p38 Expression and Modulation of STAT3 Signaling in Oral Cancer.

p38 protein belongs to Mitogen-activated protein kinases family that link extracellular stimuli with intracellular responses participating in numerous of fundamental cell processes. Persistent activation of STAT3 has been associated with cell proliferation, differentiation and apoptosis in oral squamous cell carcinoma (OSCC). This study examines the effects of p38 modulation on STAT3 signaling and cellular activities in OSCC cells and investigates possible correlation of p38 expression with tumor degree of differentiation. Phospho-p38 immunostaining was performed in 60 OSCC including well, moderately and poorly differentiated tumors. Semiquantitative analysis was used, by calculating intensity, percentage and combined scores. Protein expression levels of STAT3 (total, tyrosine and serine phosphorylated), p38 and cyclin D1 were assessed in two OSCC cell lines. p38 inhibition was achieved by pharmacological agent(SB2023580). Cell proliferation and viability rates were also evaluated. Phospho-p38 immunoexpression was intense in almost all tumor specimens, nevertheless did not correlate with tumor differentiation. Inhibition of p38 with SB203580 did not appear to affect tyrosine or serine phosphorylated STAT3 as well as cyclin D1 levels in both cell lines. Moreover, p38 inhibition resulted in mild dose-dependent decreases in cell growth and viability in both cell lines. p38 is highly expressed in OSCC but does not seem to mediate the oncogenic STAT3 pathway. However, changes found in proliferation and viability may suggest that p38 functions as potent regulator of HNSCC. Understanding the complexity of p38 signaling and cross-talk between other major molecules, may guide the development of novel pharmacologic therapies for cancer treatment and prevention.

Oral medicine in Europe: past, present and future.

Oral medicine (OM) is a relatively young dental specialty usually dealing with the oral healthcare of patients suffering from chronic recurrent and medically-related disorders of the mouth and maxillofacial region and with their diagnosis and mostly non-surgical management. The beginning of OM goes back to 1925 in the USA and 1950s in Europe. However, official specialty recognition is more recent and within Europe, it is only in the UK, Croatia and Israel where OM is recognised by local registering authorities, although in several other European countries it is viewed as a distinct field of study. Despite a broad agreement in OM syllabi and clinical practice, there are still some important differences in its definition and scopes within Europe. It is crucial that European countries agree a consensus definition of OM and clarify competencies and limits, so they may move from institution and region-specific approaches to an international framework. According to the European Directives, it is timely to recognise a minimum three year standard curriculum at a post-graduate level which will lead to uniformity of training for OM residencies in European country members and will eventually provide guidelines for a broader OM specialty recognition.

ERK1/2, JNK and STAT3 activation and correlation with tumor differentiation in oral SCC.

Signal transducer and activator of transcription 3 (STAT3) and mitogen activated protein kinases (MAPKs), including ERK and JNK, have been implicated in oral squamous cell carcinoma (OSCC) development and progression. Our purpose was to evaluate the levels of activated STAT3, ERK1/2 and JNK by immunohistochemistry in OSCC and to investigate possible correlations of these molecules with each other as well as with the degree of tumor differentiation. Immunohistochemical assessment of the phosphorylated levels of STAT3(tyrosine/ serine), ERK1/2 and JNK was performed in 60 OSCC, including well, moderately and poorly differentiated tumors. Semiquantitative scoring system was used, by calculating intensity of immunostaining, percentage of positive cells and combined scores. Statistics included Fisher's test, Student's T-Test and Kruskal-Wallis analysis, Spearman's correlation coefficient and multivariate logistic regression analyses. Immunohistochemical levels of both pSTAT3(tyr) and pERK1/2 showed statistically significant differences between well and poorly differentiated tumors with the latter receiving higher mean percentage, intensity and total scores. On the other hand, pJNK showed statistically significantly higher intensity levels in moderately compared to poorly differentiated tumors. pSTAT3(ser) immunoexpression did not appear to correlate with tumor differentiation. Between different molecules, more pronounced, pERK1/2 levels exhibited statistically significant positive correlation with pSTAT3(ser), pSTAT3(tyr) and pJNK expression. ERK1/2 and STAT3 activation (as assessed by tyrosine but not serine phosphorylation) could contribute to a less differentiated phenotype in OSCC, while JNK activation may have an opposite, although possibly less pronounced, effect. Positive correlations between MAPK and STAT3 levels may indicate a direct crosstalk and/or regulation by common upstream pathways.

