Rhabdomyosarcoma of the head and neck: impact of demographic and clinicopathologic factors on survival.

OBJECTIVE: To determine the survival factors for patients diagnosed with rhabdomyosarcoma of the head and neck. STUDY DESIGN: Data on patients diagnosed with rhabdomyosarcoma of the head and neck between 1973 and 2012 were extracted from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier and Cox proportional hazard regression models were used to determine the demographic characteristics, prognostic factors, and treatment modalities that determine overall survival (OS) and disease-specific survival (DSS). RESULTS: Data on 503 patients diagnosed with rhabdomyosarcoma of the head and neck were analyzed; 51.3% were male and 48.7% were female, with a median OS of 4.9 years. Kaplan-Meier analysis determined 5-year survival rates of 30% for OS and 50% for DSS. Multivariate analysis found that age at diagnosis, tumor extent of disease, surgical resection, and radiation therapy were independent predictors of OS and DSS. CONCLUSIONS: To our knowledge, this is the largest year-span study to date to determine the factors of survival for rhabdomyosarcoma of the head and neck. Older age at diagnosis, histologic subtype of alveolar rhabdomyosarcoma, and further extent of disease were associated with decreased survival. Surgical resection improves survival in patients with localized or regional disease, and radiation therapy confers survival benefits in patients with distant extent.

Importance of tumor extent in adenosquamous carcinoma of the head and neck: a retrospective cohort study.

OBJECTIVE: The aim of this study was to determine the correlates of survival for patients diagnosed with adenosquamous carcinoma (ASC) of the head and neck. STUDY DESIGN: Patients diagnosed with ASC of the head and neck between 1973 and 2012 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox proportional hazard regression analyses were conducted to investigate the prognostic factors and treatment modalities that determine overall survival (OS) and disease-specific survival (DSS). RESULTS: In the analysis, of the 235 patients diagnosed with adenosquamous of the head and neck, 66.8% were male and 33.2% were female with a median age at diagnosis of 64 years. Kaplan-Meier analysis determined 5-year survival rates of 30% for OS and 50% for DSS. Univariate and multivariate analyses found that age at diagnosis, tumor size, tumor extent of disease, surgical resection, and radiation therapy were independent predictors of OS and DSS. CONCLUSIONS: This study, to our knowledge, is the largest study, to date, determining the correlates of survival for ASC of the head and neck. Older age at diagnosis, larger tumor size, and further extent of disease were correlated with decreased survival. Surgical resection improves survival in patients with localized or regional disease, whereas radiation therapy confers survival benefit in patients with distant extent.

Determining the epidemiologic, outcome, and prognostic factors of oral malignant melanoma by using the Surveillance, Epidemiology, and End Results database.

BACKGROUND: The authors conducted a retrospective analysis to determine the epidemiologic, outcome, and prognostic factors in patients with oral malignant melanoma (OMM). METHODS: The authors used the US National Cancer Institute's Surveillance, Epidemiology, and End Results database to analyze patients with OMM from 1973 to 2012. Study variables included age, sex, race, decade of diagnosis, extent of disease, tumor size, treatment modality, and socioeconomic status (SES). RESULTS: The search identified 232 patients with OMM. Overall survival (OS) and disease-specific survival (DSS) were 25% and 40%, respectively, at 5 years. Age (OS, P = .004; DSS, P = .294), surgical resection (OS, P = .046; DSS, P = .005), and extent of disease (OS, P < .001; DSS, P < .001) were independent survival determinants; tumor size was an independent predictor of OS (P = .085). For confined and locally invasive disease, surgery (OS, P = .001; DSS, P = .004) and size (OS, P = .154; DSS, P = .007) were independent determinants of OS and DSS. For metastatic disease, surgery (OS, P = .675; DSS, P = .518) was a survival determinant for both OS and DSS, whereas radiotherapy predicted improved OS (hazard ratio, 0.18; 95% confidence interval, 0.03 to 0.99; P = .049). CONCLUSIONS: Age at diagnosis, decade of diagnosis, extent of disease, tumor size, and SES are prognostic factors related to OMM survival. Surgical resection and radiation therapy both improve OMM survival. PRACTICAL IMPLICATIONS: Early and detailed examinations for OMM are critical to improving the survival rate in patients with OMM, especially in older patients and patients of lower SES.

