Oral ulceration, vesiculobullous and dermatologic diseases. Markéta Hermanová Causes of oral ulceration (I) nInfective nBacterial nViral nFungal n nTraumatic nMechanical nChemical nThermal nFactitious injury nRadiation nEosinophilic ulcer (traumatic granuloma) n nIdiopathic nRecurrent aphthous stomatitis n minor aphthous ulcers n major aphthous ulcers n herpetiform ulcers n n Causes of oral ulceration (II) nAssociated with systemic disease nHaematological diseases nGIT diseases nBehcet´s disease (syndrome) nHIV infection nOther diseases n nAssociated with dermatological diseases nLichen planus nChronic discoid lupus erythematosus nVesiculobullous diseases n nNeoplastic nSquamous cell carcinoma nOther malignant neoplasms n Traumatic ulceration nA cause of trauma must be identified n nThe cause must fit the site, size, and shape of the ulcer n nOn removal of the cause the ulcer must show signs of healing within 10 days Traumatic ulceration - remarks nMechanical injury: often related to overxtended flanges of a denture (diff. dg. neoplastic ulcer!) n nRadiation injury (delayed effects: epithelial atrophy, damage of vasculature; immediate effects: erythema, radiation mucositis, ulceration, oedema dueto obstruction of lymphatics) n nFactitious ulcers (self-inflicted – manifestation of stress, anxiety, emotional disturbance,…) n nEosinophilic ulcers (traumatic or eosinophilic granuloma of the tongue) ass. with trauma and crush injury of muscle – unknown etiology n nChemical injury (caused also by chemicals used in dental practice, preparations used by patients in self-treatment, aspirin (oedema to epithelial necrosis) n Recurrent aphthous stomatitis (RAS): clinical variation nMinor aphthous ulcers (80 %) nMajor aphthous ulcers (10 %) nHerpetiform ulcers n nHistopathology: ulcerative lesion covered with fibrinopurulent membrane, mixed inflammatory infiltration; spongiosis of the epithelium Clinical features of RAS Minor Major Herpetiform Age of onset 10-19 10-19 20-29 Number of ulcers 1-5 1-10 10-100 Size of ulcers (mm) <10 >10 1-2, often coalesce Duration (days) 7-14 >30 10-30 Principal sites Lips, cheeks, tongue As for minor+palate, pharynx As for minor+floor of the mouth, palate, pharynx, gingiva Aphtous stomatitis n n Zobrazit obrázek v plné velikosti Zobrazit obrázek v plné velikosti 564-3_default minor major herpetiform Potential etiopathogenetic factors of RAS nAllergies nGenetic predisposition (HLA-B12, B51, Cw7) nNutritional abnormalities (B12, folate and iron deficiences) nHaematological disorders (anemia) nGastrointestinal diseases (avitaminosis B12 – atrophic oral mucosae, MAS, coeliac disease, ulcerative colitis, m. Crohn,…) nHormonal influences (pregnancy, luteal phase of MC,…) nInfectious agents (L form of streptococci (hypersensitivity to Streptococcus sanguis), HSV, VZV, CMV,…) nTrauma nEmotional stress nSystemic disorders n n RAS (recurrent aphthous ulcerations; canker sores) nPrimary immunodysregulation -In ulcerative stage: decreased ratio of CD4/CD8 T lymphocytes (about 1:10); increased TCRγδ+, increased TNF-α → increased activity of T cell subpopulations that mediate cytotoxic damage -Antibody-dependent cellular cytotoxicity, T-cell mediated cytotoxicity to oral epithelial cells (Ag unknown)??? cross reactivity between Ag shared by oral streptococci and oral epithelial cells??? -Patients with cyclic neutropenia n nDecrease of mucosal barrier n nIncrease in antigenic exposure n n Systemic diseases associated with RAS nBehcet´s syndrome (aphtous ulcers, genital ulcers, uveitis) nCeliac disease (gluten intolerance) nCyclic neutropenia (AD, ELA2 gene - neutrophil elastase) nNutritional deficiencies nIgA deficiency nImmunocompromised conditions, incl. HIV nInflammatory bowel disease (ulcerative colitis, Crohn´s disease) nMAGIC syndrome (mouth and genital ulcers with inflamed cartilage) nPFAPA syndrome (periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis) nReiter´s syndrome (arthritis, urethritis, conjunctivitis and skin lesions) n n Behcet´s disease (syndrome) nRecurrent oral ulceration (minor, major or herpetiform aphthae) n n+ two of the following: -Recurrent genital ulcerations -Eye lesions (uveitis, retinal vasculitis,…) -Skin lesions (erythema nodosum, pseudofolliculitis or papulopustular lesions, acneiform nodules,…) n+ arthritis, CNS involvement, cardiovascular , GIT, hematologic, pulmonary, muscular, renal systems involvement n -HLA-B51 -Immunosuppresive treatment n behcets-syn-awfig-1 Vesiculobullous diseases nIntraepithelial vesiculobullous diseases nAcantholytic lesions (produced by a breakdown of desmosomes) n pemphigus vulgaris n paraneoplastic pemphigus and other variants n Darier´s disease nNon-acantholytic lesions n viral infections of oral mucosae n nSubepithelial vesiculobullous diseases n erythema multiforme n pemphigoid (mucous membrane, cicatrical) n dermatitis herpetiformis and linear IgA disease n epidermolysis bullosa n angina bullosa haemorrhagica (oral blood blisters) n bullous lichen planus Pemphigus vulgaris nIntraepithelial, acantolytic vesicles and bullae involving skin and mucous membranes nRagged oral ulcers nOral lesions often the presenting feature nAutoimmune disease - autoantibodies to desmosomal proteins (diagnostic test – direct immunofluorescence, IgG) nMiddle age, F>M, some ethnic groups frequently affected (genetic links) Pemphigus vulgaris 00010+ IgG immunopositivita among keratinocytes 00075+ Suprabasal acantolysis, acantolytic bulla Other forms of pemphigus, oral lesions (antibodies against different proteins of desmosome complex) nPemphigus vegetans n (milder form, granulation tissue develop following rupture of bullae) n nDrug-induced pemphigus n (penicillamine, captopril,…) n nParaneoplastic pemphigus n (leukaemia, lymphoma,…) Darier´s disease (follicular keratosis) -inherited disease - AD -keratotic white coalescing papules skin (e.g. forehead, scalp; oral lesions in 50 % - hard palate and gingiva) -intraepithelial acantholytic clefts with dyskeratotic cells n n n 3 Acantholytic dyskeratosis with loss of cohesion between keratinocytes (thin arrows) and abnormal premature keratinization of epidermal cells (thick arrow) Erythema multiforme n n nMucosal vesicles and bullae variable; skin and mucous membranes nYoung adults, M>F nProdromal phase, severity variable (severe form: Stevens-Johnson sy (skin, oral, genital and ocular mucosae) nOral ulceration/circumoral crusting, haemorrhagic lesions nTarget/iris skin lesions nType III hypersensitivity reaction?, precipitated by drugs (sulphonamides)/infection (HSV) nImmune complex vasculitis 2957_2979_1 getresource Pemphigoid: subtypes nBullous pemphigoid n(skin alone or with minimal mucosal involvement) n nMucous membrane pemhigoid n(mucosa alone or with minimal skin involvement) Pemphigoid nComplex group of subepithelial blistering diseases nAutoantibodies attack hemidesmosome – basement membrane antigens (collagens, collagen-like proteins, laminins, integrins,..) nLinear binding of IgG along the basement membrane nDifferent clinical subtypes of pemphigoid reflect damage to different antigens nMucosal lesions, including mouth, occur predominantly in the mucous membrane pemphigoid subtypes Structural proteins of dermo-epidermal junction n texte_alt_jleejd00347_gr3 Pemphigoid n n A – subepidermal bulla B - linear, continuous deposition of IgG at the dermoepidermal basement membrane zone in perilesional skin Skin: Epidermal antibodies 2 Mucous membrane pemphigoid nmucosa alone or with minimal skin involvement nconjunctiva, genital, nasal, laryngeal, oesophageal, pharyngeal mucose can be also affected nSubepithelial vesicles and bullae; extensive ulceration, desquamative gingivis, scarring (cicatrical MMP) nolder women (6th decade) nautoantibodies to