J. Lemmer

Basal cell carcinoma, squamous cell carcinoma and melanoma of the head and face

Ultraviolet light (UV) is an important risk factor for cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma of the skin. These cancers most commonly affect persons with fair skin and blue eyes who sunburn rather than suntan. However, each of these cancers appears to be associated with a different pattern of UV exposure and to be mediated by different intracellular molecular pathways.Some melanocortin 1 receptor (MC1R) gene variants play a direct role in the pathogenesis of cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma apart from their role in determining a cancer-prone pigmentory phenotype (fair skin, red hair, blue eyes) through their interactions with other genes regulating immuno-inflammatory responses, DNA repair or apoptosis.In this short review we focus on the aetiological role of UV in cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma of the skin, and on some associated biopathological events.

Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events

Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption.

Epstein-Barr Virus and Its Association with Oral Hairy Leukoplakia: A Short Review.

In immunocompromised subjects, Epstein-Barr virus (EBV) infection of terminally differentiated oral keratinocytes may result in subclinical productive infection of the virus in the stratum spinosum and in the stratum granulosum with shedding of infectious virions into the oral fluid in the desquamating cells. In a minority of cases this productive infection with dysregulation of the cell cycle of terminally differentiated epithelial cells may manifest as oral hairy leukoplakia. This is a white, hyperkeratotic, benign lesion of low morbidity, affecting primarily the lateral border of the tongue. Factors that determine whether productive EBV replication within the oral epithelium will cause oral hairy leukoplakia include the fitness of local immune responses, the profile of EBV gene expression, and local environmental factors.

Review: allergic contact stomatitis

Allergic contact stomatitis (ACS) is an oral mucosal immunoinflammatory disorder variably characterized clinically by erythematous plaques, vesiculation, ulceration, and/or hyperkeratosis and by pain, burning sensation, or itchiness. ACS is brought about by a T cell-mediated, delayed hypersensitivity immune reaction generated by a second or subsequent contact exposure of an allergen with the oral mucosa, in a genetically susceptible, sensitized subject. Lichenoid contact reaction is a variant of ACS brought about by direct contact with the oral mucosa of certain metals in dental restorations. The features of ACS are neither clinically nor histopathologically specific, so the diagnosis is usually presumptive and can only be confirmed by resolution of the inflammation after withdrawal or removal of the suspected causative allergen. When ACS is suspected but an allergen cannot be identified, patch testing is necessary. In persistent cases, topical corticosteroids are the treatment of choice, but for severe and extensive lesions, systemic corticosteroid and systemic antihistamines may be indicated. In this short review, we highlight the clinical, immunologic, and histopathological features of ACS, and provide some guidelines for diagnosis and management.

Is chronic ulcerative stomatitis a variant of lichen planus, or a distinct disease?

Chronic ulcerative stomatitis is an immune-mediated mucocutaneous disorder characterized clinically by erosions or ulcers. Most cases are limited to the mouth. The histopathological features are non-specific or mimic those of oral lichen planus, and studies by immunofluorescent microscopy are essential for definitive diagnosis. The defining immunopathogenic mechanism is the binding of IgG to the nuclear protein deltaNp63alpha of keratinocytes in the basal and parabasal cell layers of the oral stratified epithelium. DeltaNp63alpha functions as a regulator of epithelial stem cell activity and as an antiapoptotic agent and regulates the expression of cell-to-cell and cell-to-basement membrane adhesion molecules. The autoimmune IgG-deltaNp63alpha interaction is thought to result in damage to the structural attachment of keratinocytes to one another and to the epithelial basement membrane zone and in dysregulation of the cell cycle and apoptosis of basal keratinocytes with the development of erosions or ulcers. The aims of treatment are to suppress the pathogenic immunoinflammatory responses, to prevent local infection and to promote healing. The purpose of this article is to provide a succinct review of the diagnostic, clinical and etiopathogenic features of, and treatment guidelines for chronic ulcerative stomatitis, and to argue that this disease should be regarded as a variant of oral lichen planus, rather than as a distinct entity.

Discoid lupus erythematosus-related squamous cell carcinoma of the lip in an HIV-seropositive black male

Discoid lupus erythematosus (DLE) is an autoimmune disease commonly affecting sun-exposed areas of the skin. Subjects with DLE have high-levels of plasmacytoid dendritic cells -derived interferon-α, which mediates both loss of immune tolerance to self-antigens and exaggerated inflammatory state, and supports proliferation and differentiation of hyperactive B-cells. In a few cases, DLE of the lips, scalp, ears or nose may eventually progress to squamous cell carcinoma (SCC). Photosensitivity and the long-standing immune-mediated chronic inflammation and dysregulated healing characterized by atrophy, hypopigmentation or scarring inherent to DLE are risk factors for progression to SCC. We review some aspects of the pathogenesis of DLE and the possible roles of inflammation and photosensitivity in the carcinomatous transformation of DLE keratinocytes, and present an illustrative case of DLE of the lower lip in an HIV-tuberculosis co-infected black person, that progressed to SCC.

