administered adjunctively with anticancer drugs such as cyclophosphamide/methotrexate/5-fluorouracil, epirubicin in combination with cyclophosphamide or docetaxel, and doxorubicin.

Synchronous Paget disease of bone and hyperparathyroidism: report of a case with extensive craniofacial involvement.

Paget disease of bone (PDB) and hyperparathyroidism (HPT) are metabolic osseous disorders which affect ≥2% of the population. As these diseases may share clinical, radiographic, biochemical, and histopathologic features, knowledge of their phenotypic overlap may provide diagnostic utility and improve clinical outcome. Scant information is available in the dental literature regarding patients concurrently affected with both pathologies. We present an unusual case report of a 63-year-old woman coaffected with primary HPT, attributed to a functional oxyphilic parathyroid adenoma, and PDB. Bone scintigraphy revealed pagetoid lesions of the skull, humeral head, spine, sacrum, and hemipelvis. Salient craniofacial features noted were bony involvement of the calvarium and midface, resulting in extensive maxillary overgrowth, hearing loss, telecanthus and consequent visual impairment, nasal deformity, and leontiasis ossea. The patient underwent a partial parathyroidectomy and bisphosphonate administration was to be initiated upon extraction of the remaining dentition.

Lateral periodontal cysts arising in periapical sites: a report of two cases.

INTRODUCTION: The lateral periodontal cyst is an uncommon odontogenic developmental lesion and chiefly arises in the alveolar bone between the roots of a pair of erupted teeth or lateral to a tooth root. Two atypical cases of the lateral periodontal cyst occurring in periapical sites are reported. METHODS: Both lesions presented as an incidental radiographic finding, appearing as an apical radiolucency with well-circumscribed sclerotic borders. One lesion, initially suspected to be of pulpal origin, persisted after endodontic therapy; the other case was first considered to be an odontogenic keratocyst. A biopsy was performed on each patient for lesional identity. RESULTS: Histopathologic assessment of each lesion was consistent with a lateral periodontal cyst and revealed thin, nonkeratinized epithelial linings containing nodular plaques and clear cells. The cyst walls were thickened and had minimal inflammation. CONCLUSIONS: The featured cases show that the lateral periodontal cyst is not always confined to the interradicular region and can masquerade as a lesion of endodontic origin. Aberrant cases warrant long-term surveillance.

Oral melanoacanthoma in an adolescent.

The etiopathogenesis of oral pigmentation is diverse. One such process is the oral melanoacanthoma, a reactive, melanocytic lesion, infrequently found in the pediatric subpopulation. To extend the knowledge of this lesion, we provide a case of gingival melanoacanthoma in a 17-year-old male patient. In addition, a comprehensive differential diagnosis for gingival hyperpigmentations in young patients is detailed.

Microbial interactions and differential protein expression in Staphylococcus aureus -Candida albicans dual-species biofilms.

The fungal species Candida albicans and the bacterial species Staphylococcus aureus are responsible for a majority of hospital-acquired infections and often coinfect critically ill patients as complicating polymicrobial biofilms. To investigate biofilm structure during polymicrobial growth, dual-species biofilms were imaged with confocal scanning laser microscopy. Analyses revealed a unique biofilm architecture where S. aureus commonly associated with the hyphal elements of C. albicans. This physical interaction may provide staphylococci with an invasion strategy because candidal hyphae can penetrate through epithelial layers. To further understand the molecular mechanisms possibly responsible for previously demonstrated amplified virulence during coinfection, protein expression studies were undertaken. Differential in-gel electrophoresis identified a total of 27 proteins to be significantly differentially produced by these organisms during coculture biofilm growth. Among the upregulated staphylococcal proteins was l-lactate dehydrogenase 1, which confers resistance to host-derived oxidative stressors. Among the downregulated proteins was the global transcriptional repressor of virulence factors, CodY. These findings demonstrate that the hyphae-mediated enhanced pathogenesis of S. aureus may not only be due to physical interactions but can also be attributed to the differential regulation of specific virulence factors induced during polymicrobial growth. Further characterization of the intricate interaction between these pathogens at the molecular level is warranted, as it may aid in the design of novel therapeutic strategies aimed at combating fungal-bacterial polymicrobial infection.

Protection of the oral mucosa by salivary histatin-5 against Candida albicans in an ex vivo murine model of oral infection.

