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PLEURAL MESOTHELIOMA
DR TINKU JOSEPH
DM ResidentDepartment of Pulmonary Medicine
AIMS, KochiEmail-: [email protected]
Contents
Introduction Etiology/Risk factors Types Clinical presentation Diagnosis Staging Treatment
Mesothelioma is a form of Cancer that most frequently arises from the cells lining the sacs of the chest (the pleura) or the abdomen (the peritoneum) and almost always caused by exposure to asbestos.
The type of mesothelioma are pleural, peritoneal, and pericardial mesothelioma.
Mesothelioma-Introduction
At that time, the diagnosis was extremely controversial
(required autopsy examination) Today, the diagnosis is still problematic
– 15 % of cases cannot be differentiated from Adenocarcinoma
The term was first used in 1921 byEastwood & Martin
to describe primary tumors of the pleura
Mesothelioma: 1960
• Wagner, South African miners [Br J Ind Med]– first evidence implicating asbestos in the pathogenesis– landmark paper, began widespread investigation
• Incidence has reached “Epidemic”– European Experience: (2,700 - 9,000 deaths/yr.)
– U.S. Experience: Peaked in the 1970’s & since 1980
the incidence has been decreasing
Incidence
the increase in general incidence has been attributed
to the widespread use of asbestos in the
post-World War II period
[McDonald 1987]
Precautions were first taken in the U.S.Europe was “slow” to respondEffect on third-world countries
Incidence
• Industrialized Countries– 2 per million in females– 10 - 30 per million in males
Regional differences are due to the level of industrial activity
Areas with shipyards are at the highest risk
Type is also a Factor: Crocidolite & Amosite > Chrysotile
Incidence
The occurrence of mesothelioma is related to an
Occupational Exposure to Asbestos
Non-occupational environmental exposure leading
to it’s development is uncommon
Only 7.2 % of asbestos workers, will develop the disease Up to 50 % of patients, do not have any history of exposure
Incidence
cases due to exposure in buildings
with asbestos insulation
are extremely rare !
[Hughes et al. 1986: “quantitative risk”]
[Lilienfield 1991: “four cases in school teachers”]
Risk Factors
Asbestos
1.3 million workers exposed in the U.S.
construction industry
renovation, demolition heaviest exposures
General industry manufacture of asbestos products automotive brake and clutch repair housekeeping, custodial
Uses of AsbestosAsbestos has been used for centuries
Egyptians; Greeks & Romanswrapping Mummys; lamp wicks, cloth
Middle Agesinsulating armor
Industrial Revolutioninsulating boilers, steam pipes, turbines
Twentieth century – World War II + next 30 years. Insulating; fireproofing; sound-proofing; decorating; strengthening
Uses of Asbestos
Thermal system insulation
Surfacing materials Reinforcement of
materials Fireproofing Acoustic and decorative
plaster Textiles
Asbestos insulated pipe in utility space
Asbestos “CAB” siding
Uses of Asbestos
Friction materials (brakes, clutches, etc.)
Asphalt and vinyl felts
Papers and adhesives
Flooring and roofing materials
Filters, sealants and gaskets
Vinyl flooring
Sprayed-on fireproofing material
Types of Asbestos
Chrysotile
“White Asbestos”
Amosite “Brown Asbestos”
Crocidiolite (Dangerous)
Chrysotile fibers, high magnification
Most common:
Others Types:mostly found as
contaminants in other materials
Tremolite (possible contaminant in vermiculite)
Actinolite
Anthophyllite
Asbestos is an Inhalation Hazard
Breathable fibers are deposited in the alveoli.
Body’s defense mechanisms cannot break down the fibers.
Fibers may also travel to the pleura.
Lung Cancer/Asbestosis/ Mesothelioma.
Airborne asbestos fibers inhaled deep into the lung can cause damage.
Alveoli
Pleura
Carbon nanotubes are allotropes of carbon with awide array of applications in electronics, optics
similar dimensions and chemical property as asbestos
Carbon Nanotubes
What are the current applications of carbon nanotubes?
