Malignant mesothelioma is a rare and aggressive malignancy of the pleura (but also of other serous membranes), with a strong causal link to asbestos exposure. The diagnosis of mesothelioma is not straightforward, and pleural fluid cytology is a reliable diagnostic tool only in very experienced health centers.
Therefore a majority of patients require highly invasive procedures (such as video-assisted thoracoscopy or open biopsy) in order to adequately establish the diagnosis. Serum and cytological markers that have recently emerged could help in non-invasive confirmation or exclusion of mesothelioma.
Current recommendations for screening of patients who have been exposed to significant amounts of asbestos is that screening is not advised, as no effective early intervention that alters the outcome. Still, the principal aim of developing markers is to pursue a non-invasive diagnosis of mesothelioma in order to prevent invasive tests on the already weakened patient.
Early reliable diagnosis of malignant mesothelioma is extremely difficult as time intervals from exposure in the disease can be long and variable. Currently, there are no blood-based markers for routine use in clinical practice to diagnose malignant mesothelioma; however, promising biomarkers emerged in the recent years that help in establishing the correct diagnosis by indicating the need for a biopsy of the pleura at an earlier stage.
Mesothelin was identified as a potential biomarker for malignant mesothelioma over 10 years ago. It is a membrane-bound glycoprotein expressed by mesothelial cells and over expressed in mesothelioma. Soluble mesothelin related proteins (SMRP) represent a split product of such bound mesothelin, which is abundant on serosal cells of the pleura and peritoneum and involved in intracellular contact.
An enzyme-linked immunosorbent assay (ELISA test) using monoclonal antibodies against SMRP epitopes has been developed and validated by the Food and Drug Administration (FDA) for the measurement of SMRP levels in the circulation. Positive test for mesothelin at a high specificity threshold is a strong impetus for further diagnostic steps, if renal failure is excluded. However, the poor sensitivity of mesothelin at diagnosis (only up to 50%) limits the value of this biomarker.
According to the recent data, osteopontin has a great potential as a marker for mesothelioma with a positive predictive power equivalent to CA-125 for ovarian cancer. It is a type of glycoprotein involved in communication between cells, including signaling pathways involved in the development of cancer. Studies have suggested a sensitivity and specificity for mesothelioma of 77% and 85% respectively, although increased levels do not exclude other possible malignancies.
Megakaryocyte Potentiating Factor (MPF) is a soluble protein that is also produced by proteolytic cleavage of the mesothelin precursor protein. Recent studies show that MPF was elevated in 91% of malignant mesothelioma patients compared with controls, with its levels returning to normality after surgery in patients with peritoneal mesothelioma. Hence this marker is potentially useful in the monitoring of treatment response in mesothelioma.
The ideal serum marker for mesothelioma should offer early diagnosis, differentiation of this malignant entity from benign pleural disease or other metastatic pleural malignancies, proper identification of all the subtypes and survival prediction. Accurate quantification and reporting of the added value of mesothelioma markers are necessary for their clinical implementation.
Emerging prognostic markers
Resistance proteins involved in DNA repair mechanisms such as the excision repair cross-complementation group 1, mutL homolog 1 and βIII-tubulin are found to be associated with outcomes to specific, platinum-based type chemotherapy in patients with mesothelioma. Therefore the future use of these enzymes is to tailor platinum-based chemotherapy for malignant mesothelioma patients who may expect the largest clinical benefit.
CD24 immunoreactivity was recently recognized as potential novel marker in differentiating malignant mesothelioma from pulmonary adenocarcinoma. A short non-coding RNA molecule miR-126 in association with SMRPs acts as a marker for early detection of malignant pleural mesothelioma. Furthermore, another study suggested another micro-RNA (miR-625-3p) as a promising new candidate marker.
Recent studies pointed to secreted glycoprotein fibulin-3 as a marker with impressive diagnostic accuracy for the diagnosis of malignant mesothelioma, but also for differentiating subtypes of this disease. Effusion levels of fibulin-3 were significantly prognostic in assessing survival rates, thus further investigation of fibulin-3 is warranted since complete understanding of its biological role may result in new treatment options for malignant mesothelioma.