The oral cavity is a primary target for opportunistic infections, particularly oral candidiasis caused by Candida albicans. A commensal fungus commonly colonizing mucosal surfaces, under conditions of immune dysfunction, C. albicans can become a pathogen causing recurrent infections. Yet, the role of host oral innate immunity in the development of candidiasis is not fully elucidated. Specifically, the host salivary antimicrobial peptide histatin-5 (Hst-5) has been proposed to play a protective role in the oral cavity against C. albicans. However, investigations demonstrating its efficacy on oral tissue have been lacking. To this end, in this study, an ex vivo murine model of oral infection was developed. Viable C. albicans counts and histopathological analyses demonstrated a significant protective effect for Hst-5 on mouse oral tissue against C. albicans. More importantly, host saliva exerted a comparable anticandidal effect. However, this effect was neutralized upon treatment of saliva with proteases and C. albicans, previously shown to degrade Hst-5, indicating that Hst-5 is likely the salivary component responsible for the observed protection. Combined, the findings from this study demonstrate for the first time the efficacy of salivary Hst-5 in protecting host oral tissue against C. albicans infection, thereby affirming the therapeutic potential of this natural host peptide.

Are we on the brink of nonsurgical treatment for ameloblastoma?

OBJECTIVE: Recent identification of altered molecular signaling pathways in neoplasia has begun to elucidate mechanisms of oncogenesis, differentiation, and tumor progression, and to suggest plausible nonsurgical considerations for treatment. Here we review the sonic hedgehog (SHH) and PI3K/Akt/mTOR signaling pathways, their role in ameloblastoma, a locally aggressive odontogenic tumor, and evidence for consideration of therapeutic approaches that target these molecular pathways. In so doing, some of the gaps will be revealed that may impel investigations and translate to patient care, helping to minimize or eliminate the need for extensive surgery. STUDY DESIGN: This is a comprehensive review of the literature regarding alterations in signaling mechanisms associated with ameloblastomas. In addition, this review attempts to explore and discuss possible inhibitors to these pathways that may have utility in treating ameloblastoma. RESULTS: The expression of SHH signaling molecules in ameloblastomas at the mRNA and protein levels has intimated that these molecules may play a role in cell proliferation of these tumors. Immunohistochemical analysis has revealed aberrant signaling in the PI3K/Akt/mTOR pathway in ameloblastomas and appears to be a valuable tool for elucidating pathogenesis and aggressiveness, and selecting optimal therapeutics. CONCLUSION: The understanding of altered pathways in ameloblastoma may soon provide nonsurgical options for the treatment of this condition. The demonstration of cross talk in SHH signal transduction with PI3K signaling through Akt has shown that these pathways converge to control the Gli transcription factors. Thus, tumors that entirely depend on active SHH signaling for survival/growth and maintenance may well be susceptible targets for combined chemotherapy with SHH-specific inhibitors together with PI3K, Akt, or mTOR blocking agents. Some of these inhibitors could be used locally, thereby minimizing major systemic effects.

Diminutive, interradicular "hybrid" desmoplastic/acanthomatous ameloblastoma.

Ameloblastomas are benign aggressive odontogentic tumors that exhibit insidious growth rates with attainment of extensive dimesions. Because ameloblastomas are not usually symptomatic until late in their clinical course, few are detected early. This article reports an atypical case of a small, painful ameloblastoma arising between the roots of the mandibular left canine and lateral incisor in a 66-year-old female. The patient underwent an en bloc resection of the mandible, and no recurrence was demonstrated on an 11-month recall examination. Histopathology revealed a "hybrid" ameloblastoma with a pronounced desmoplastic pattern and acanthomatous changes. Practitioners should be vigilant for diminutive radiolucent lesions of the jaws with poorly defined borders. Timely recognition and intervention of ameloblastomas may improve treatment outcomes.

A novel bioassay model to determine clinically significant bisphosphonate levels.

PURPOSE: Bisphosphonate-associated osteonecrosis (BON) is a recently recognized oral complication of bisphosphonate (BP) therapy. Currently, research into the pathogenesis of BON has been hampered by being deficient in studies capable of measuring the level of BP in saliva or at the bone-soft tissue interface. The objective of this current study was to develop a novel bioassay model representative of the oral levels of BPs in patients presenting with or at risk for BON. METHODS: Zoledronic acid (ZA) injectable was used to develop standardized MTS cell proliferation assay curves at concentrations of 0-10 microM, which were used either in a dilution in normal media, mimicking BP freed from bone or used to "spike" saliva individuals not taking BPs and mimicking BP levels being excreted. This bioassay was then used to estimate BP levels from samples of saliva and bone ex vivo from patients with and without BON. RESULTS: Saliva and bone from patients with existing BON showed levels of BP ranging from 0.4 to 4.6 microM, while patients receiving IV infusion of BP and naïve to BON showed levels in saliva ranging from 0.4 to 5 microM. All control specimens and patients naïve to BP showed levels at 0 microM. CONCLUSIONS: Given the fact that BPs are poor candidates for detection using standard methods (HPLC), this bioassay provides us with the ability to estimate clinically relevant concentrations of BP capable of producing apoptosis and the inhibition cell proliferation of oral mucosal cells based on previous studies. Subsequently, apoptosis and the inhibition of proliferation could lead to BON, secondary to the exposure of the bone in the unique microenvironment of the oral cavity.

