Etiology,risk factors and diagnosis

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