Keratoses and precancerous and premalignant lesions and conditions. Markéta Hermanová Keratoses nIncrease and/or abnormal keratin production n nNot removed by scraping n nClassified on basis of aetiology Histopathological terms nOrthokeratosis nParakeratosis nHyperkeratosis nHyperparakeratosis nAcanthosis nEpithelial atrophy nCellular atypie nEpithelial dysplasia Precancerous and premalignant lesions and conditions: premalignant and tissue lesions and changes with statistically increased risk of progression to cancer n nPrecancerous/premalignant lesions: -dysplasia/intraepithelial neoplasia -in situ carcinoma -actinic keratosis (lips) n nPrecancerous conditions/facultative precanceroses n- morphologically and cytologically still no signs of neoplastic transformation, but in these lesions statistically significant increased risk of cancer n Precancerous/premalignant lesions: nDysplasia/intraepithelial neoplasia: loss of uniformity and architectural arrangement of epithelial cells n nProgression of dysplastic changes/intraepitelial neoplasias in invasive cancer: nlow grade dysplasia → high grade dysplasia → carcinoma in situ → invasive carcinoma (with invasion through basement membrane) n ncarcinoma in situ: dysplastic changes involve all thickness of the epithelium – preinvasive neoplasia – high risk of progression into invasive carcinoma n nmost low grade dysplasias do not progress into carcinoma, but the risk of progression of high grade dysplasias and in situ carcinomas is very high n n n Precancerous conditions/facultative precanceroses n -Conditions assoc. with epithelial atrophy (e.g. siderophenic dysphagia) n -Oral submucous fibrosis § §Lichen planus § §Lupus erytematodes § §Epidermolysis bullosa § §Xeroderma pigmentosum (AR, defect of DNA reparation) n Aetiological classification of white lesions of the oral mucosa nHereditary -oral epithelial naevus (white sponge nevus); AD, genes encoding CK 4 and 13 mutated -oral manifestation of other rare genodermatoses -leukoedema (in persons with racial pigmentation; whiteness of slightly folded mucosa) - nTraumatic (mechanical – frictional keratosis, chemical, thermal injury, nicotinic stomatitis) n nInfective -Candidosis -Syphilitic leukoplakia -Hairy leukoplakia - nIdiopathic (leukoplakia) n nDermatological -Lichen planus -Lupus erythematosus - nNeoplastic -Carcinoma in situ -SCC Genodermatoses nPachyonychia congenita -AD, thickening of nail, oral white lesions n nDyskeratosis congenita -?, M, skin pigmentation, dystrophic nails, mucosal hyperkeratosis, gingivitis/periodontal destruction, premalignant hyperkeratotic lesions n nTylosis -AD, hyperkeratosis palms/soles; predisposes to oesophageal ca, oral hyperkeratosis n nHereditary benign intraepithelial dyskeratosis -AD, US, oral epithelial naevus-like lesion, premature keratinisation-dyskeratosis - nFollicular keratosis (Darier´s disease) -AD, keratotic coalescing papules skin (e.g. forehead, scalp, oral lesions in 50 % - hard palate and gingiva) -intraepithelial acantholytic clefts with dyskeratotic cells 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) n -intraepithelial acantholytic clefts with dyskeratotic cells n n 3 Acantholytic dyskeratosis with loss of cohesion between keratinocytes (thin arrows) and abnormal premature keratinization of epidermal cells (thick arrow) Leukoplakia nWHO definition: white patch or plaque that cannto be characterized clinically or histopathologically as any ather disease n nDysplastic or non-dysplastic Leukoplakia nThe diagnosis of leukoplakia is one of the exclusion n nIt is a clinical diagnosis n nIt has no histological connotation n nEpithelial dysplasia may or may not be present (may be precancerous) n nThe severity of dysplasia is assessed subjectively Clinical features of leukoplakia nHomogeneous -flat, uniform, predominantly white plaques -may show shallow cracks/fissures n nNon-homogeneous -irregular nodular/thickened surface -often speckled with areas of erytroplakia n nNon-homogeneous lesions have a worse prognosis (more likely to be dysplastic, precancerous) n nErythroplakia: a bright red velvety plaque on oral mucosa, homogeneous and well defined or intermigled with leukoplakia (erythroleukoplakia), may represent carcinoma in situ Aetiological factors – multifactorial aetiology nTobacco n nAlcohol n nCandida (superimposed infection?) n nViruses n nOral epithelial atrophy (in iron deficiency, tertiary syphilis, submucous fibrosis, in vitamin deficiences, sideropenic dysphagia) n nInactivation of tumor suppressor genes n n Epithelial dysplasia – reflects abnormalities in proliferation, maturation and differentiation of cells nIncreased and abnormal mitoses nBasal cell hyperplasia nDrop-shaped rete ridges (wider at their deepest part) nDisturbed polarity of cells, losss of cellular orientation nIncreased N/C ration nNuclear hyperchromatism nProminent and enlarged nucleoli nIrregular epithelial stratification and disturbed maturation nNuclear and cellular pleomorphism nAbnormal keratinization nLoss or reduction of intercellular adhesion (or cohesion) n Prognosis of oral leukoplakia nA proportion undergo malignant transformation nTransformation times vary from one to several years nDysplastic lesions carry the risk of malignant tranformation nMalignant transformation likely to be due to progressive accumulation of genetic abnormalities over the time nThe potential for malignant tranformation greater in high-risk sites (ventral tongue, floor of the mouth, lingual aspect of the lower alveolar mucosa) nLesions with abnormal DNA content (e.g. aneuploid – abnormal number of chromosomes) likely to progress to carcinoma n Elevated keratotic lesion of lateral part of the tongue – biopsy: focal benign keratosis. 1048885-1079861-1823 Patchy, focally thickened, keratotic lesions over the right lateral and ventral tongue surfaces – biopsy: focal moderate dysplasia A 27-year-old woman with patchy, focally thickene... A mixed red and white lesion on the right ventral part of the tongue with atypical brush biopsy results and corresponding severe dysplasia by scalpel biopsy. A mixed red and white lesion on the right ventral... Well-defined velvety patch of the maxillary alveolar ridge – biopsy: carcinoma in situ. Initially, a biopsy was performed on this well-de... During a routine postradiation therapy examination, a focal red granular surface lesion was detected – biopsy: identification of recurrent invasive squamous cell carcinoma During a routine postradiation therapy examinatio... Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author Proliferative activity in benign and dysplastic oral lesions. Carcinoma in situ skinBowen2 Oral lichen planus nAlone or associated with skin lesions n nF>M; adults 3rd-5th decade n nUsually bilateral mucosal oral lesions n nNon-erosive forms symptomless n nBuccal mucosa mostly affected n 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 LichenPlanus2.jpg 00160+ Lupus erythematosus (LE) nChronic discoid LE (localized LE) -Facial skin may be involved (butterfly pattern) -Cheeks commonest oral site -Discoid area of erythema with keratotic borders nSystemic LE (disseminated disease) -Skin rashes and systemic involvement -Oral lesion variable nF>M nAutoimmune disease (a variety of autoantibodies (ANA)) nHistology of oral lesion often nonspecific (lymphocytic infiltration – perivascular, in connective tissue, may be liquefactive degeneration of basal cells; abundant deposits of Ig (IgG) and complement in the basement membrane zone forming a prominent „lupus band“ Lupus erythematosus (LE) 00215+ 00191+ Lupus erythematosus subacutus Lupus erythematosus chronicus Lupus erythematosus (LE) 00192+ 00571+ Direct immunofluorescence: granular deposits subepidermally Lupus erythematosus chronicus 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 Thank you for your attention …