Gnathodiaphyseal dysplasia: report of a family with a novel mutation of the ANO5 gene.

Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant disorder characterized by florid osseous dysplasia of the jaws, bone fragility, and diaphyseal cortical thickening and bowing of long bones. We present a family with previously undiagnosed GDD. The disorder was identified by the characteristic gnathic and skeletal manifestations in the father. Clinical and radiologic examination of the patient's son also revealed the characteristic features of GDD. Gene sequencing revealed a novel mutation (c. 1067 G>A, p. Cys356 Tyr) in the ANO5 gene, which is causative for GDD. This mutation was predicted to be detrimental by computational analyses and by structural modeling of the protein. The implications for recognition and management of this disease are discussed.

Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes.

OBJECTIVE: To determine the demographic characteristics, prognostic factors, and optimal treatment modalities of patients diagnosed with malignant primary tumors of the sublingual gland. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry contains 210 patients diagnosed with sublingual gland tumors in the SEER database. Kaplan-Meier and multivariate Cox regression analysis were performed on age, sex, race, histologic subtype, stage, and treatment modality. RESULTS: Kaplan-Meier analysis found an overall survival and disease-specific survival at 5 years of 69% and 83%, respectively. Multivariate analysis demonstrated that age, sex, stage, and surgery were predictors of overall survival, whereas stage was a predictor of disease-specific survival. CONCLUSIONS: Here we report, to our knowledge, the largest study to date investigating demographic characteristics, prognostic factors, and treatment modalities of patients diagnosed with primary malignant tumors of the sublingual gland. Increased age and stage correlated with decreased survival, whereas female gender and surgical therapy correlated with increased survival in the overall population. Radiation therapy for patients diagnosed with adenoid cystic carcinoma in the sublingual gland was correlated with increased survival.

Epidemiology, prognostic factors, and management of malignant odontogenic tumors: an analysis of 295 cases.

OBJECTIVE: To determine the demographic characteristics, prognostic factors, and management for patients diagnosed with a malignant odontogenic tumor (MOT). STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) registry was reviewed for patients diagnosed with MOT from 1973 to 2011. Kaplan-Meier and multivariate Cox regression analyses were performed on patient demographic characteristics and pathologic variables. RESULTS: The SEER database identified 295 MOT patients. The mean age at diagnosis was 50.5 years (range 5-89 years). Of these patients, 61.7% were male and 38.3% were female. The racial composition was 66.4% White, 22% Black, 6.1% Asian, 3.1% Pacific Islander, 0.3% Native American, and 2.1% Other/Unknown. Kaplan-Meier analysis found an overall survival (OS) and disease-specific survival (DSS) at 5 years of 54% and 67%, respectively. Multivariate analysis of the entire cohort found that age and stage were predictors of OS and that age was a predictor for DSS. For stage I/II MOTs, age and surgical therapy were predictors of OS and DSS, respectively. CONCLUSIONS: Here we report the largest study to date investigating demographic characteristics, prognostic factors, and management of MOT patients. Determinants of survival for OS and DSS include age, stage, and surgical therapy.

Epidemiology, Prognostic Factors, and Treatment of Malignant Submandibular Gland Tumors: A Population-Based Cohort Analysis.

