Oral epithelial tumors. Markéta Hermanová Human papillomavirus (HPV) nInfect keratinocytes n nHPV infection associated with abnormal epithelial proliferation -Benign epithelial lesion (squamous cell papiloma, verruca vulgaris, focal epithelial hyperplasia) -Oral precancerous/premalignant lesions -Malignant tumours (squamous cell carcinomas/SCC) - nMay be present in normal epithelium Benign epithelial lesions associated with human papillomavirus (HPV) low risk HPV infection (2,4,6,11,13,32,…) nSquamous cell papilloma n nVerruca vulgaris (common wart) n nCondyloma acuminatum (venereal wart) n nFocal epithelial hyperplasia (Heck´s disease) n - ethnic occurance (Inuits, Indians) + immunosuppressed n - lower lip, buccal mucosa Squamous cell papilloma nUsually solitary, in adults and children n nPedunculated or sesile n nMay be warty or cauliflower-like n nFinger-like processes of proliferating stratified squamous epithelium supported by fibrovascular cores; hyperkeratosis n nNo dysplasia, no premalignant lesion nVerruca vulgaris (HPV 2, 4) n- sesile, pedunculated; single, multiple -papillary processes of proliferating stratified squamous epithelium supported by fibrovascular cores; hyperkeratosis - nCondyloma acuminatum (HPV 6, 11) n nFocal epithelial hyperplasia (HPV 13, 32) Squamous cell carcinoma - epidemiology nIncidence varies around the world n nOne of the 10 commonest cancers n nIncidence in developed countries now on the increase n nM>F, usually in people over the age 40 n nIncreasing incidence in people aged under 40 years n nFatal clinical outcome in 30-40 per cent Aetiological factors in oral cancer nTabacco smoking nSmokeless tabacco (inhalation of powdered tabacco, tabacco chewing) nBetel chewing, betel quid, areca nut nAlcohol (spirit, wine, beer; alcohol and tabacco synergism) nDiet and nutrition (iron deficiency, vit A, C; nutritional deficiencies, alcoholism) nDental factors nUltraviolet light nViruses (HPV, HSV, HIV, EBV) nImmunosuppression nChronic infection (candidosis, syphilis) nOccupation (in agriculture, forestry, fishing – UV light – ca lips; chemicals, dust???) n Tabacco and alcohol nIndependent risk ofooral cancer nSynergistic effecr nRelative risk increases with amount and duration of use nRelative risk influenced by method of use and type nMain carcinogens in tabacco: N-nitrosamines from nicotine nCarcinogenic constituents and/or contaminants in alcoholic drinks nAlcoholic drinks may enhance transport of carcinogens across the mucosal barrier nMucosal barriers impaired by nutritional deficiences in chronic alcohol abuse nLiver disease in alcoholism impair its ability to detoxify carcinogens nImmunosupression in chronic alcohol abuse may increase the risk of developing cancer Diet and oral cancer nDietary deficiences or imbalances may account for 15 per cent of oral cancer n nDeficiences of iron and of the antioxidant vitamins A, C, and E increase the risk of oral cancer n nDiets high in fresh fruit and vegetables decrease the risk of oral cancer Genetic abnormalities in oral cancer nAccumulation of 6 to 10 genetic alterations in an epithelial cell leading to uncontrolled proliferation and clonal expansion nActivation of oncogenes; inactivation of tumor suppressor genes nGenetic progression model: normal epithelium→dysplasia→carcinoma in situ→invasive cancer nLoss of chromosomal material from specific areas of a chromosome: LOH (loss of heterozygosity) nLOH at 9p – predysplastic lesion n LOH at 3p, 17p (p53 gene)– leading to dysplasia n LOH at 11q, 13q (retinoblastoma gene), 14q – leading to carcinoma in situ n LOH at 6p, 8p, 4q – invasive cancer nOncogenes -Derived from mutated proto-oncogenes in normal cells -Mutation results in enhanced