Immunohistochemical evaluation of the mTOR pathway in intra-oral minor salivary gland neoplasms.

OBJECTIVES: The aim of this study was to investigate the expression of upstream and downstream molecules of the oncogenic mTOR signaling pathway in intra-oral minor salivary gland tumors (SGTs). MATERIALS AND METHODS: Tissue samples consisted of 39 malignant and 13 benign minor SGTs, and 8 controls of normal minor salivary glands (NMSG). An immunohistochemical analysis for phosphorylated Akt, 4EBP1 and S6 (total and phosphorylated), and eIF4E was performed. RESULTS: Expression of pAkt and 4EBP1 was observed in all SGTs and in most NMSG. p4EBP1 was detected in almost all SGT cases, NMSG being negative. S6 immunoreactivity was observed in 37.5% of NMSG, 92.3% of benign and 100% of malignant SGTs, while pS6 expression was observed in 77% of benign and 95% of malignant SGTs, but not in NMSG. Finally, eIF4E was expressed in 12.5% of NMSG, 69.2% of benign, and 76.9% of malignant tumors. All molecules studied had statistically significantly lower expression in NMSG compared with SGTs. Moreover, malignant neoplasms received higher scores compared with benign tumors for all molecules with the exception of eIF4E. CONCLUSION: The mTOR signaling pathway is activated in SGTs, especially in malignancies. Therefore, the possible therapeutic role of targeting the mTOR pathway by rapamycin analogs in SGTs needs further investigation.

The role of mTOR signaling pathway in premalignant and malignant cervical lesions.

PURPOSE OF THE STUDY: Aberrant activation of the Akt/mTOR/pS6 signaling pathway has been identified in various types of cancer and is under investigation in cervical cancer. The purpose of this study was to assess the expression of the phosphorylated/activated forms of Akt (upstream molecule), 4E-BP1 and pS6 (downstream molecules) in biopsy samples of cervical low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), and squamous cell carcinoma (Ca) compared to normal cervical epithelium. MATERIAL AND METHODS: The study included 38 cases diagnosed as LSIL, 31 cases as HSIL, 29 cases as Ca, and eight control cases from normal cervix. Immunohistochemistry was used to assess the expression of pAkt, p4E-BP1 and pS6. RESULTS: Statistical analysis revealed significant differences between HSIL and Ca groups compared to controls regarding intensity, positivity, and total scores for all three molecules (p < 0.001). A trend for higher expression with increasing grade of dysplasia was demonstrated. CONCLUSION: These results strongly support the view that the mTOR signaling pathway is involved in cervical carcinogenesis.

Periapical lesions are not always a sequelae of pulpal necrosis: a retrospective study of 1521 biopsies.