hemidesmosomal proteins n Dermatitis herpetiformis nChronic, pruritic, subepidermal autoimmune blistering disease of the skin nOral manifestation variable n (erythematous area→extensive erosions) nGranular deposits of IgA in the tips of the connective tissue papillae together with complement components (activation of the alternative complement pathway by Ig A, chemotaxis of neutrophils) nAssociated with coeliac disease – gluten hypersensitivity Dermatitis herpetiformis n n dermatitis-herpetiformis13 Granular deposits of IgA in the tips of the connective tissue papillae Dermatitis_herpetiformis_6 Subepidermal blister Linear IgA disease nSubepidermal blistering disease overlaping with dermatitis herpetiformis and bullous pemphigoid nOral lesions reported nLinear binding of IgA along the basement membrane nass. with coeliac disease – gluten hypersensitivity Epidermolysis bullosa nInherited disease, 30 types nMutations in genes coding specific keratins in the basal epithelial layer (intraepithelial bullae), collagens and other attachement proteins (subepithelial bullae) nExtreme fragility of the skin nMucosae also affected EB type EB subtype Involved genes EBS EBS, Weber-Cockayne K5, K14 EBS, Koebner K5, K14 EBS, Dowling-Meara K5, K14 EBS with muscular dystrophy plectin JEB JEB, Herlitz laminin 5 JEB, non-Herlitz laminin 5, collagen XVII JEB with pyloric atresia α6β4 integrin DEB DDEB collagen VII RDBE, Hallopeau-Siemens collagen VII RDEB, non- Hallopeau-Siemens collagen VII EBS, epidermolysis bullosa simplex JEB, junctional epidermolysis bullosa DDEB, dominant dystrophic epidermolysis bullosa RDEB, recessive dystrophic epidermolysis bullosa Epidermolysis bullosa: immunofluorescence n Absence of collagen VII in DE junction Normal control with presence of collagen VII Epidermolysis bullosa: ultrastructural examination Lysis of keratinocytes in EB dystrophica Regenerating keratinocyte Lamina densa Tonofilament clumps EB simplex Epidermolysis bullosa acquisita n n nAutoimmune blistering nSubepithelial bullae, oral lesion also nLinear binding of IgG and C3along the basement membrane n 1 2 Angina bullosa haemorrhagica (oral blood blister) nSpontaneous blood-filled subepithalial bullae on the oral mucosa nSolitary, in adults n2-3 cm in diameter nSoft palate most often affected nPerforation and uneventfull healing nEtiology unknown????, immunological findings negative n Oral lichen planus nAlone or associated with skin lesions nF>M; adults 3rd-5th decade nUsually bilateral mucosal oral lesions nNon-erosive forms symptomless nBuccal mucosa mostly affected nGingival lesions presented as desquamative gingivitis Aetiology of lichen planus nAetiology not fully understood – cell-mediated immune responses to an external antigen, or to internal antigenic changes in the epithelial cells (T-cell mediated, resembles type IV hypersensitivity reaction, CD8+ T cells damage basal epithelium) n nOften associated with other systemic disease n nMay be associated HCV n nMay be a part of GVHD (graft versus host reaction in recipients of transplants) n nDifferential diagnosis: lichenoid reactions – hypersensitivity to drugs or dental materials n Clinical type of lichen planus nReticular (lace-like striae) nAtrophic (resemble erythroplakia) nPlaque-like (resemble leukoplakia) nPapular nErosive nBullous n Lichen planus morphology and histopathology nViolaceous, itchy papule with white streaks on the surface (Wickham´s striae) nPapules have a variable pattern (discrete, annular, linear, widespread rash,…) nTypically flexor surface of the wrists affected, fingernail also affected (10 %); skin LP – 85 % resolve in 18 months; oral LP more chronic nOrtho- or parakeratinized surface nAcanthotic or atrophic epithelium nSubepithelial band of T lymphocytes nLiquefactive degeneration of basal cells Oral lichen planus n LichenPlanus2.jpg 00160+ Thanks for your attention……..