IMPORTANCE: Malignant tumors of the submandibular gland are uncommon, leading to limited information regarding prognostic factors and difficulty in evaluating treatment modalities. OBJECTIVE: To investigate the correlates of survival in patients with primary malignant tumors of the submandibular gland. DESIGN, SETTING, AND PARTICIPANTS: Data from 2626 patients with a diagnosis of primary tumors of the submandibular gland between 1973 and 2011 in the Surveillance, Epidemiology, and End Results database were used in a retrospective population-based cohort analysis. Kaplan-Meier analysis along with multivariate Cox regression analysis was performed to determine prognostic factors in overall survival (OS) and disease-specific survival (DSS). INTERVENTIONS: Patients were treated with surgery, radiation therapy, both, or neither. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: We identified 2626 patients with a diagnosis of primary malignant tumors of the submandibular gland, 52.9% male and 47.1% female, with a mean (range) age of 61.3 (7-101) years. Adenoid cystic carcinoma (36.0%) was the most prevalent histologic subtype, followed by squamous cell carcinoma (18.1%), mucoepidermoid carcinoma (16.9%), and adenocarcinoma (13.7%). Kaplan-Meier analysis demonstrated an OS and DSS of 65% and 74%at 2 years, 54% and 67% at 5 years, and 40% and 60% at 10 years, respectively. Multivariate Cox regression analysis revealed independent predictors of OS and DSS to be age (HR, 1.04 [95% CI, 1.03-1.04], P < .001; HR, 1.02 [95% CI, 1.01-1.03], P < .001), sex (HR, 0.69 [95% CI, 0.57-0.84], P < .001; HR, 0.73 [95% CI, 0.56-0.96], P = .02), tumor grade (HR, 1.47 [95% CI, 1.19-1.81], P < .001; HR, 1.67 [95% CI, 1.25-2.25], P = .001), stage at presentation (HR, 1.56 [95% CI, 1.41-1.72], P < .001; HR, 1.96 [95% CI, 1.69-2.28], P < .001), and surgical resection (HR, 0.55 [95% CI, 0.41-0.74], P < .001; HR, 0.51 [95% CI, 0.35-0.75], P = .001). CONCLUSIONS AND RELEVANCE: We report, to our knowledge, the largest study to date focused on correlates of survival in submandibular gland malignant neoplasms. Multivariate analysis found that older age at diagnosis, high tumor grade, and later stage at presentation were correlated with decreased survival whereas female sex and surgical resection were correlated with increased survival. In addition, a 3-cm tumor cutoff size was demonstrated above which was associated with a significantly less favorable prognosis. Radiation therapy had mixed association with survival, dependent on tumor size and subtype.

Characteristics and prognostic factors of osteosarcoma of the jaws: a retrospective cohort study.

IMPORTANCE: Osteosarcoma of the jaws is rare and clinically distinct from osteosarcoma of the long bones of the body with different treatment and outcomes. The literature on these tumors is limited to case reports and small case series mostly from single institutions. We used data from the population-based national Surveillance, Epidemiology and End Results (SEER) cancer registry to determine the epidemiology and prognostic factors associated with osteosarcoma of the jaws. OBJECTIVE: To investigate the epidemiologic characteristics and prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, population-based cohort study of 541 patients in the SEER tumor registry diagnosed with osteosarcoma of the jaws from 1973 through 2011 were reviewed. EXPOSURES: Patients had been treated with surgery, radiation, both, or neither. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: A total of 541 patients diagnosed with osteosarcoma of the jaws were identified (49.9% male and 50.1% female, with a mean age of 41.3 years). Kaplan-Meier analysis demonstrated an overall survival (OS) and disease-specific survival (DSS) of 53% and 62%, respectively, at 5 years and 35% and 54%, respectively, at 10 years. Multivariate Cox regression analysis revealed that independent predictors of OS and DSS included age at diagnosis (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04 [P < .001] for OS; and HR, 1.03; 95% CI, 1.02-1.05 [P < .001] for DSS); stage at presentation (HR, 1.37; 95% CI, 1.10-1.71 [P = .006] for OS; and HR, 1.34; 95% CI, 1.01-1.76 [P = .04] for DSS); and surgical resection (HR, 0.31; 95% CI, 0.16-0.60 [P < .001] for OS; and HR, 0.22; 95% CI, 0.09-0.56 [P = .001] for DSS). Tumor size was not significant for OS (HR, 1.00; 95% CI, 1.00-1.01 [P = .11] but significant for DSS (HR, 1.01; 95% CI, 1.00-1.01 [P = .003]). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study to date investigating prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. Determinants of survival include age at diagnosis, stage at presentation, tumor size, and surgical therapy. Radiation therapy was not associated with improved survival, reflecting the controversy surrounding its use in clinical literature.

Extensive carcinoma cuniculatum of the mandible.

Carcinoma cuniculatum (CC) is a rare variant of squamous cell carcinoma first described in 1954. Cases of CC in the head and neck are exceedingly rare, with 66 cases reported since 1977. These tumors are generally low-grade, well-differentiated and locally aggressive malignancies. Patients are often subjected to a long period of misdiagnoses given the clinical similarity of these entities to odontogenic cysts and abscesses. We report a case of a carcinoma cuniculatum of the mandible with very advanced local involvement of disease, highlighting the unusual characteristics of this rare tumor that are important for clinicians to recognize. Clinical presentation, histology, risk factors, treatment options, and prognosis are also reviewed.

Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells.

Mounting effective anti-tumor immune responses by cytotoxic effectors is important for the clearance of tumors. However, accumulated evidence suggests that the cytotoxic function of immune effectors is largely suppressed in the tumor microenvironment by a number of distinct effectors and their secreted factors. The aims of this review are to provide a rationale and potential mechanism for immunosuppression in cancer, and to demonstrate the significance of such immunosuppression in cellular differentiation and tissue regeneration in pathological conditions, and progression of cancer. We have recently shown that increased NK cell function was seen when they were cultured with primary oral squamous carcinoma stem cells (OSCSCs) as compared to their more differentiated oral squamous carcinoma cells (OSCCs). In addition, human embryonic stem cells (hESCs), Mesenchymal Stem Cells (hMSCs), dental pulp stem cells (hDPSCs) and induced pluripotent stem cells (hiPSCs) were significantly more susceptible to NK cell mediated cytotoxicity than their differentiated counterparts or parental cells from which they were derived. We have also reported that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or targeted knock down of COX2 augmented NK cell function significantly. Total population of monocytes and those depleted of CD16(+) subsets were able to substantially prevent NK cell mediated lysis of OSCSCs, MSCs and DPSCs. Taken together, our results suggest that stem cells are significant targets of the NK cell cytotoxicity. The concept of split anergy in NK cells and its contribution to tissue repair and regeneration and in tumor resistance and progression will be discussed in this review. Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation at the site of the tumor for specific elimination of cancer stem cells.

Expression and mutation analysis of heterogeneous nuclear ribonucleoprotein G in human oral cancer.

We previously reported that wild type (wt) hnRNP G exhibited tumor suppressive activity in human oral squamous cell carcinoma (HOSCC) cell lines lacking hnRNP G. Wt hnRNP G markedly inhibited the proliferation capacity, anchorage independency and in vivo tumorigenicity of HOSCC cells and notably enhanced the DNA repair capabilities of these cells. In the present study, we studied the genetic and expression states of hnRNP G in normal, premalignant and malignant human oral tissues to further understand the relationship between the hnRNP G alterations and the development of human oral cancer. To correlate the cancer development and the level of hnRNP G expression, we performed an immunohistochemistry staining of hnRNP G in normal, premalignant and malignant human oral tissues. Moreover, we examined the entire coding regions of hnRNP G from selected samples to understand the cause of the alterations of the gene expression. The expression of hnRNP G was notably decreased or completely abolished in 80% of premalignant-dysplastic and malignant oral epithelial tissues, whereas 100% of normal and 90% of hyperplastic non-dysplastic epithelium showed high level of hnRNP G in the nucleus of the basal cell layers. Approximately 80% of HOSCC lacking the expression of hnRNP G showed genetic alteration in hnRNP G, i.e., point mutation and exonic deletion. This study suggest that genetic alterations and aberrant expression of hnRNP G occurring during oral carcinogenesis might be useful markers for the early detection of human oral cancer.

The role of the microenvironment in tumor immune surveillance.

The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O'Shea & Paul, 2010 [4]). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.

Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats.

Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate-related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 microg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(-)]. The prevalence of ONJ in the VitD(-)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(-) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end label-positive (TUNEL(+)) osteoclasts significantly increased on the surface of post-tooth extraction alveolar bone of the VitD(-)/ZOL group, where sustained inflammation was depicted by [(18)F]fluorodeoxyglucose micro-positron emission tomography (microPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity.

A case of Kombucha tea toxicity.