Metastatic neuroendocrine carcinomas to the head and neck: report of 4 cases and review of the literature.

Neuroendocrine carcinoma (NEC) is a cancer arising from neuroendocrine cells, most commonly in the lungs. Rarely, NEC may metastasize to the head and neck. Here, we present 4 cases of metastatic NEC to the jaws and major salivary glands. Patients were 3 females and 1 male, ages ranging from 48 to 82 (mean 59). Three primaries were located in the lung and one in the breast. The parotid was the site of metastasis in 2 patients, with the jaws being involved in the other 2. Histologic and immunohistochemical examination revealed 2 well-differentiated NEC and 2 poorly differentiated NEC. Treatment included surgery, radiation, and chemotherapy. Our series shows these lesions can present in the oral and maxillofacial region as frank malignancies or mimic benign processes. Although rare, these tumors should be included in the differential diagnosis of head and neck lesions, particularly when the patient presents with a history of a previous NEC.

Farnesol-induced apoptosis in Candida albicans.

Farnesol, a precursor in the isoprenoid/sterol pathway, was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. Farnesol is involved in the inhibition of germination and biofilm formation by C. albicans and can be cytotoxic at certain concentrations. In addition, we have shown that farnesol can trigger apoptosis in mammalian cells via the classical apoptotic pathways. In order to elucidate the mechanism behind farnesol cytotoxicity in C. albicans, the response to farnesol was investigated, using proteomic analysis. Global protein expression profiles demonstrated significant changes in protein expression resulting from farnesol exposure. Among the downregulated proteins were those involved in metabolism, glycolysis, protein synthesis, and mitochondrial electron transport and the respiratory chain, whereas proteins involved in folding, protection against environmental and oxidative stress, actin cytoskeleton reorganization, and apoptosis were upregulated. Cellular changes that accompany apoptosis (regulated cell death) were further analyzed using fluorescent microscopy and gene expression analysis. The results indicated reactive oxygen species accumulation, mitochondrial degradation, and positive terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) in the farnesol-exposed cells concurrent with increased expression of antioxidant-encoding and drug response genes. More importantly, the results demonstrated farnesol-induced upregulation of the caspase gene MCA1 and the intracellular presence of activated caspases. In conclusion, this study demonstrated that farnesol promotes apoptosis in C. albicans through caspase activation, implying an important physiological role for farnesol in the fungal cell life cycle with important implications for adaptation and survival.

A novel immune evasion strategy of candida albicans: proteolytic cleavage of a salivary antimicrobial peptide.

Oropharyngeal candidiasis is an opportunistic infection considered to be a harbinger of AIDS. The etiologic agent Candida albicans is a fungal species commonly colonizing human mucosal surfaces. However, under conditions of immune dysfunction, colonizing C. albicans can become an opportunistic pathogen causing superficial or even life-threatening infections. The reasons behind this transition, however, are not clear. In the oral cavity, salivary antimicrobial peptides are considered to be an important part of the host innate defense system in the prevention of microbial colonization. Histatin-5 specifically has exhibited potent activity against C. albicans. Our previous studies have shown histatin-5 levels to be significantly reduced in the saliva of HIV+ individuals, indicating an important role for histatin-5 in keeping C. albicans in its commensal stage. The versatility in the pathogenic potential of C. albicans is the result of its ability to adapt through the regulation of virulence determinants, most notably of which are proteolytic enzymes (Saps), involved in tissue degradation. In this study, we show that C. albicans cells efficiently and rapidly degrade histatin-5, resulting in loss of its anti-candidal potency. In addition, we demonstrate that this cellular activity is due to proteolysis by a member of the secreted aspartic proteases (Sap) family involved in C. albicans pathogenesis. Specifically, the proteolysis was attributed to Sap9, in turn identifying histatin-5 as the first host-specific substrate for that isoenzyme. These findings demonstrate for the first time the ability of a specific C. albicans enzyme to degrade and deactivate a host antimicrobial peptide involved in the protection of the oral mucosa against C. albicans, thereby providing new insights into the factors directing the transition of C. albicans from commensal to pathogen, with important clinical implications for alternative therapy. This report characterizes the first defined mechanism behind the enhanced susceptibility of HIV+ individuals to oral candidiasis since the emergence of HIV.

