The Ljubljana Classification

The Ljubljana grading system does not follow the criteria used for cervical SILs, but was devised to cater for the special clinical and histological problems related to laryngeal conditions. Briefly, the different aetiology of SILs in the upper aerodigestive tract in comparison with cervical lesions probably triggers a different pathway of genetic events from those established in cervical lesions. Additionally, different anatomic specificities, various clinical approaches to obtaining adequate biopsy specimens, as well as different treatment modalities for high-risk lesions of cervical and upper aerodigestive tract SILs, were the basis for establishing the Ljubljana classification more than three decades ago and this was further formulated in 1997 by the working group on SILs of the European Society of Pathology [125, 150, 178, 181, 182, 183, 242].

The main feature of the Ljubljana classification is that it separates the group of lesions with a minimal risk of progression to invasive carcinoma, including squamous and basal-parabasal cell hyperplasia on the one hand, and the potentially malignant group, i.e. those lesions more likely to progress to invasive carcinoma (atypical hyperplasia or risky epithelium), on the other. Carcinoma in situ is considered a separate entity within the spectrum of SILs.

The general principles of the classification presented, which hold for all of its grades, are the following: the epithelium is generally thickened, although in a minority of cases the epithelium may show areas of diminished thickness, but even these cases show basal-parabasal cell hyperplasia; the basement membrane is generally preserved at all grades, with no definite evidence of even minimal invasion. The presence of a surface keratin layer, which is often present in all grades of SIL, is of no importance in this classification.

Group of Reactive Lesions with a Minimal Risk of Progression to Invasive Carcinoma

Squamous (simple) hyperplasia is a benign hyperplastic process with retention of the normal architectural and cytological pattern of the squamous epithelium.

Fig. 1.9. Squamous cell hyperplasia. Thickened epithelium shows increased prickle cell layer, the basal layer remains unchanged

The epithelium is thickened as a result of an increased prickle cell layer. The cells of the basal and parabasal region, which comprise one to three layers, remain unchanged. There is no cellular atypia; infrequent, regular mitoses are seen in the basal layer (Fig. 1.9).

Basal and parabasal cell hyperplasia (abnormal hyperplasia) can be defined as a benign augmentation of basal and parabasal cells in the lower part of the epithelial layer while the upper part, containing regular prickle cells, remains unchanged.

Stratification of the laryngeal squamous epithelium, characterised by its layered construction, is seen as a smooth transition from an epithelial layer composed of basal cells that are aligned perpendicular to the basement membrane to the more superficial part in which the prickle cells are orientated horizontal to the basement membrane. Thickened epithelium consists of an increased number of basal and parabasal cells occupying up to one-half or occasionally slightly more of the entire epithelium. These cells do not show significant nuclear changes and are aligned perpendicularly with preservation of normal polarity and organisation. Basal and parabasal cells contain moderately enlarged nuclei and uniformly distributed chromatin, slightly more cytoplasm than those of the basal layer and, in addition, few or no intercellular prickles or bridges. Rare, regular mitoses may be seen, always located in or near the basal layer. Less than 5% of epithelial cells show characteristics of

Fig. 1.10. Basal and parabasal cell hyperplasia. Augmented cells of the basal and parabasal cell layer extend up to the midportion of the epithelium. Occasional mitoses are seen in the lower part of the epithelium

dyskeratosis, a premature and abnormal keratinisation of individual cells or groups of cells that have no prickles and strongly eosinophilic cytoplasm (Fig. 1.10).

Group of Potentially Malignant Lesions

Atypical hyperplasia (risky epithelium), considered to be a potentially malignant lesion, i.e. a lesion with a definitely increased risk of progressing to invasive carcinoma, is characterised by preservation of stratification in the epithelium, by alterations of epithelial cells with mild to moderate degrees of cytological atypia occupying the lower half or more of the epithelial thickness, and by increased mitotic activity.

Stratification is still preserved in the epithelium. There is an increased number of epithelial cells that are frequently orientated perpendicular to the basement membrane. The nuclei of many of them show mild to moderate changes of atypia, such as: enlargement, irregular contours, and marked variations in staining intensity with frequent hyperchromaticity; nucleoli are increased in number and size, showing enhanced staining characteristics. The nuclear/cytoplasmic ratio is generally increased. This type of epithelial cell may occupy the lower half, or more of the entire epithelial thickness. Mitoses are moderately increased. They are usually found in the lower two-thirds of the epithelium, although they may occasionally appear at a higher level. Mitoses are rarely, if ever, abnormal. Dyskeratotic cells are frequent within the entire epithelium. Apoptotic cells may be present; they are smaller in size and with hyaline eosin-ophilic cytoplasm and conspicuous nuclear chromatin



Fig. 1.11. a Atypical hyperplasia. Augmented epithelial cells showing mild to moderate grades of atypia, preserved stratification and some regular mitoses. b Augmented epithelial cells with increased nuclear/cytoplasmic ratio and some regular mitoses. The cells are aligned perpendicularly to the basement membrane

Fig. 1.11. a Atypical hyperplasia. Augmented epithelial cells showing mild to moderate grades of atypia, preserved stratification and some regular mitoses. b Augmented epithelial cells with increased nuclear/cytoplasmic ratio and some regular mitoses. The cells are aligned perpendicularly to the basement membrane condensation or nuclei crumbled into smaller fragments (Fig. 1.11). Two subdivisions of atypical hyperplasia are recognised: (a) The more frequent "basal cell type" with no intercellular prickles and no cytoplasmic eosinophil-ia, and the cells aligned perpendicularly or at an acute angle to the basement membrane, and (b) The less frequent "spinous cell type" (analogous to so-called "ke-ratinising dysplasia" by Crissman and Zarbo [79]) with intercellular prickles and increased cytoplasmic eosino-

Fig. 1.12. Carcinoma in situ. The lesion shows loss of stratification, malignant cells with increased mitotic activity replace the entire epithelial thickness

philia. The cells may be aligned horizontal to the basement membrane.

Group of Actually Malignant Lesions

The term squamous cell carcinoma in situ (CIS) is reserved for lesions showing the features of carcinoma without invasion. Three distinct morphologic characteristics are usually present:

a) Loss of stratification or maturation of the epithelium as a whole; however, the surface of the epithelium may be covered by one or at most a few layers of compressed, horizontally stratified, and sometimes kera-tinised cells.

b) Epithelial cells may show all the cytologic characteristics of invasive squamous cell carcinoma.

c) Mitotic figures are usually markedly increased throughout the whole epithelium, often more than five per high power field. Abnormal mitoses are frequently seen. Hyaline bodies and dyskeratotic cells are present, often in high numbers (Fig. 1.12).

In CIS, as in atypical hyperplasia, the lesion may fall within one or the other of the two subdivisions of atypical hyperplasia:

a) Basal cell type with no intercellular prickles and no cytoplasmic eosinophilia;

b) Spinous cell type with intercellular prickles and increased cytoplasmic eosinophilia [125, 150, 242].

In the differential diagnosis of SILs, regenerative changes of the squamous epithelium after trauma, inflammation or irradiation therapy may simulate various cyto-architectural disturbances resembling different grades of SILs.

Clinical data are always of considerable help in distinguishing different grades of SILs from regenerative processes in which epithelial abnormalities are generally less pronounced than in atypical hyperplasia or CIS, and atypical mitoses are almost never present.

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