or inappropriate gene expression which may lead to uncontrolled cell growth - nTumor suppressor genes -Present in normal cells -Regulatory protein of cell proliferation -Mutation/deletions→defective/deficient protein→uncotrolled celll growth -Mutations in p53 also in oral cancer Molecular basis of cancer onkol The role of tumor suppressor p53 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 Carcinoma in situ 10_01B Clinical features of invasive oral squamous cell carcinoma nEarly lesion usually asymptomatic; early detection – determination of prognosis n nLocal invasion -Induration and fixation of tissues -Destruction of tissues -Distortion of tissues -Dysfunction of tissues - nMetastatic spread to regional lymph nodes -Enlarged, firm nodes -Mobile or fixed nodes n Histopathological features related to prognosis of oral SCC nDiameter of tumor (clinical T stage) nDepth of invasion, incl. bone invasion nNon-cohesive pattern of invasion nPerineural invasion nLymphatic and vascular invasion nMetastatic disease (clinical N and M stage) nExtracapsular spread of nodal metastases n nPrognosis decreases with increasing clinical stage nSite and late onset adversely affect early diagnosis nWorse prognosis in SCC at the back of the mouth: late diagnosis, rich lymphatic drainage around the base of the tongue n Squamous cell carcinoma. Scc _tongue-carcinoma-2 Carcinoma of the tongue. Lymph node metastases nLevel I: nodes of submandibular and submental triangles nLevel II: nodes of upper cervical (jugular) chain nLevel III: nodes of mid-cervical (jugular) chain nLevel IV: nodes of the lower cervical (jugular) chain nLevel V: nodes of posterior triangle of the neck Oral squamous cell carcinoma nWell differentiated nModerately differentiated nPoorly differentiated n nCytologically malignant squamous epithelium nKeratinization varies with degree of differentiation nVerrucous carcinoma (distinctive pathological variety of LG SCC) nBasal cell carcinoma (lips, older people (or in younger with naevoid BCC sy), UV exposure Squamous cell carcinoma spinaliom01 Squamous cell carcinoma spinaliom02 Squamous cell carcinoma spinaliom04 Squamous cell carcinoma spinaliom05 Oral SCC nTongue, base of the oral cavity: the worst prognosis, rapid spread into deep cervical lymph nodes and hematogeneously into lungs nLips: late metastatic spread into submandibular and submentl lymph nodes nGingiva: most frequent at 3rd molar, slower progression n HPV and head and neck SCC nHPV: assoc. with a subgroup of head and neck SCC (most common HPV 16) n nYounger patients, non-smokers, non-alcoholics n nBetter prognosis, better responce to chemotherapy and chemoradiotherapy n nBetter clinical status of patients at diagnosis, earlier diagnosis n nHPV+ carcinomas – half risk of death compared with HPV- carcinomas n nBasaloid morphology, non-keratinising n nHPV associated carcinomas most common arising from tonsilla lingualis and tonsillae palatinales - oropharyngeal squamous cell carcinoma (OSCC) HPV+ OPSCC Expression of p16 in SCC nTSG product, cyclin-dependent kinase 4A inhibitor n nProduction of p16 normally inhibited by pRB (repression of transcription ) n nDegradation of pRB in HPV+ tumours → ↑p16 expression n np16 expressed HPV+ tumours and premalignant lesion n np16 = surrogate marker of high risk HPV High grade dysplasia, HPV+, p16 expression in 2/3 epithelial thickness. p16+/HPV mediated OPSCC: strong nuclear and cytoplasmic p16 expression Basal cell carcinoma (rodent ulcer) nUsually on the skin of the face in elderly patienty (UV exposure) nOccasionally lips (upper) nMultiple naevoid BCC in naevoid BCC syndrome nSlow-growing nodule ncentrally ulcerated 1177364140731_low Thank you for your attention …