Hyaluronan in malignant pleural mesothelioma with special reference to diagnosis, tumourbiology and prognosis

Sammanfattning: Malignant pleural mesothelioma (MPM), the primary malignant tumour of the pleural cavity, is an uncommon and treatment resistant tumour. The prognosis is poor. In many, but not all cases the concentration of hyaluronan (Hya) is increased in pleural effusion. The clinical relevance of Hya in MPM is not clear. The primary aims of the present study were to examine the role of Hya in the diagnosis, the clinical follow-up, the prognosis and to immunohistochemically characterize Hya-producing MPM. A secondary aim was to evaluate the safety and efficacy of augmenting the antineoplastic effect of cisplatin by combining it with tirapazamine in a phase II trial in patients with MPM.All the cases of MPM in the present study were histologically confirmed. The compatibility of three different methods, a high-performance liquid-chromatographic method (HPLC), a radiometric assay and a semiquantitative precipitationtest for analysis of Hya in pleural effusion was examined. Hya- and non-Hya-producing MPM were immunohistochemically characterized using monoclonal antibodies towards epithelial membrane antigen (EMA), vimentin and cytokeratin (CAM 5.2). Various clinical variables, including Hya in the pleural exudate were evaluated for prognosis in 100 patients with MPM. The relation between circulating Hya and tumourvolume as estimated from serially performed CT scans was investigated in two studies. Twenty-two patients were included into the phase II study.The HPLC-method for analysis of Hya in pleural effusion recognized significantly more cases of MPM than the precipitation test. The HPLC-method and the radiometric assay were comparable in diagnosing MPM although the former in general showed higher values of Hya.The ability of MPM to produce Hya was correlated to strong reactivity towards EMA , CAM 5.2 and weak reactivity against vimentin. Elevated content of Hya in the pleural fluid was identified as a significantly favourable prognostic factor. In the subgroup of Hya producing MPM changes in tumourvolume were related to changes in concentration of Hya in serum. The response to the combination therapy of cisplatin and tirapazamine was poor. In summary, Hya may qualify as a tumour marker for MPM. Analysis of Hya in pleural effusion may serve as a diagnostic aid and analysis of circulating Hya may help monitor patients with increased synthesis of Hya in pleural effusion. The ability of the tumour to produce Hya is a marker for better prognosis. The biological properties, immunophenotype and capacity to synthesize Hya, should be taken into account in future therapeutic trials in MPM