AIM: To record the incidence of lesions that were not the sequelae of pulpal necrosis (non-SPN) amongst 1521 biopsies of periapical lesions submitted with a clinical diagnosis of a sequelae of pulpal necrosis (SPN). METHODOLOGY: A retrospective study of 1521 biopsy request forms of specimens submitted for histopathological examination with a clinical diagnosis 'periapical inflammation', 'periapical abscess', 'periapical granuloma' or 'periapical cyst' during an arbitrarily selected 14-year period was undertaken. Gender and age of the patient, site and maximum diameter of the lesion, symptoms, inclusion of the final diagnosis in the differential diagnosis and specialty of the clinician submitting the biopsy material were recorded in each case. The final diagnosis for each case was extracted from the pathology report, and two groups were formed, SPN and non-SPN lesions. Differences between the respective features of SPN and non-SPN cases were analysed with Yate's chi-square test and t-test (significance level P < 0.05) RESULTS: In 52 of the 1521 cases examined (3.42%), the histological diagnosis was not consistent with a SPN. In most non-SPN cases, the histopathological diagnosis was not included in the differential diagnosis. The keratocystic odontogenic tumour [odontogenic keratocyst (OKC)] was the most frequent non-SPN lesion (34.62%). Other, yet less frequent, non-SPN lesions included glandular odontogenic cysts, lateral periodontal cysts, central ossifying fibromas as well as malignancies (metastatic carcinomas and Langerhans cell histiocytosis). CONCLUSIONS: Non-SPN lesions appeared in the periapical region mimicking a SPN, although rarely. Most of them were developmental cysts, in particular OKCs, but odontogenic tumours, such as ameloblastoma, or malignant lesions were also diagnosed. Histological examination of tissue harvested from periapical lesions should be performed, in particular when those lesions are large.

Odontogenic keratocyst expresses vascular endothelial growth factor: an immunohistochemical study.

BACKGROUND: Vascular endothelial growth factor (VEGF) expression may act as a sensitive measure of the angiogenic potential of a lesion. Furthermore, VEGF has been implicated in the pathogenesis of cystic tumors and inflammatory odontogenic cysts. Thus, we studied the expression of VEGF in the epithelium of odontogenic keratocyst (OK) in association with cell proliferation and apoptosis. METHODS: Forty-two cases of OK, 26 cases of dentigerous cyst (DC), and 15 cases of residual cyst (RC) were retrospectively examined by immunohistochemistry for VEGF, Ki67/Mib-1 and anti-caspase-3. For VEGF and caspase-3, the intensity of immunostaining was qualitatively assessed, while for the evaluation of Ki67 the average number of positively stained nuclei in 10 high-power microscopic fields (x 400) was calculated. RESULTS: The VEGF expression was stronger in OK when compared with DC (P < 0.007). The rate of nuclear Ki67 expression in OK was significantly higher than that in DC (P < 0.001) and RC (P < 0.001). Cytoplasmic caspase-3 expression was statistically more intense in RC than in OK (P = 0.001) or DC (P < 0.001). A statistically significant correlation was seen in OK for Ki67 (P < 0.001) and VEGF (P = 0.023), but not for caspase-3. Multiple regression analysis revealed a linear relationship between VEGF and Ki67. CONCLUSIONS: The VEGF was expressed in the epithelium of OK, DC, and RC with a variable intensity, and in OK VEGF expression was related to Ki67. It is suggested that VEGF expression by the odontogenic epithelium is not induced solely by inflammation.

Spindle cell hemangioma (hemangioendothelioma) of the head and neck: case report of an unusual (or underdiagnosed) tumor.

Spindle cell hemangioma (SCH), also known as spindle cell hemangioendothelioma, is a unique vascular tumor with combined microscopic features of both a cavernous hemangioma and Kaposi sarcoma. It almost exclusively affects the dermis and subcutis of the distal extremities. A review of the literature disclosed only 5 cases of SCH reported in detail in the soft tissues of the head and neck. An additional case of SCH manifesting as a submucosal nodule in the upper lip of a 29-year-old woman is presented. Because this is the second case reported from the same institution, it is suggested that SCH is an underdiagnosed lesion.

Eosinophilic granuloma masquerading as aggressive periodontitis.

BACKGROUND: Eosinophilic granuloma (EG) is the mildest and mainly localized form of the clinicopathologic spectrum of Langerhans' cell histiocytosis. It is a destructive osseous lesion characterized by a vast number of eosinophils and histiocytes. The etiology remains unknown. In this paper, a case of EG is presented that was initially diagnosed and treated as aggressive periodontitis (AP). METHODS: Despite treatment procedures, the EG continued to expand very quickly, destroying the lingual cortical bone and the neighboring soft tissues and exhibiting periosteal reaction. Diagnosis of EG was established on the basis of histopathologic and immunohistochemical evaluation. Moreover, certain manifestations in the skeletal and respiratory system were observed. RESULTS: Surgical curettage of the lesions was effective; however, corticosteroids and low-dose radiation were used as adjunctive therapy. CONCLUSION: The rapid progress of eosinophilic granuloma, the diagnostic problems, and the consequences of late diagnosis and treatment are discussed.

