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Slide 1: Mesothelioma Joe Bast, M.D. 2/1/07
Slide 2: Malignant Mesothelioma    Pleural vs. peritoneal Pleural: breathlessness, pleural effusion, chest wall pain or incidentally Peritoneal: distention from ascites, abd. Pain, occasionally SBO
Slide 3: Causes  Asbestos Long thin fibers: amphiboles (blue): main Ca causer  Feathery fibers: serpentine or chrysotile (white)  Simian virus 40 (SV40): also implicated cofactor (oncogenic virus) 
Slide 4: Pathogenesis  4 mechanisms: Asbestos fibers irritate pleura  Fibers pierce or sever mitotic spindle of cells and disrupt mitosis  Cause generation of iron related ROS thus causing damage to DNA  Induce phosphorylation of MAPK and ERK1/2: increasing expression of proto-oncogenes 
Slide 5: Diagnosis    Correct diagnosis important for treatment reasons but also can’t forget Litigation! Pleural Bx vs. VATS vs. open thoracotomy 10% seed biopsy site and develop local tumor expansion
Slide 6: Diagnosis   Cytology: + in 1/3 to >3/4 of cases Stain + for calretinin or wilms tumor antigen 1 (WT1) determines if mesothelial cells  (adenoCA does not)    Stain for epithelial membrane Ag (EMA) or CA15-3 to determine if malignant NEJM pic Or via histopathology via Bx
Slide 8: Diagnosis  Imaging:         CXR: can show effusion, pleural mass or plaques (not a precursor to cancer) CT: effusions or mass (pleural based) Can see thickening of intralobular septum Can see uniform rind of tumor encasing lung Can see local tumor mass Can see invasion into chest wall ~20% usually from a procedure MRI: good to see extent of tumor particularly when invading into local structures PET: used to help differentiate benign from malignant pleural lesions and extra thoracic disease (helps with staging)
Slide 10: Diagnosis  Serum markers:  serum mesothelin-related protein (SMRP) -Glycoprotein on mesothelial cells -elevated in > 80% pt with disease -elevated in <2% with benign disease -used for diagnosis in conjunction with cytology -also for therapy b/c increase with progression and decrease with regression  Osteopontin: glycoprotein that may help distinguish benign pleural disease from malig. Mesothelioma  Other markers being studied: CA 125, CA 15-3…
Slide 11: Prognosis and Staging      Median survival: from time of diagnosis: 12 months (range 6-18m): for treated patients survival: from time of diagnosis: 4-13 months: for untreated patients CT/MRI/PET important in staging pt. Also role for mediastinoscopy/laparoscopy for staging Use modified TMN staging system  International Mesothelioma Interest Group •Poor prognosis: thrombocytosis, leukocytosis, low HgB, fever, age>65, poor performance status, male •Good prognosis: epithelial histo, stage 1, age <65, low perform score, no CP, symptoms present > 6 months before Dx
Slide 12: Studies   CALGB: Cancer and Leukemia Grp B EORTC: European Organization for Research and Treatment of Cancer  Anthracyclines: doxorubicin: first line therapy  If respond (14%) MST 30m  Platinum: cisplatin about 7 m inc survival in responders
Slide 13: Treatment   Surgery: most useful for palliation and should be combined with radiotherapy or chemotherapy Chemo: Past response rate <20%  New advances:      Pemetrexed (inhibits dihydrofolate reductase and thymidylate synthase): overall survival increased 11 months Pemetrexed + cisplatin: increased survival another 3m Similar response with other combo chemo regimens with 3-6 m increase in addition to single agent Gemcitabine: subjective improvement Gleevac and Iressa (block PDGF/EGF): no response   Radiotherapy: palliative relief for pain Trials with immune and gene therapy on going
Slide 14: Peritoneal mesothelioma    Treatment usually includes surgical cytoreduction Intraperitoneal chemo For recurrent or unresectable disease: palliative chemo (pemetrexed and cisplatin)
Slide 15: Palliative treatment   Recurrent pleural effusions: talc application or pleurodesis Somatic, visceral (organ involvement) and neuropathic pain:  Opiods, nsaids, other