1. Pleural mesothelioma is a rare and highly aggressive cancer associated with asbestos exposure. It has a long latency period of 20-40 years from initial exposure. 2. The main risk factor is asbestos exposure, with erionite and radiation also established causes. Molecular changes including alterations in BAP1, NF2, CDKN2A and p53 genes drive carcinogenesis. 3. Presentation includes chest pain, dyspnea and pleural effusions. Diagnosis involves imaging, biopsy and immunohistochemistry staining for markers like calretinin and WT1. Prognosis is poor with non-epithelial histology, male sex and elevated markers associated with worse outcomes

1. PLEURAL MESOTHELIOMA
DR NEELAM AHIRWAR
DNBSS RESIDENT (SURGICAL ONCOLOGY)
APOLLO CBCC

2. Introduction
• Highly aggressive rare neoplasm
• Australia- highest death rate
• M:F – 4.5:1
• Long latency period
• High Risk Group - Workers of shipbuilding industry ,plumbers, pipe fillers,
steamers
• Wives of the risk factor group due to washing of clothes

4. Risk Factors
• Most pleural mesotheliomas (70% to 90%) are attributable to asbestos exposure
• In certain geographic locations other types of mineral fibers (erionite, fluoroedenite) can
induce mesothelioma
• Therapeutic radiation for other malignancies is a well-established cause of mesothelioma,
with relative risks as high as 30
• Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty.
• SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a
causative role.
Malignant Mesothelioma and Its Non-Asbestos Causes
Richard L. Attanoos, MBBS, FRCPath; Andrew Churg, MD; Francoise Galateau-Salle, MD; Allen R. Gibbs, MBChB, FRCPath;
Victor L. Roggli, MD

5. Asbestos

6. Asbestos

7. Asbestos
• 16-19% Pleural mesothelioma associated with Asbestos
• Erionite,Crocidolite, Amosite – most potent
• Chrysolite accounts for >90% of exposure
• Large fibers – direct extension/ via lymphatics – pleura- chronic
inflammation- pleural plaques, fibrosis, mesothelioma

8. Mechanism of carcinogenesis
CELLS SURVIVE
TOXIC INSULT &
GENETIC
DAMAGE
NFKβ PATHWAY
ACTIVATION IN
MESOTHELIAL
CELLS
CYTOKINES,TNF
,MACROPHAGES
HIGH MOBILITY
GROUP BOX1
(HMGB1)
RELEASE IN ECF
ASBESTOS
DEPOSITION -
CELLS
UNDERGOING
NECROSIS

9. Molecular Mechanism
1. Somatic alteration in BAP1 – most common, >50% MM
2. NF2 ( encoding Merlin)
3. CDKN2A (p16INK4A ,p14ARF)
4. p53

10. Molecular Mechanism
1. BAP1 (BRCA1 Associated Protein1)
• Homozygous – embryonic lethal
• Increases the susceptibility to Asbestos
BAP1 cancer syndrome
• Germline mutation
• Uveal melanoma, clear cell RCC, BCC and SCC Skin, Cutaneous Melanoma

11. Molecular Mechanism
CDKN2A
• P16 and p14ARF inactivation
• FISH on pleural fluid - >70% homozygous deletion
• Loss of p16 protein expression by IHC and homozygous deletion of
p16 by FISH – adverse prognosis

12. Neurofibromatosis
• Merlin encoded by NF2, chr 22q12
• Mutated in 40% mesothelioma
• Loss results in upregulation of mTOR, FAK, Hippo signalling

13. Types
• Benign Multicystic
Adenomatoid
well differentiated papillary
Localised mesothelioma (Fibrous tumor of Pleura)
• Malignant Epithelial (50-60%)
Sarcomatoid (10%)
Biphasic

14. Clinical Features
• Non pleuritic chest pain, located posterolaterally
• Dyspnoea ( 50-70%)
• Pleural effusion and dyspnoea (80%)
• 5-25% patients have metastatic disease at presentation

15. Examination
• Decreased breath sounds, dullness on percussion, decreased chest
wall movement
• Failure to relieve dyspnea after thoracocentesis (trapped lung)
• Cachexia, hypertrophy of contralateral hemithorax
• 25% patients present with chest wal mass at site of thoracocentesis,
thoracotomy, thoracoscopy wounds

16. IHC Markers
• Diffusely positive for pankeratin, keratin 5/6, Calretinin, WT1 (most
specific 80%)
• Negative for TTF, CEA,CD15,PAX-8
• Positive staining for Pankeratin, WT1, Calretinin and negative staining
for 3 epithelial markers are sufficient for diagnosis

17. IHC Markers
HEG1( newer marker , 99% specific)

18. Laboratory examination and Blood Biomarkers
• Non specific- Thrombocytosis (>4 lac), hypergammaglobulinemia, vit B12
deficiency, eosinophilia
• SMRP(soluble mesothelin related peptide)
• Osteopontin
• MPF(megakaryocyte potentiating factor)
• Fibulin 3
• HMGB1
Biomarkers for Malignant Pleural Mesothelioma Current Status
Laurent Greillier,1,2 Paul Baas,3 John J. Welch,1 Baktiar Hasan1 and Alexandre
Passioukov1

19. • Mesothelin and MPF lacks sensitivity
• Osteopontin lacks specificity

20. Diagnostic workup
• Chest Xray – Pleural effusion, pleural thickening, pleural mass
• CT Chest – pleural plaques, diffuse thickening, effusion, lung collapse
• MRI – for staging and recurrence
• PET Scan – to look for extrathoracic metastasis
• Thoracocentesis and closed pleural biopsy
• Thoracoscopy (VATS)
- large effusion and negative studies on thoracocentesis
-Recurrence after thoracocentesis

21. Prognostic indicators
EORTC and Cancer and Leukemia Group B
Poor prognosis
• Poor performance status
• Non epitheloid histology
• Male gender
• Low Hb
• Increased platelets and Leucocytes
• Increased LDH
Other indicators like SUV uptake not yet approved

22. CONTINUED..
MANAGEMENT OF PLEURAL MESOTHELIOMA