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The incidence of feline primary lung tumors has increased over the last decades. Yet, by comparison, feline lung tumors are poorly examined. Little is known about correlations between tumor subtypes, tumor cell origin, prognosis and clinical outcome. Currently, feline lung tumors are usually diagnosed based on the classification of the World Health Organization (WHO), which is based solely on histological features. This classification is not only interpreted differently, but also criticized by various authors. A simple and reliable diagnosis is essential for determining the tumor dignity and origin, because feline primary lung tumors are frequently malignant and metastasize in over 75 % of cases. Apart from that, the lung is one of the major centers for metastases, making it difficult to differentiate primary lung tumors only on the basis of histologic criteria.
The aim of this study was to investigate the sensitivity and specificity of Thyroid Transcription Factor-1 (TTF-1) and the function of Ki67 as malignancy markers for feline primary lung tumors and to examine, whether they support or facilitate the application of the current WHO classification. For this purpose, 1) the actual applicability of the existing WHO classification was determined, 2) relevant tumor characteristics were acquired, 3) the specificity of TTF-1 for feline lung tumors was examined, 4) correlations between TTF-1 expression levels, the tumor characteristics and tumor dignity were discussed, 5) the expression of the proliferation marker Ki67 was surveyed in the tumors, 6) the diagnostic potential of a combination of TTF-1 and Ki67 was analyzed and 7) the benefit of both markers and their combination for the classification of feline primary lung tumors was tested.
According to the histological criteria of the WHO guidelines, 61 feline lung tumors were initially classified. In the process, various features, specific for different tumor subtypes, occurred frequently in the same tumor. Furthermore, the described cell characteristics associated with certain growth patterns (papillary, bronchioloalveolar) differed from the actually occurring tumor cells. The applicability of the tumor classification remained generally very limited, since the feature descriptions were unclear and partly contradictory.
In the second part of this thesis, the lung tumor marker TTF-1, already established in human medicine, was examined for its specificity for feline lung tumors. Immunohistochemical stainings confirmed its specificity for feline lung tumors and a relation between its expression and the tumor dignity. The results revealed a positive correlation between the TTF-1
expression and tumor differentiation grade. Since TTF-1 is only expressed in benign but not all malignant lung tumors, its potential as a tumor marker is limited in diagnostic practice.
Furthermore, the expression of the proliferation marker Ki67 was also explored in the tumors. As expected, its expression negatively correlated with the degree of differentiation. Thus, the Ki67 expression was inversely proportional to TTF-1, which verified the connection between a positive TTF-1 expression and a good degree of differentiation. Unfortunately, neither the use of TTF-1 nor Ki67 could unequivocally separate benign and malignant lung tumors. However, by determining a combination of the two markers (combined expression value (KE)), both the sensitivity and specificity for lung tumors could be increased. The KE provides a possible, promising option to ascertain the tumor dignity.
Moreover, the results confirm a correlation between the tumor cell character and the tumor dignity. Adenomas consisted almost exclusively of cuboidal, monolayered cells and showed a significantly higher TTF-1 expression. With an increasing number of columnar and / or multilayered cells, both, the degree of differentiation and the TTF-1 level decreased. In parallel, the Ki67 expression level increased. Both markers and the actually found cell characteristics could not confirm the WHO classification. The results rather show a mismatch between the actual tumor characteristics and the WHO group definitions.
Finally, it turned out that by applying the WHO classification it was not possible to precisely classify the tumors based on their histological descriptions. The WHO classification could not be reproduced or simplified, neither with the aid of the TTF-1 nor the Ki67 expression intensities. Moreover, the investigation of the individual subtypes revealed that the division of the groups was not unequivocal and thus in parts very questionable. This bares the urgent need for a new classification. Nevertheless, the results demonstrate that the use of a specific TTF-1 antibody helps to identify the lung as the tumor origin more easily. In addition, the KE value facilitates an accurate separation between adenomas and carcinomas. Besides, the use of the markers and KE values allows for a more reliable diagnosis despite poor sample quantities. What is more, TTF-1 seems to have a prognostic potential.