INTRODUCTION: Kombucha "mushroom'' tea is touted to have medicinal properties. Here, we present a case of hyperthermia, lactic acidosis, and acute renal failure within 15 hours of Kombucha tea ingestion. CASE PRESENTATION: A 22 year old male, newly diagnosed with HIV, became short of breath and febrile to 103.0F, within twelve hours of Kombucha tea ingestion. He subsequently became combative and confused, requiring sedation and intubation for airway control. Laboratories revealed a lactate of 12.9 mmol/L, and serum creatinine of 2.1 mg/dL. DISCUSSION: Kombucha tea is black tea fermented in a yeast-bacteria medium. Several case reports exist of serious, and sometimes fatal, hepatic dysfunction and lactic acidosis within close proximity to ingestion. CONCLUSION: While Kombucha tea is considered a healthy elixir, the limited evidence currently available raises considerable concern that it may pose serious health risks. Consumption of this tea should be discouraged, as it may be associated with life-threatening lactic acidosis.

LCK, survivin and PI-3K in the molecular biomarker profiling of oral lichen planus and oral squamous cell carcinoma.

T cell signaling is critical in oral lichen planus (OLP) based on the pathogenesis of this chronic inflammatory autoimmune mucocutaneous lesion. Lck plays a key role in T cell signaling; ultimately this signaling affects other targets such as PI-3K. Excessive activity in PI-3K inhibits apoptosis and promotes uncontrolled cell growth. Molecular biomarker profiling in OLP, Chronic Interface Mucosities (CIM), Epithelial Dysplasia (EpD) and Oral Squamous Cell Carcinoma (SCCA) with application of the principle of biomarker voting may represent a new frontier in the diagnosis, assessment and the arguable debate of OLP transformation to cancer. The presence of Lck, PI-3K and Survivin, a cancer specific anti-apoptotic protein was assessed, using immunohistochemistry and tissue micro-array on patient samples, in OLP, SCCA, CIM and EpD. Lck expression was very high in 78.6 % of OLP patients compared to 3.7% in SCCA; PI-3K was high in 63% of SCCA, 100% of EpD, and 35.7% OLP cases. Survivin was high in 64.3% of OLP cases, 96.3% of SCCA, and 100% of EpD. CIM cases may be slightly different molecularly to OLP. Taken together, our data suggest that biomarker protein voting can be effectively used to isolate high-risk OLP cases. Specifically, we show data with four remarkable cases demonstrating that molecular factors are predictive of histopathology. We conclude that it is safer to treat OLP as premalignant lesions, to adopt aggressive treatment measure in histopathologic described well and moderately differentiated SCCA, and to monitor progress of these diseases molecularly using individualized auto-proteomic approach. The use of Lck inhibitors in OLP management needs to be investigated in the future.

HIV-1 Tat enhances replicative potential of human oral keratinocytes harboring HPV-16 genome.

Introducing highly active antiretroviral therapy (HAART) has significantly decreased the morbidity and mortality in human immunodeficiency virus-positive (HIV+) individuals by decreasing the viral loads and increasing the CD4+ T-cell counts. Subsequently, the occurrence of many HIV-associated diseases has been dramatically declined except human papillomavirus (HPV)-associated lesions. Such notion suggests that immune response is not a major determinant, and that the direct interaction between HIV and HPV may be involved in the HPV-associated pathogenesis. In the current study, we investigated whether HIV plays a direct role in HPV-associated oral carcinogenesis by using HIV-1 transactivator protein (Tat), which is known to have oncogenic properties. We found that HIV-1 Tat not only increased the expression of HPV-16 E6 and E7 oncogenes in human oral keratinocytes harboring the HPV type-16 genome (HOK-16B), but also notably enhanced the proliferative capacity of the cells in vitro. Moreover, HOK-16B cells expressing HIV-1 Tat was capable of inducing cystic nodules in nude mice, while the control HOK-16B cells failed to produce nodules in the mice. Our results indicate that HIV could play a role in the HPV-associated pathogenesis by exerting oncogenic stimulus via Tat protein.

Heterogeneous nuclear ribonucleoprotein G shows tumor suppressive effect against oral squamous cell carcinoma cells.

