Pathology of the Head and Neck

12 N. Gale · N. Zidar1whereas in the Ljubljana classification, basal-parabasalhyperplasia is considered a benign lesion with a minimumrisk of malignant transformation. Atypical hyperplasiaof the Ljubljana classification is similar to moderatedysplasia, but also partially includes severe dysplasia.The analogy is, thus, only approximate [150]. Carcinomain situ is equal to the carcinoma in situ of the WHO2005 classification. However, some cases of severe dysplasiawould fall into the category of carcinoma in situof the Ljubljana classification, and the analogy is againonly approximate [150].The Ljubljana classification was devised to satisfythe specific clinical and histological requirements ofthe diagnosis of SILs in the regions of the upper aerodigestivetract where common aetiological, clinical andmorphological aspects are found. Recently, the Ljubljanaclassification has also been successfully applied tooral SILs, which share the same aetiology, and similarclinical and histological specificities with laryngeal lesions[225].Over the many years in practical use, it has beenfound to be more precise for daily diagnostic work thanother grading systems and provides data that have beenshown to be closely correlated with the biological behaviourof the lesions [125].1.2.6 Biomarkers Related to MalignantPotential of SILs Recognisedby Auxiliary and AdvancedMolecular MethodsA genetic progression model with specific genetic alterationsfor different stages of laryngeal SILs has increasedthe possibilities of recognising potential biomarkers incorrelation with histopathologic changes that mightsignal a stage of carcinogenesis from initiation to invasivegrowth [60]. This model has revealed that bothoncogenes and tumour suppressor genes are involvedin tumour progression with a distinct order of progressionstarting with loss of heterozygosity (LOH) at 9p21and 3p21 as the earliest detectable events, followed by17p13 loss. Additional genetic alterations, which tend tooccur in severe dysplasia (atypical hyperplasia), or evenin SCC, are cyclin D1 amplification, pTEN inactivation,and LOH at 11q13, 13q21, 14q32, 6p, 8q, 4q27, and 10q23 [60, 117]. For some chromosomal areas involved thetarget genes have been recognised, such as tumour suppressorgenes p16 at 9p21, p53 at 17p13, and cyclin D1oncogene at 11q13 [60, 117, 381].A similar genetic basis, associated with histopathologicalstages, has been designed for oral carcinogenesis,based on LOH, gene mutations and telomerase reactivation[231]. Recent approaches to identifying geneticchanges as predictors of malignancy risk for low gradeoral dysplasia show that LOH at 3p and 9p could serveas an initial screening marker for the cancer risk of earlylesions [306]. Additionally, telomerase reactivation hasbeen shown to be an early event of laryngeal and oralcarcinogenesis, already detectable at the stage of atypicalhyperplasia in 75% and 43% respectively. However, forprogression towards invasive SCC other genetic eventsseem to be necessary [225, 226].Special attention has been recently devoted to moleculargenetic studies of potentially malignant lesions inan attempt to establish their risk of progression more reliablythan static conventional histological diagnosis enables.In terms of prognostic value, genetic events suchas LOH of 3p, 9p21 and 17q 13 and DNA aneuploidy areconsidered a substantial risk of malignant transformation[344, 381].Predictive factors of different grades of SILs inhead and neck carcinogenesis have also been widelystudied at the level of abnormal protein expressionof the oncogenes and tumour suppressor genesinvolved. Overexpression of p16, p21waf1, p27, p53,epidermal growth factor receptor (EGFR), and cyclinD1 proteins have been examined in an attempt to increasediagnostic sensitivity and predictive values ofSILs [12, 64, 102, 127, 156, 162, 169, 199, 251, 255, 282,363, 369].Additionally, various proliferation and differentiationmarkers, including keratins and carbohydrate antigens,are widely used as predictive factors for determiningthe biological behaviour of oral and laryngealSILs [297]. The detection of proliferative activity, suchas the counting of nucleolar organiser regions (Ag-NORs) and immunohistochemical labelling for proliferatingcell nuclear antigen (PCNA) and Ki-67 antigenare useful adjuncts to light microscopy and may providepredictive information on the clinical outcome ofSILs in the larynx and oral cavity [73, 129, 181, 251, 279,357, 394].The expression of lectins and cytokeratins, particularlythose of low molecular weight, has been shown tobe a good marker of epithelial maturation in normal andpathologic conditions, and may thus facilitate a moreprecise evaluation of SIL [152, 182, 229, 365].1.2.7 Treatment and Prognosis1.2.7.1 Oral Cavity and OropharynxSurgical excision, performed either classically witha cold knife or a CO 2 laser, is the treatment of choicefor oral SILs. However, in highly suspicious lesions asin OE on the floor of the mouth, an incisional biopsy isalways the preferred method for establishing a microscopicdiagnosis. Surgical treatment is only the beginningof therapy for such lesions; the long-term follow-