TNF-alpha expression and apoptosis-regulating proteins in oral lichen planus: a comparative immunohistochemical evaluation.

Apoptosis appears to be the mode of cell death by which damaged cells are removed from the lesional tissue in oral lichen planus (OLP). In the present study, OLP biopsies were immunohistochemically evaluated for TNF-alpha and apoptosis-regulating proteins in an attempt to compare their phenotypic expression. Deparaffinized tissue sections from 22 OLP and 10 control oral biopsy specimens were immunohistochemically stained with anti-Bcl-2, anti-Bcl-x, anti-Bax and anti-TNF-alpha antibodies. Keratinocytes did not show any immunoreactivity for Bcl-2, while a uniform intense staining for this protein was evident in the lymphocytic infiltrate of OLP specimens. Immunoreactivity for TNF-alpha was seen in 17/22 OLP cases. All control tissues were TNF-alpha negative, thus indicating a possible involvement of this cytokine in the pathogenesis of OLP The differences in the staining intensities of Bcl-x and Bax between OLP and normal epithelium were slight; therefore an obvious association of the phenotypic TNF-alpha expression with these apoptosis-regulating proteins was not apparent.

Paraneoplastic pemphigus: a review.

Paraneoplastic pemphigus (PNP) is a relatively recently described autoimmune disorder, distinguished from pemphigus vulgaris or foliaceus by specific clinical, histologic and immunologic criteria. In the present review, 18 cases of paraneoplastic pemphigus reported so far are discussed. The polymorphism, extent and persistence of skin and mucosal lesions are discussed while the problems of differential diagnosis and the significance of the associated neoplasms are also stressed. The underlying malignancy in the majority of the cases has been of lymphoid origin and has preceded the clinical presentation of pemphigus. All patients have had oral and cutaneous lesions. In 66.6% of the patients there was a poor response to therapy.

True fibroma of the oral mucosa: a case report.

A case of true fibroma of the maxillary alveolar mucosa in a 44-year-old woman is reported. The clinical and histologic criteria for its distinction from irritation fibroma are discussed.

Alteration in peripheral blood mononuclear cell function and serum cytokines in oral lichen planus.

Different activation parameters of peripheral blood mononuclear cells (PBMC) from 31 patients with oral lichen planus (OLP) were examined and compared with 23 healthy donors. Impaired spontaneous (450 +/- 241 vs 1290 +/- 480 cpm) and mitogen-induced (39580 +/- 14470 vs 67000 +/- 11810 cpm) lymphocyte blastogenesis was observed in OLP patients. Furthermore, reduced cytokine production was found after phytohemagglutinin A (PHA) stimulation for all cytokines studied-tumour necrosis factor alpha (TNF alpha, 432.2 +/- 73.4 vs 979.8 +/- 46.3 units/ml), interleukin 2 (IL-2, 156.2 +/- 14.9 vs 572.6 +/- 12.9 pg/ml), interferon gamma (IFN gamma, 48.5 +/- 11.9 vs 82.6 +/- 12.4 pg/ml) and interleukin 6 (IL-6, 253.6 +/- 57.7 vs 1,419.0 +/- 279.6 units/ml)-except for interleukin 1 beta (IL-1 beta) and lymphotoxin (LT). In contrast, unstimulated culture supernatants showed increased TNF alpha (38.2 +/- 13.1 vs 8.0 +/- 0.2 units/ml), LT (10.2 +/- 2.2 units/ml vs < 0.4) and IL-6 (18.5 +/- 5.6 units/ml vs < 0.5) activity. Similarly, elevated concentrations of TNF alpha (19.6 +/- 6.3 units/ml) and IL-6 (22.9 +/- 4.7 units/ml) were detected in the sera of OLP patients. Combination of PHA and phorbol myristate acetate (PMA) could restore OLP proliferative T cell response and cytokine production to the level of healthy donors, whereas exogenous recombinant human IL-2 (rhuIL-2) plus PMA did not seem to be an effective stimulant for OLP T cells. These results indicate an alteration in the immune condition of OLP patients and an impairment in T lymphocyte function.