Wind turbines
Marine paints
Ice hockey sticks
Surf boards
Baseball bats
Maritime vessels
Handlebars
Seat posts
Scaffolding for bone growth
Golf clubs
Simian Virus 40
SV-40 is a polio vaccine contaminant in the 50s & 60s
BAP1 gene defects
BAP1 gene is located on chromosome 3BRCA1 Associated Protein-1regulate key histones and transcription factors related to tumor development
Radiation therapy
Radiation to supradiaphragmatic fields
Intrapleural thorium dioxide
Zeolites
OtherPotential
Causes
An example is erionite which is common in Turkey
3 Main Groups
Benign Localized Mesothelioma
“pleural fibroma” Unassociated with asbestos
exposure Paraneoplastic syndromes occur in
1/3 Arise from the visceral pleura Unless incomplete, surgical
resection is curative
Paraneoplastic Syndromes
Seen mostly in the Benign Localized Form Migrating Thrombitis Thrombocytosis Hemolytic Anemia Hypoglycemia Hypercalcemia Pulmonary Hypertrophic Osteoarthropathy
[Boutin 1998]
3 Main Groups
• Malignant Localized Mesothelioma– 20 % of all primary malignant pleural tumors are localized
– Present as Symptomatic Masses– Difficult to differentiate from Chest Wall Neoplasms
– Treatment Wide enbloc excision of all involved tissue Lung, Chest Wall, Soft Tissues, & Skin With incomplete excision, the prognosis is bad External beam radiation is of little benefit
3 Main Groups
Malignant Diffuse Mesothelioma Classical form Related to exposure Latent Period of 20 years Smoking is an associated factor
• not for mesothelioma, but for overall survival rate
TYPICAL SCENARIOmiddle-aged man with pleuritic chest pain, shortness of breath,
& a clear history of asbestos exposure
Malignant Mesothelioma
• 3 Cell Types
– Epithelial Type : 50 % of cases• most often confused with adenocarcinoma
– Mesenchymal Type : 16 % of cases
– Mixed Type : 34 % of cases
Pathogenecity
Benign pleural plaques are the most common manifestation of asbestos exposure
usually develop on the parietal or diaphragmatic pleura
malignant mesothelioma is thought to originate from the parietal pleura
high concentrations of asbestos fibers in the lung are associated with bronchial carcinoma
[Antilla 1993]
Clinical Presentation
Mean Age of Patients: 60– has been reported in children (unrelated to asbestos)
[Fraire 1988]
Clinical signs/symptoms depend on the stage:– TNM Classification
– Early-Stage Disease: Symptoms are Rare, Cough
– Late-Stage Disease: Pain, Dyspnea, Moderate Effusion
Mesothelioma is typically a unilateral disease – B/L in 10% of patients
Clinical Presentation
The initial chest radiograph leading to a
diagnosis of mesothelioma
reveals a pleural effusion 92 % of the time
7 % of the time, a Multinodular Pleural Tumor was found 0.5 % of the time, an Empyema 0.5 % of the time, a Spontaneous Pneumothorax
[Boutin 1993]
DIAGNOSIS
CXR Thoracentesis Chest C.T., MRI PET Thoracoscopy with Biopsy VATS
Chest X-Ray
Large unilateral pleural effusion- often with contralateral mediastinal shift.
Right side involved (60%) Pleural plaques/calcifications. Ipsilateral mediastinal shift (pleural
thickening) Advanced mesothelioma- mediastinal
widening (direct tumour invasion/lymph node/pericardial effusion), rib destruction, soft tissue masses extending into the chest wall
Thoracocentesis
Pleural fluid is an Exudate with little evidence of inflammation & a high number of mesothelial cells.
Elevated PF.Protein (4-5 g/dl) PF. LDH (>600 IU/L) Lymphocytic Low PH & glucose (advanced disease and poor prognosis) Highly viscous PF-: Elevated Hyaluronic acid level Cytology of the fluid is 30 % sensitive !
