The Ljubljana Classification and WHO 2005 Classification

Comparing the two classifications, one should be aware that there is no simple relationship and overlapping between the WHO 2005 and the Ljubljana classifications (Table 1.1).

The group of the so-called benign lesions, including squamous and basal-parabasal cell (abnormal) hyperplasia is comparable in both classifications. Disagreement starts with the presumption of the WHO 2005 classification [381] that each grade of the whole series of dyspla-sia is considered to be a precursor or potentially malignant lesion. Histologically, however, there are some similarities between the basal and parabasal cell hyperpla-sia of the Ljubljana classification and the mild dysplasia of the WHO 2005 [381]. Mild dysplasia, in contrast to basal and parabasal cell hyperplasia, was classified as the initial grade within a potentially malignant group,

Table 1.1. Comparison between two classifications of squamous intraepithelial lesions: WHO 2005 and Ljubljana classification [381]

WHO dysplasia system

Hyperplasia* Mild dysplasia Moderate dysplasia Severe dysplasia Carcinoma in situ

Ljubljana classification of squamous intraepithelial lesions

Squamous cell hyperplasia Hyperplasia of basal and parabasal cell layers Atypical hyperplasia - risky epithelium Carcinoma in situ

""Hyperplasia may be in the spinous and/or in the basal/parabasal cell layers whereas in the Ljubljana classification, basal-parabasal hyperplasia is considered a benign lesion with a minimum risk of malignant transformation. Atypical hyper-plasia of the Ljubljana classification is similar to moderate dysplasia, but also partially includes severe dysplasia. The analogy is, thus, only approximate [150]. Carcinoma in situ is equal to the carcinoma in situ of the WHO 2005 classification. However, some cases of severe dys-plasia would fall into the category of carcinoma in situ of the Ljubljana classification, and the analogy is again only approximate [150].

The Ljubljana classification was devised to satisfy the specific clinical and histological requirements of the diagnosis of SILs in the regions of the upper aerodi-gestive tract where common aetiological, clinical and morphological aspects are found. Recently, the Ljubljana classification has also been successfully applied to oral SILs, which share the same aetiology, and similar clinical and histological specificities with laryngeal lesions [225].

Over the many years in practical use, it has been found to be more precise for daily diagnostic work than other grading systems and provides data that have been shown to be closely correlated with the biological behaviour of the lesions [125].

1.2.6 Biomarkers Related to Malignant Potential of SILs Recognised by Auxiliary and Advanced Molecular Methods

A genetic progression model with specific genetic alterations for different stages of laryngeal SILs has increased the possibilities of recognising potential biomarkers in correlation with histopathologic changes that might signal a stage of carcinogenesis from initiation to invasive growth [60]. This model has revealed that both oncogenes and tumour suppressor genes are involved in tumour progression with a distinct order of progression starting with loss of heterozygosity (LOH) at 9p21 and 3p21 as the earliest detectable events, followed by 17p13 loss. Additional genetic alterations, which tend to occur in severe dysplasia (atypical hyperplasia), or even in SCC, are cyclin D1 amplification, pTEN inactivation, and LOH at 11q13, 13q21, 14q32, 6p, 8q, 4q27, and 10q 23 [60, 117]. For some chromosomal areas involved the target genes have been recognised, such as tumour suppressor genes p16 at 9p21, p53 at 17p13, and cyclin D1 oncogene at 11q13 [60, 117, 381].

A similar genetic basis, associated with histopatho-logical stages, has been designed for oral carcinogene-sis, based on LOH, gene mutations and telomerase reactivation [231]. Recent approaches to identifying genetic changes as predictors of malignancy risk for low grade oral dysplasia show that LOH at 3p and 9p could serve as an initial screening marker for the cancer risk of early lesions [306]. Additionally, telomerase reactivation has been shown to be an early event of laryngeal and oral carcinogenesis, already detectable at the stage of atypical hyperplasia in 75% and 43% respectively. However, for progression towards invasive SCC other genetic events seem to be necessary [225, 226].

Special attention has been recently devoted to molecular genetic studies of potentially malignant lesions in an attempt to establish their risk of progression more reliably than static conventional histological diagnosis enables. In terms of prognostic value, genetic events such as LOH of 3p, 9p21 and 17q 13 and DNA aneuploidy are considered a substantial risk of malignant transformation [344, 381].