The oncogenic effects of constitutive Stat3 signaling in salivary gland cancer cells are mediated by survivin and modulated by the NSAID sulindac.

OBJECTIVE: Constitutive activation of the signal transducer and activator of transcription 3 (Stat3) has been detected in various human cancers and has been linked to tumor development and progression. Oncogenic Stat3 signaling results in induction of specific target genes, among which survivin is implicated in the proliferation and survival of cancer cells. Targeting of Stat3 constitutive expression by the nonsteroidal antiinflammatory drug (NSAID) sulindac has been demonstrated to exert antineoplastic effects in oral squamous cell carcinoma cells in vitro and in vivo. STUDY DESIGN: The expression and functional role of Stat3 and survivin was evaluated in 2 salivary gland adenocarcinoma cell lines (HSY and HSG). In addition, the effects of the NSAID sulindac and other cyclooxygenase (COX) inhibitors on Stat3 and survivin expression and on cell proliferation and apoptosis of HSY and HSG cells were analyzed. RESULTS: Messenger RNA and protein expression of Stat3 and survivin was detected in HSY and HSG cell lines. Treatment of these cells with siRNA against Stat3 or survivin inhibited cell proliferation and induced apoptosis. Moreover, Stat3 siRNA treatment down-regulated the protein and mRNA expression of survivin, and survivin forced expression partially reversed the antineoplastic effects of Stat3 siRNA treatment. Treatment of HSY and HSG cells with the NSAID sulindac, but not other COX inhibitors, induced significant decreases in cell proliferation and increases in apoptosis, accompanied by down-regulation of Stat3 and survivin expression. In contrast, survivin forced expression or transfection with constitutively active Stat3 attenuated the effects of sulindac on cell growth and apoptosis. CONCLUSIONS: Taken together, these data support the importance of the constitutive Stat3 signaling for growth and survival of salivary gland cancer cells through the induction of survivin. Inhibition of the oncogenic Stat3-survivin pathway in these cells can be achieved by selective targeting techniques or treatment with the NSAID sulindac and holds promise for the treatment of salivary gland cancer.

Immunohistochemical expression of the oncogenic molecules active Stat3 and survivin in benign and malignant salivary gland tumors.

OBJECTIVE: Signal transducer and activator of transcription 3 (Stat3) and survivin have been shown to exert oncogenic effects in various human neoplasms. The purpose of this study was to evaluate the expression of tyrosine phosphorylated (active) Stat3 and survivin in various benign and malignant salivary gland tumors (SGTs). STUDY DESIGN: Eighty-six SGTs (65 malignant and 21 benign tumors of various histopathologic subtypes) were immunohistochemically stained with antisurvivin or anti-phosphorylated tyrosine-705 (p-tyr) Stat3 antibodies. Immunohistochemical reactivity was graded in a semiquantitative manner; a combined score of immunohistochemical positivity (0-6) was calculated for each tumor by adding the individual scores for percentage of tumor cells (0-3) and intensity of staining (0-3). RESULTS: Survivin was immunohistochemically detected in all studied benign and malignant SGTs; p-tyr Stat3 was also detected in the majority (91%) of SGTs. The average combined scores for survivin and p-tyr Stat3 immunohistochemical expression in the studied malignant SGTs was 4.40 and 3.35, respectively; the corresponding combined scores for survivin and p-tyr Stat3 in the studied benign SGTs were 4.37 and 3.22, respectively. No statistically significant differences (P > .05) in p-tyr Stat3 or survivin expression were detected between the benign and malignant groups, or among the various examined histopathologic subtypes of SGTs. In contrast, normal salivary gland tissues revealed only weak and focal survivin or p-tyr Stat3 immunoreactivity, mainly localized to ductal and mucous cells. CONCLUSIONS: Our data indicate an almost universal expression of activated Stat3 and survivin in benign and malignant SGTs. Considering the well established proliferative and antiapoptotic properties of these molecules and their functional interrelationship, selective targeting techniques against Stat3 and/or survivin may represent promising therapeutic strategies against neoplasms of salivary gland origin.