[Renshaw 1997]
Cytokine profile – Elevated IL-6, TGF-Beta, low levels of IL-1beta and TNF -alpha
Serum Markers
Soluble form of protein Mesothelin (SMRP) Found on normal mesothelial cells, mesothelioma
and ovarian cancer cells. Adjunctive role in diagnosis & screening (high
risk group)
IHC Markers
Malignant Mesothelioma Calretinin CK 5/6 Wilm’s tumour 1 (WT-1) D2 40
To differentiate Malignant Mesothelioma from Adenocarcinoma.
Adenocarcinoma (CEA, TTF-1, Leu M1, MOC 31, Ber-EP4, B72.3)
CT Scan
Chest C.T.• Irregular, nodular pleural
thickening• Spread into the diaphragm,
pericardium, chest wall, or mediastinal lymph nodes is difficult to assess
[Masilta 1991]
MRI Scan
Helpful in assessing the extend of disease – especially through the diaphragm into the peritoneal cavity.
Mediastinal nodes ( diagnostic accuracy = CT)
Better than CT (diaphragm, endothoracic fascia or chest wall
PET
Role is multifold Diagnosis/Staging Mediatinal lymph nodes, tumour
invasion into lung, thoracic wall, extra thoracic metastasis.
Treatment response to chemotherapy and radiotherapy
Role in planning radiation treatment. Screening of high risk patients
(potential future use)
Thoracoscopy
Thoracoscopy is indicated in any patient without a precise histopathological diagnosis in whom clinical & laboratory findings raise the suspicion of mesothelioma
V.A.T.S.
Mesothelioma takes on a “grape-like” appearance– patches of closely-spaced, smooth, translucid,
poorly-vascularized nodules with a clear to yellowish color
• not unique to mesothelioma
• also seen with metastatic cancer of the pleura
unlike benign inflammation (pleurisy),
the pleura becomes hard & non-elastic - with biopsy,
the cut edges do not bleed
V.A.T.S.
10 - 15 % of cases, the observed lesions are nonspecific
path report: “benign pleural inflammation”
The more unimpressive the picture, the more biopsies should be taken (up to 20)
Look for involvement of the Lung or Visceral Pleura
V.A.T.S.
98 % sensitive in establishing the diagnosis
Mortality is 1:8000
Complications are minimal– Subcutaneous Emphysema
– Localized Infection
– Minor Bleeding (< 100 cc)
[Viallat 1991]
Seeding of the Trocar Pathunknown incidence but can occurhas been documented after thoracentesis & blind pleural biopsy
can be prevented by performing Prophylactic
Radiotherapy after healing to the point of entry
Staging
Staging
Expected Survival
– Stage I: 16 months
– Stage II: 9 months
– Stage III: 5 months[Cohen 1995]
Median survival-: 9 to 12 months.
Depends on stage, histological subtype and concomitant medical problems.
Mortality
Mortality occurs due to-: local extension, respiratory failure.
Tumour extension below the diaphragm -: small bowel obstruction.
Arrythmias, heart failure, stroke
Prognostic factors
Poor prognostic factors-: Thrombocytosis, leukocytosis, low Hb, PUO, sarcomatoid or mixed histology, age >65, Male gender, poor performance status, associated smoking.
Good prognosis-: Epithelial histology (stage 1), age <65, performance status of 0 to 1, absence of chest pain.
CALGB Prognostic Index
EORTC Prognostic Index
Treatment
There is no single treatment which has
proven effective...
Surgery Radiation Chemotherapy Immunotherapy Gene Therapy
Treatment: Surgery
To ensure that surgery will be as curative as possible, resection must include:
– the Pleura: Stage Ia– the Lung: Stages Ib, II, and III
Many cases will require resection of the diaphragm,
pericardium, & chest wall
Treatment: Surgery
But does surgery improve survival ?
• Worn 1974, 248 Patients
– 62 Patients with Radical Pneumonectomy • 2-yr. Survival, 37 % 5-yr. Survival, 10 %
– Conservative Treatment• 2-yr. Survival, 12.5 % 5-yr. Survival, 0
%
Treatment: Surgery
• Probst 1990, 111 cases
– Median survival was longer after pneumonectomy than any other method (1.4 months)
operative mortality
for radical pneumonectomy, across the board,
is 25 %
Treatment: Surgery
A current review of all surgical series suggests that
treatment protocols including surgery
do extend survival...