Predictive factors of different grades of SILs in head and neck carcinogenesis have also been widely studied at the level of abnormal protein expression of the oncogenes and tumour suppressor genes involved. Overexpression of p16, p21waf1, p27, p53, epidermal growth factor receptor (EGFR), and cyclin D1 proteins have been examined in an attempt to increase diagnostic sensitivity and predictive values of SILs [12, 64, 102, 127, 156, 162, 169, 199, 251, 255, 282, 363, 369].

Additionally, various proliferation and differentiation markers, including keratins and carbohydrate antigens, are widely used as predictive factors for determining the biological behaviour of oral and laryngeal SILs [297]. The detection of proliferative activity, such as the counting of nucleolar organiser regions (Ag-NORs) and immunohistochemical labelling for proliferating cell nuclear antigen (PCNA) and Ki-67 antigen are useful adjuncts to light microscopy and may provide predictive information on the clinical outcome of SILs in the larynx and oral cavity [73, 129, 181, 251, 279, 357, 394].

The expression of lectins and cytokeratins, particularly those of low molecular weight, has been shown to be a good marker of epithelial maturation in normal and pathologic conditions, and may thus facilitate a more precise evaluation of SIL [152, 182, 229, 365].

1.2.7 Treatment and Prognosis

1.2.7.1 Oral Cavity and Oropharynx

Surgical excision, performed either classically with a cold knife or a CO2 laser, is the treatment of choice for oral SILs. However, in highly suspicious lesions as in OE on the floor of the mouth, an incisional biopsy is always the preferred method for establishing a microscopic diagnosis. Surgical treatment is only the beginning of therapy for such lesions; the long-term follow-

up and avoidance of exposure to known risk factors is important due to the risk of malignant transformation [47, 263, 334]. Recurrences of high-risk SILs are not infrequent events, being reported in 18% of lesions that had been excised with free surgical margins [366]. If the size or other clinical obstacles make surgical treatment of oral SILs difficult, various antioxidants, such as beta-carotene and the retinoids, are most commonly used for chemoprevention [191].

The occurrence of the higher grades (moderate and severe dysplasia, atypical hyperplasia) of oral SILs is considered the most important risk of SCC development. The reported frequency of malignant transformation of OL ranges from 3.1% [373] to 17.5% [323]. Several locations of OL, together with histological abnormalities, are linked with higher malignant transformation. The floor of the mouth is, thus, the highest risk site, followed by the tongue and lip [319].

The clinical appearance of non-homogenous or speckled OL may correlate with the likelihood that the lesion will show epithelial changes or malignant transformation. In a study by Silverman and Gorsky the overall malignant transformation of OL was 17.5%, for the homogenous form only 6.6%, and for speckled OL 23.4%. A special subtype of OL, PVL, was found to develop SCC in 70.3% of patients [322]. Compared with OL, OE has significantly worse biological behaviour, with 51% proceeding to malignant transformation [319].

The main task of the pathologist dealing with laryngeal SILs is to separate non-risky or a minimally risky from risky changes. Patients with benign hyperplastic lesions (simple and basal-parabasal hyperplasia) do not require such a close follow-up after excisional biopsies as those with atypical hyperplasia and CIS, although elimination of known detrimental influences is advised [125, 150]. Diagnosis of atypical hyperplasia in laryngeal lesions requires close follow-up and often repeated histological assessment to detect any possible persistence or progression of the disease [125, 150, 178, 181]. Patients with CIS may require more extensive surgical treatment or radiotherapy, although this is controversial [79, 181, 254, 299, 336].

The histopathologic degree of severity of larynge-al SILs is still used as the most reliable predictive factor [39, 125, 150, 178, 181, 239]. The frequency of subsequent malignant alteration markedly increases from squamous (simple) and basal-parabasal (abnormal) hy-perplasia (0.9%), compared with atypical hyperplasia (11 %) [150]. Barnes's review of the literature shows that the risk of SCCs developing in mild, moderate and severe laryngeal dysplasia ranges from 5.5% to 22.5% and 28.4% respectively [20].

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  • minto
    Who head and neck larynx dysplasia?
    5 months ago

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