A physician may suspect malignant mesothelioma in a patient who has symptoms suggesting this cancer and who reports a history of asbestos exposure. Careful medical examination may also reveal the presence of fluid in the pleural or abdominal cavity. Once malignant mesothelioma is suspected, a number of methods are available to help confirm the diagnosis.

Imaging methods, such as x-rays, CT scans, MRIs and PET scans, help determine the location, size and extent of the cancer, and specifically detect pleural or peritoneal thickening, fluid in the pleural or abdominal cavity, or nodules of cancer cells. However, a definitive diagnosis of malignant mesothelioma can only be made after the examination of cells from abnormal tissue.

A biopsy of abnormal tissue is performed to find out whether the cells in this tissue are cancerous or not. Such tissue can be removed through minimally invasive surgery. Fluid in the pleural or abdominal cavity may also contain cancer cells, and may also be removed for analysis. Cells from abnormal tissue or fluid are examined under the microscope, and can be identified as normal or cancerous. However, such examination does not necessarily confirm the type of cancer. Cells found in pleural mesotheliomas can resemble lung cancer cells, and cells found in peritoneal mesotheliomas can resemble ovarian cancer cells. To differentiate between these different forms of cancer, a method called immunohistochemistry is often used. This method detects proteins on the surface of cancer cells that are specific to certain types of cancers. A newer method called DNA microarray analysis examines the genes of cancer cells. Malignant mesothelioma cancer cells have different gene patterns from other cancer cells and from normal cells.

While no blood tests confirm a diagnosis of malignant mesothelioma, there are certain blood abnormalities that suggest the presence of a cancer. Recent research suggests that elevated levels of a blood protein called osteopontin may help in the early detection of mesothelioma.