Childhood cicatricial pemphigoid with exclusive gingival involvement.

A case of cicatricial pemphigoid in a 13-year-old boy presenting in the form of desquamative gingivitis is described. There are only 7 documented cases of childhood cicatricial pemphigoid reported in the literature.

[Linear IgA bullous dermatosis (LABD): a recently recognized entity]. / Pompholygodes dermatopatheia me grammike enapothese IgA: Mia anexartete nosologike ontoteta.

In previous years linear IgA bullous dermatosis (LABD) of the adults has caused considerable discussion as to its classification. Some investigators considered LABD to be a subgroup of pemphigoid and others regarded it as being more closely related to dermatitis herpetiformis. However a growing body of evidence points to LABD as a distinct disease entity which is characterized by IgA staining along the basement membrane zone in a linear pattern (Chorzelski et al 1979). In this paper a review of this newly recognized entity is attempted, based on the reports from the literature. The clinico-pathologic and immunologic features of LABD are analyzed and discussed and emphasis is given to the problem of differential diagnosis with other bullous dermatoses.

[Calcifying epithelioma of Malherbe. Case report]. / Enasbestiomeno epithelioma tou Malherbe. Parousiase periptoses.

Calcifying epithelioma of Malherbe of pilomatrixoma is a rare benign tumor of the skin. The whites are mainly affected. There appears to be a 3:2 female- to male incidence ratio. 40 percent of pilomatrixomas present before the age of 10 and more than 60 percent arise in the first two decades of life. The most common site of location of calcifying epithelioma is the head and neck region and the lower extremity. The prognosis is good and the treatment is surgical removal. A rare case of pilomatrixoma in a man 62 years old with an intraoral location is presented. The lesion treated successfully.

[Molluscum contagiosum]. / Molysmatike terminthos.

Molluscum contagiosum is a common disease of the skin caused by a virus of the pox group, most commonly seen in children. The lesion is very rare in the oral cavity, since review of the English literature revealed only 5 documented cases. Oral lesions have no pathognomic clinical picture and may cause diagnostic problems.

[Oral condyloma acuminatum: a rare viral epithelial lesion. Report of two cases and a review]. / Oxytenes kondyloma tou stomatikou blennogonou. Mia spania epitheliake iogenes blabe. Anaskopise kai anaphora 2 periptoseon.

Condyloma acuminatum is a benign, sexually transmitted papillary lesion, primarily found in the anogenital region. Although reports of oral condyloma acuminatum are appearing more frequently, they still are sparse. The lesion is caused by the Papova virus and the differentiation from other papular growths of the oral cavity is often difficult. In the present study two histologically documented cases of the lesion are presented and the clinicopathologic features of all cases with oral involvement reported in the literature are analyzed.

Oral psoriasis: report of a case and review of the literature.

Psoriasis is a chronic inflammatory skin disease which very rarely affects the oral mucosa. In the present article, an interesting case of psoriasis with exclusive oral involvement is described. The patient's history, clinical, microscopic features, and HLA typing were consistent with a diagnosis of psoriasis. A review of the 68 reported cases of oral psoriasis is presented in table form.

[Myxoma of the mandible. Report of a case]. / Odontogenes myxoma kato gnathou. anaphora periptoses.

Myxoma is a benign tumor of the jaws of mesenchymal origin. A case of such a lesion of the mandible is reported, which was treated by peripheral ostectomy through an oblique-buccal incision, with satisfactory functional and aesthetic results.