– Pleurectomy(2-yr. Survival): 11- 35 %– Radical Pneumonectomy: 10 - 37 %
[Boutin 2008]
Treatment: Radiation
Despite in-vivo success against mesothelial cells,
this mode has not been proven successful in
the clinical setting
– Problem: size of the target area
– Post-radiation fibrosis can further aggravate pain • via compression of the chest wall & intercostal nerves
– Is effective to prevent “seeding”
Treatment: Chemotherapy
Responses seen in
20 -30 % of patients, but
without improvement in overall mortality
Doxorubicin Cisplatin Methotrexate Combined Protocols : 33 - 66 % response
New Approaches
Emerging Mesothelioma Treatments
Anti-Angiogenesis Treatment
Angiogenesis refers to the growth/development of blood vessels
Cancerous tumors require their own blood vessels to grow.
One possible method of treatment involves anti-angiogenesis drugs that inhibit tumor growth by preventing vascular endothelial growth factor, a protein secreted by some cancerous cells, from reaching receptors that help build blood vessels
Immunotherapy/Biological Therapy
Immunotherapy is using the body’s own immune system to target cancerous cells.
Researchers have discovered that the immune system can be capable of recognizing healthy cells vs. cancerous cells and can target cancerous cells for removal.
Substances used to promote immunotherapy are called biological response modifiers (BRM)s
• BRMs may be used to: Enhance the immune system Eliminate, regulate, or suppress body responses that
permit cancer growth. Make cancer cells more susceptible to destruction by
the immune system. Alter cancerous cell growth patterns to those of normal
cells. Block or reverse the transformation of a normal cell
into a cancer cell. Prevent a cancer cell from spreading (metastasis)
Immunotherapy
Intrapleural delivery of cytokines are currently being tested
– Interferon-Gamma
– Interleukin-2
Studies began in 1987 (150 patients)
– Response Rates: 6 - 44 %
– Effect on Survival is unknown at present[Dreisen 1992]
Treatment: Gene Therapy
Trials have begun to evaluate the genetic
transfer
of thymidine kinase
(from herpes virus to adenovirus)
too early to judge effect or outcome…
[Smythe 2010]
Photodynamic Therapy PDT
Based on the premise that cells treated with photosensitive drugs will die when exposed to light at particular frequencies.
Drug is administered intravenously and accumulates in diseased cells and is removed from healthy cells.
Laser light is administered to cancerous sites and the light activates an active form of oxygen that destroys surrounding cancer cells
Timing is crucial because the therapy needs to occur when the drug has been removed from healthy cells but is still present in cancerous cells
Virotherapy
Virotherapy attempts to attack a tumor by using a virus that is created to attack certain cells
This form of treatment is in the laboratory stages but virotherapy has produced some promising results
Management of Dyspnoea
Repeated pleural aspiration Repeated pleural aspiration Pleurodesis –Pleurodesis –
(Talc/Betadine/Tetracycline)(Talc/Betadine/Tetracycline)
Management of pain
Due to the complex nature of pain in mesothelioma, adjunct analgesia may frequently be required in addition to opiates. In cases of refractory pain unresponsive to the usual measures, a specialist pain management or specialist palliative medicine opinion should be sought.
Occasionally neuroablative techniques may be required.
Palliative radiotherapy may be proposed and effective in treating pain due to tumour nodules
Conclusions
Mesothelioma kills - slowly & effectively…
Early-stage disease: most important predictor of outcome
To find “early-stage disease”, remember the risk factors– Age between 55 - 65– Previous occupational exposure to asbestos– Pleural Effusion– C.T. / MRI (with nodular lesions of the parietal
pleura)
Conclusions
• Diagnosis is best established by V.A.T.S. Following invasive procedures, “seeding”
will occur & should be treated by radiotherapy
• Treatment: “it is currently, the clinician’s choice” Multimodal approach including radical
surgery “Limited-Role for Limited-Surgery”
• Palliative
• Relief of symptoms