The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health

Vitamin D plays an important role in calcium homeostasis and bone metabolism, with the capacity to modulate innate and adaptive immune function, cardiovascular function, and proliferation and differentiation of both normal and malignant keratinocytes. 1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR). In turn, VDR/RXR binds to DNA sequences termed vitamin D response elements in target genes, regulating gene transcription. In order to exert its biological effects, VDR signalling interacts with other intracellular signalling pathways. In some cases 1,25(OH)2D exerts its biological effects without regulating either gene expression or protein synthesis. Although the regulatory role of vitamin D in many biological processes is well documented, there is not enough evidence to support the therapeutic use of vitamin D supplementation in the prevention or treatment of infectious, immunoinflammatory, or hyperproliferative disorders. In this review we highlight the effects of 1,25(OH)2D on bone and calcium homeostasis, on cancer, and refer to its effects on the cardiovascular and immune systems.

Biomechanical cell regulatory networks as complex adaptive systems in relation to cancer

Physiological structure and function of cells are maintained by ongoing complex dynamic adaptive processes in the intracellular molecular pathways controlling the overall profile of gene expression, and by genes in cellular gene regulatory circuits. Cytogenetic mutations and non-genetic factors such as chronic inflammation or repetitive trauma, intrinsic mechanical stresses within extracellular matrix may induce redirection of gene regulatory circuits with abnormal reactivation of embryonic developmental programmes which can now drive cell transformation and cancer initiation, and later cancer progression and metastasis. Some of the non-genetic factors that may also favour cancerization are dysregulation in epithelial-mesenchymal interactions, in cell-to-cell communication, in extracellular matrix turnover, in extracellular matrix-to-cell interactions and in mechanotransduction pathways. Persistent increase in extracellular matrix stiffness, for whatever reason, has been shown to play an important role in cell transformation, and later in cancer cell invasion. In this article we review certain cell regulatory networks driving carcinogenesis, focussing on the role of mechanical stresses modulating structure and function of cells and their extracellular matrices.

Oral manifestations of thrombocytopaenia

The appearance in the mouth of haemorrhagic petechiae, ecchymoses or blood blisters with spontaneous bleeding is suggestive of a haemorrhagic disorder that may be caused either by functional impairment of platelets or of blood vessel walls, by an abnormal decrease in the number of circulating platelets (thrombocytopaenia), or by defects in the blood clotting mechanism. Thrombocytopaenia from decreased production or increased destruction of platelets may be caused by multiple factors including immune mediated mechanisms, drugs or infections. A diagnosis of thrombocytopaenic purpura can be made when any other disease entity that might be causing the purpura is excluded on the basis of the medical history, the physical examination, a complete blood count and a peripheral blood smear. In this paper, we outline the clinical features of oral thrombocytopaenic purpura and briefly discuss some aspects of its aetiopathogenesis and treatment.

Vitamin D Deficiency as It Relates to Oral Immunity and Chronic Periodontitis

The biologically active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)2D) and its receptor, the vitamin D receptor (VDR), play roles in maintaining oral immunity and the integrity of the periodontium. Results of observational cross-sectional clinical studies investigating the association between vitamin D serum level and the incidence and severity of chronic periodontitis indicate that, perhaps owing to the immunomodulatory, anti-inflammatory, and antibacterial properties of 1,25(OH)2 D/VDR signalling, a sufficient serum level of vitamin D is necessary for the maintenance of periodontal health. In cases of established chronic periodontitis, vitamin D supplementation is associated with reduction in the severity of periodontitis. As cross-sectional studies provide only weak evidence for any causal association and therefore are of questionable value, either longitudinal cohort studies, case controlled studies, or randomized control trials are needed to determine whether or not deficiency of vitamin D is a risk factor for chronic periodontitis, and whether or not vitamin D supplementation adjunctive to standard periodontal treatment is in any way beneficial. In this article, we discuss the relationship between vitamin D, oral immunity and periodontal disease and review the rationale for using vitamin D supplementation to help maintain periodontal health and as an adjunct to standard periodontal treatment.