PURPOSE: Heterogeneous nuclear ribonucleoproteins (hnRNP) are nucleic acid binding proteins involved in RNA processing. We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC). The current study was designed to test the hypothesis that hnRNP G is a tumor suppressor. EXPERIMENTAL DESIGN: We investigated the expression levels of hnRNP G protein in normal, precancerous, and malignant oral tissues by in situ immunohistochemistry. In addition, wild-type or mutant hnRNP G was ectopically overexpressed in HOSCC cells and their effects on cellular replication kinetics, colonogenic efficiency, anchorage-independent growth, and in vivo tumorigenicity were determined. RESULTS: In situ immunohistochemical staining showed robust presence of hnRNP G in the basal cell layers of normal oral epithelium but the level of its staining was markedly reduced in dysplastic or cancerous tissues. Ectopic expression of wild-type hnRNP G in cancer cells lacking hnRNP G expression or containing mutant hnRNP G resulted in severe retardation of proliferation, reduction of colonogenic efficiency, loss of anchorage-independent growth, and reduction of in vivo tumorigenicity in immunocompromised mice. In addition, hnRNP G overexpression led to up-regulation of the expression of TXNIP, a cell cycle inhibitory gene, and significantly reduced the expression of the genes that promote cellular proliferation, such as EGR1, JUND, JUNB, FOS, FOSL1, ROS, and KIT. CONCLUSIONS: These results indicate that hnRNP G is a tumor suppressor against HOSCC but its mechanisms of action remain to be further investigated.

Neuro-immunity in stress-related oral ulcerations: a fractal analysis.

By testing archival paraffinized biopsy blocks obtained from the oral pathology library with immunohistochemistry, we tested the hypothesis that substantial alterations are demonstrable in the cross-talk between sympathetic (VMAT) and para-sympathetic innervation (VAchT), and resident CD3+ T cells in the mucosa from oral lichen planus (OLP), compared to recurrent aphthous stomatitis (RAS) and control biopsies. We quantified fractal dimension and Euclidean dimension of CD3+ cells between the two pathologies, and across the set of CD3+ cells proximal to the vesicles of monoamines transport (VMAT)+ or the vesicles of acetylcholine transport (VAchT)+ innervation, compared to cells relatively distal to the nerve endings. The data show exquisite organization of the punctuate sympathetic and para-sympathetic staining about the resident CD3+ T cells in the OLP lesions, but not in the aphthous lesions or in control mucosa. Fractal analysis reveals that aphthous lesions are characterized by CD3+ T cells of larger size (Euclidean dimensional map), compared to control mucosa. CD3+ T cells in OLP lesions are also found to be significantly larger than those found in control lesions, when they are not proximal to sympathetic or para-sympathetic vesicles. The membrane of CD3+ T cells is overall more complex (fractal dimension) in aphthous lesions, compared to control sections. A similar trend is apparent, albeit not statistically significant, in CD3+ T cells resident in OLP lesions, whether or not they are located proximal to nerve endings. An overall decrease in the ratio of fractal dimension-over-topological dimension was also observed across the pathological lesions, compared to control. Taken together, these data indicate that as CD3+ T cells grow larger in the pathological conditions, they, in effect, stretch their plasma membrane, and that the cells may be at different stage of the cell cycle, relative to their position vis a' vis nerve endings. Because fractal analysis is performed on individual cells, it has the potential of being developed in a novel diagnostic test, as well as a prognostic tool for monitoring the etiology and the course of treatment at the individual cellular level. Our findings also open new frontiers of fundamental, clinical and translational biosciences of OLP.

Psychoneuroimmunology in oral biology and medicine: the model of oral lichen planus.

Rheumatoid arthritis involves psychoneuroendocrine-immunopathological comorbidities. In the stoma, patients with rheumatoid arthritis frequently show signs of periondontal disease consequent to elevated levels of crevicular proinflammatory cytokines. It is not clear whether rheumatoid arthritis may manifest in association with immunopathological manifestations of the oral soft mucosa. Oral lichen planus (OLP), first described by E. Wilson in 1859, is a T-cell-mediated inflammatory disease whose lesions characteristically lack B cells, plasma cells, immunoglobulin. or complement. It is increasingly well characterized and recognized as a model for psychoneuroimmunology research in oral biology and medicine. To date, we have shown an association between changes in hypothalamic-pituitary-adrenal (HPA) regulation, systemic markers of cellular immunity and mood states, with clinical stages of OLP (i.e., atrophic vs. erosive vs. bullous lesions). We report significant associations (p < 0.05) between the stage of OLP, HPA deregulation, and altered distribution and functional responses of naïve CD4(+) cells. We emphasize the need to study in greater details the psychoneuroendocrine-immune inter-relationships in OLP, and we propose a novel neuroimmune hypothesis for OLP.